Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in DementiaClick to copy article linkArticle link copied!
- Mingeun KimMingeun KimDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaMore by Mingeun Kim
- Juhye KangJuhye KangDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaMore by Juhye Kang
- Misun LeeMisun LeeDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaDepartment of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of KoreaMore by Misun Lee
- Jiyeon HanJiyeon HanDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaMore by Jiyeon Han
- Geewoo NamGeewoo NamDepartment of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of KoreaMore by Geewoo Nam
- Eunyoung TakEunyoung TakAsan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaMore by Eunyoung Tak
- Min Sun KimMin Sun KimAsan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaMore by Min Sun Kim
- Hyuck Jin LeeHyuck Jin LeeDepartment of Chemistry Education, Kongju National University, Gongju 32588, Republic of KoreaMore by Hyuck Jin Lee
- Eunju NamEunju NamDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaMore by Eunju Nam
- Jiyong ParkJiyong ParkDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaCenter for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of KoreaMore by Jiyong Park
- Soo Jin OhSoo Jin OhAsan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaMore by Soo Jin Oh
- Ji-Yoon LeeJi-Yoon LeeAsan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaMore by Ji-Yoon Lee
- Joo-Yong Lee*Joo-Yong Lee*[email protected]Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaMore by Joo-Yong Lee
- Mu-Hyun Baik*Mu-Hyun Baik*[email protected]Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaCenter for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of KoreaMore by Mu-Hyun Baik
- Mi Hee Lim*Mi Hee Lim*[email protected]Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of KoreaMore by Mi Hee Lim
Abstract
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-β (Aβ), and metal-bound Aβ that are implicated in the most common form of dementia, Alzheimer’s disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aβ, leading to chemical modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.
Introduction
Figure 1
Figure 1. Overview of a rational strategy of designing compact aromatic molecules with multiple reactivities against pathological factors found in the AD-affected brain and the chemical series studied in this work. (a) Structures of 1–4 (Group-I) and 5–10 (Group-II). 1, benzene-1,4-diamine; 2, 4-aminophenol; 3, N1,N1,N4,N4-tetramethylbenzene-1,4-diamine; 4, 4-(dimethylamino)phenol; 5, aniline; 6, 4-aminobenzoic acid; 7, pyridine-4-amine; 8, N,N-dimethylaniline; 9, 4-(dimethylamino)benzoic acid; 10, N,N-dimethylpyridine-4-amine. (b) Summary of the multiple targets and the desired effects in vitro and in vivo.
Results and Discussion
Figure 2
Figure 2. Redox behaviors of 1–10 and vitamin C measured by cyclic voltammetry. (a) Cyclic voltammograms of 1–4 in CH3CN with 1% v/v DMSO. (b) Values of Epa1 and E1/2 at the scan rate of 250 mV/s. aQuasi-reversible redox behavior was indicated for 2. Conditions: [compound] = 1 mM; [TBAPF6] = 100 mM (for supporting electrolyte and reference electrode); [AgNO3] = 10 mM (for reference electrode); N2(g); scan rates = 25, 50, 100, 150, 200, and 250 mV/s; three electrodes: glassy carbon working electrode, Ag/Ag(I) reference electrode, and platinum counter electrode; room temperature.
Scavenging Free Organic Radicals
Figure 3
Figure 3. Scavenging capability of 1–10 and vitamin C against free organic radicals determined by the TEAC assay in cell lysates. The TEAC values are relative to that of an analogue of vitamin E, Trolox (6-hydroxy-2,5,7,8-tetramethlychroman-2-carboxylic acid). The error bars indicate the standard error from four independent experiments. *TEAC values of 5–10 were not obtained because they showed no measurable capacity to quench free radicals.
Impact on Aβ Aggregation
Figure 4
Figure 4. Effects of 1–5 on the formation of metal-free or metal-treated Aβ40 aggregates. (a) Scheme of the inhibition experiments. (b–d) Gel/Western blots (an anti-Aβ antibody, 6E10) of the Aβ40 species generated in the (b) absence and (c and d) presence of metal ions. Lanes: (c) Aβ40; (1) Aβ40 + 1; (2) Aβ40 + 2; (3) Aβ40 + 3; (4) Aβ40 + 4; (5) Aβ40 + 5. (e) Quantification of Aβ40 species visualized in the gel by the ImageJ software. The intensity of the gel from the sample was normalized to that from the corresponding control (ISample/IControl). (f) TEM images of the samples obtained from (b) metal-free Aβ40 and Aβ40 with 1 equiv of (c) Cu(II) and (d) Zn(II). Conditions: [Aβ40] = 25 μM; [Cu(II) or Zn(II)] = 12.5, 25, and 50 μM; [compound] = 50 μM; 20 mM HEPES, pH 7.4 [for metal-free or Zn(II)-containing samples] or pH 6.6 [for Cu(II)-added samples], 150 mM NaCl; 37 °C; 24 h; constant agitation. Scale bar = 200 nm.
Oxidative Reactions
Figure 5
Figure 5. Analyses of 1’s transformation and interactions with metal-free Aβ40 or Cu(II)-added Aβ40. (a) Oxidative transformation of 1 in the presence of Aβ40 with or without Cu(II) detected by UV–vis spectroscopy. Conditions: [Aβ40] = 25 μM; [Cu(II)] = 25 μM; [1] = 50 μM; 20 mM HEPES, pH 7.4 (for metal-free samples) or pH 6.6 [for Cu(II)-added samples], 150 mM NaCl; 37 °C; 0–24 h; no agitation. (b–d) Interactions of 1 with metal-free Aβ40 and Cu(II)-treated Aβ40 monitored by ESI-MS, ESI-MS2, and MALDI-MS. Aβ40 monomer incubated with 1 in the (b and d) absence and (d) presence of Cu(II) was analyzed by (b) ESI-MS or (d) MALDI-MS. The oxidized Aβ40 and the BQ–Aβ40 adduct are indicated with red and blue circles, respectively. The covalent bond with Aβ40 (green circle) was only observed from 1-treated samples. (c) ESI-MS2 spectrum of the singly oxidized Aβ403+ produced upon addition of 1. Conditions (for ESI-MS studies): [Aβ40] = 50 μM; [1] = 100 μM; 1 mM ammonium acetate, pH 7.4; 37 °C; 24 h; constant agitation. The samples were diluted by 10-fold with ddH2O before injection to the mass spectrometer. Conditions (for MALDI-MS measurements): [Aβ40] = 25 μM; [Cu(II)] = 25 μM; [1] = 50 μM; pH 7.4 (for metal-free samples) or pH 6.6 [for Cu(II)-added samples]; 37 °C; 24 h; constant agitation.
Interactions with Metal-Free Aβ or Metal–Aβ
Biological Applicability
In Vivo Efficacies
Figure 6
Figure 6. Analysis of the amounts of Aβ species in 1- or BQ-treated 5×FAD mice. (a) Levels of soluble Aβ42, insoluble Aβ42, total Aβ42, and oligomeric Aβ measured in triplicate per sample by ELISA. Soluble phosphate buffered saline (PBS)- and sodium dodecyl sulfate (SDS)-soluble fractions (for soluble Aβ42), formic acid (FA)-soluble fractions (for insoluble Aβ42), and the sum of PBS-, SDS-, and FA-soluble fractions (for total Aβ42) were analyzed. Lanes: (Vehicle) 5×FAD + vehicle; (BQ) 5×FAD + BQ; (1) 5×FAD + 1. (b) Loads of amyloid deposits and plaques in the brain expressed as the percent area of 4G8-immunoreactive deposits or the number of congophilic plaques per mm2 of a region of interest, which was taken from hippocampal (hip), cortical (ctx), and thalamic (tlm) areas. (c) Representative images of 4G8-immunoreactive (1st row) or Congo red-positive (2nd and 3rd rows) amyloid deposits or plaques in hip and ctx (1st and 3rd rows) or tlm (2nd row) regions in the brains of vehicle- (1st column), BQ- (2nd column), or 1-treated (3rd column) 5×FAD mice are shown. Congo red-stained brain sections were also counter-stained with hematoxylin to differentiate the nuclei of neural cells (2nd and 3rd rows). Subiculum (sub), corpus callosum (cc), and fornix (fx). Scale bars = 500 μm (white) or 200 μm (black). The measurements were performed in five sagittal sections taken every 200 μm from midline per animal. Bars denote mean ± standard errors of mean (s.e.m.) (animal numbers; n = 19 for vehicle-treated 5×FAD mice; n = 9 for BQ-treated 5×FAD mice; n = 12 for 1-treated 5×FAD mice). *P < 0.05 or **P < 0.01 by unpaired two-tail t-test.
Figure 7
Figure 7. Measurement of spatial learning and memory improvements in 1- or BQ-administrated 5×FAD mice. (a) Escape latency time daily assessed for 5 days from the day of the 30th compound treatment in the MWM test. From the second training trial to the fifth trial, the latency time became significantly shorter in nontransgenic wild-type mice [WT; P = 0.012 by one-way analysis of variance (ANOVA) with Student–Newman–Keuls post hoc test] or 1-treated 5×FAD mice (1; P = 0.0017) but not in vehicle- (Vehicle; P = 0.054) or BQ-treated (BQ; P = 0.40) 5×FAD mice. (b) After the MWM test, the probe trials were performed in the same water pool without the escape platform. All images present the representative paths of the mice to search for the previous platform location [the small circle area in the gray, northwest (NW) target quadrant] for 60 s (from point S to point E). (c–f) In the probe test, we recorded (c) the path distance to first enter the target quadrant, (d) the latency time to touch the previous location of the platform, (e) the crossing frequency to traverse across the target platform, and (f) the times spent in the target quadrant to search for the platform. Lanes: (WT) wild-type; (Vehicle) 5×FAD + vehicle; (BQ) 5×FAD + BQ; (1) 5×FAD + 1. The statistical comparisons were performed between vehicle-treated 5×FAD and their wild-type littermate mice (*) or between vehicle- and 1-treated 5×FAD mice (#). Bars denote mean ± s.e.m. Animal number: n = 17 for wild-type mice; n = 19 for vehicle-treated 5×FAD mice; n = 9 for BQ-treated 5×FAD mice; n = 12 for 1-treated 5×FAD mice. *,#P < 0.05, **,##P < 0.01, or ***,###P < 0.001 by unpaired two-tail t-test.
Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b13100.
Experimental Section, Tables S1–S4, and Figures S1–S15 (PDF)
Terms & Conditions
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Acknowledgments
This research is supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government [NRF-2017R1A2B3002585 (to M.H.L); NRF-2017R1D1A1B03030567 (to J.-Y.L.)]; the Institute for Basic Science (IBS-R010-A1) in Korea (to M.-H.B.); Asan Institute for Life Sciences, Asan Medical Center [Seoul, Korea; 2019-396 (to J.-Y.L.)]. We thank the DMPK core facility at the Convergence Medicine Research Center (CREDIT), Asan Medical Center, for support and instrumentation.
References
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- 9Savelieff, M. G.; Nam, G.; Kang, J.; Lee, H. J.; Lee, M.; Lim, M. H. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade. Chem. Rev. 2019, 119, 1221– 1322, DOI: 10.1021/acs.chemrev.8b00138Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOis7jL&md5=ee3763784767afe96c57e10439183f82Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis in the Last DecadeSavelieff, Masha G.; Nam, Geewoo; Kang, Juhye; Lee, Hyuck Jin; Lee, Misun; Lim, Mi HeeChemical Reviews (Washington, DC, United States) (2019), 119 (2), 1221-1322CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a neg. outlook. Although a large amt. of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathol. features shared across multiple neurodegenerative disorders. In addn., these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compds. capable of simultaneously interacting with several pathol. components has been suggested as a soln. to undertake the complex pathologies of neurodegenerative diseases. In this review, the authors outline and discuss possible therapeutic targets in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and mols., previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addn., underrepresented areas of research are discussed to indicate new directions.
- 10Martins, R. N.; Villemagne, V.; Sohrabi, H. R.; Chatterjee, P.; Shah, T. M.; Verdile, G.; Fraser, P.; Taddei, K.; Gupta, V. B.; Rainey-Smith, S. R.; Hone, E.; Pedrini, S.; Lim, W. L.; Martins, I.; Frost, S.; Gupta, S.; O’Bryant, S.; Rembach, A.; Ames, D.; Ellis, K.; Fuller, S. J.; Brown, B.; Gardener, S. L.; Fernando, B.; Bharadwaj, P.; Burnham, S.; Laws, S. M.; Barron, A. M.; Goozee, K.; Wahjoepramono, E. J.; Asih, P. R.; Doecke, J. D.; Salvado, O.; Bush, A. I.; Rowe, C. C.; Gandy, S. E.; Masters, C. L. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies. J. Alzheimer's Dis. 2018, 62, 965– 992, DOI: 10.3233/JAD-171145Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXks1ygsrc%253D&md5=4763da2ac699e78b6800d3976a6af52bAlzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort StudiesMartins, Ralph N.; Villemagne, Victor; Sohrabi, Hamid R.; Chatterjee, Pratishtha; Shah, Tejal M.; Verdile, Giuseppe; Fraser, Paul; Taddei, Kevin; Gupta, Veer B.; Rainey-Smith, Stephanie R.; Hone, Eugene; Pedrini, Steve; Lim, Wei Ling; Martins, Ian; Frost, Shaun; Gupta, Sunil; O'Bryant, Sid; Rembach, Alan; Ames, David; Ellis, Kathryn; Fuller, Stephanie J.; Brown, Belinda; Gardener, Samantha L.; Fernando, Binosha; Bharadwaj, Prashant; Burnham, Samantha; Laws, Simon M.; Barron, Anna M.; Goozee, Kathryn; Wahjoepramono, Eka J.; Asih, Prita R.; Doecke, James D.; Salvado, Olivier; Bush, Ashley I.; Rowe, Christopher C.; Gandy, Samuel E.; Masters, Colin L.Journal of Alzheimer's Disease (2018), 62 (3), 965-992CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Worldwide there are over 46 million people living with dementia, and this no. is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extd. from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clin. AD using PET amyloid tracers, a method now serving as the gold std. for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E .vepsiln.4, as well as better understanding the role of lifestyle factors particularly diet, phys. activity and sleep to cognitive decline and the accumulation of cerebral Aβ.
- 11Mecocci, P.; Polidori, M. C. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim. Biophys. Acta, Mol. Basis Dis. 2012, 1822, 631– 638, DOI: 10.1016/j.bbadis.2011.10.006Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1GrtbY%253D&md5=516667c4e9e8840318acc5f92cf325a6Antioxidant clinical trials in mild cognitive impairment and Alzheimer's diseaseMecocci, Patrizia; Polidori, Maria CristinaBiochimica et Biophysica Acta, Molecular Basis of Disease (2012), 1822 (5), 631-638CODEN: BBADEX; ISSN:0925-4439. (Elsevier B. V.)A review. Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing no. of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclin. phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clin. trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clin. trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clin. benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
- 12Persson, T.; Popescu, B. O.; Cedazo-Minguez, A. Oxidative stress in Alzheimer’s disease: why did antioxidant therapy fail?. Oxid. Med. Cell. Longevity 2014, 2014, 427318, DOI: 10.1155/2014/427318Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cnptFKjtg%253D%253D&md5=289bc2a9f4e64c73055b9f2b86e91b29Oxidative stress in Alzheimer's disease: why did antioxidant therapy fail?Persson Torbjorn; Cedazo-Minguez Angel; Popescu Bogdan OOxidative medicine and cellular longevity (2014), 2014 (), 427318 ISSN:.Alzheimer's disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. A remarkable amount of data supports the hypothesis that oxidative stress is an early and important pathogenic operator in AD. However, all clinical studies conducted to date did not prove a clear beneficial effect of antioxidant treatment in AD patients. In the current work, we review the current knowledge about oxidative stress in AD pathogeny and we suggest future paths that are worth to be explored in animal models and clinical studies, in order to get a better approach of oxidative imbalance in this inexorable neurodegenerative disease.
- 13Kepp, K. P. Bioinorganic chemistry of Alzheimer’s disease. Chem. Rev. 2012, 112, 5193– 5239, DOI: 10.1021/cr300009xGoogle Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVejtbnK&md5=e9eaffc178654ba1c0ecc0393ca2bc8dBioinorganic Chemistry of Alzheimer's DiseaseKepp, Kasper P.Chemical Reviews (Washington, DC, United States) (2012), 112 (10), 5193-5239CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The role of genetic and environmental risk factors as exogenous metal exposure-mediated neuronal accumulation in brain of β-amyloid peptides in pathogenesis of Alzheimer's disease is discussed.
- 14Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018, 14, 450– 464, DOI: 10.1016/j.redox.2017.10.014Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslans73L&md5=f61600ab9e355cd49838961d26de5c4fOxidative stress and the amyloid beta peptide in Alzheimer's diseaseCheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F.Redox Biology (2018), 14 (), 450-464CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)A review. Oxidative stress is known to play an important role in the pathogenesis of a no. of diseases. In particular, it is linked to the etiol. of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathol. hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding mol. (proteins, lipids, ...). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding mols. in terms of oxidative damage. In addn., the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS prodn. are discussed, along with both in vitro and in vivo oxidn. of the Aβ peptide, at the mol. level.
- 15Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297, 353– 356, DOI: 10.1126/science.1072994Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Cju7s%253D&md5=f7b8db1bc6f13e85f887b73f3042e86eThe amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeuticsHardy, John; Selkoe, Dennis J.Science (Washington, DC, United States) (2002), 297 (5580), 353-356CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. It has been more than 10 yr since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles contg. tau protein, is proposed to result from an imbalance between Aβ prodn. and Aβ clearance.
- 16Barnham, K. J.; Bush, A. I. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem. Soc. Rev. 2014, 43, 6727– 6749, DOI: 10.1039/C4CS00138AGoogle Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12msLrK&md5=59061ef7a1462599c78d5ec47fb3ceb0Biological metals and metal-targeting compounds in major neurodegenerative diseasesBarnham, Kevin J.; Bush, Ashley I.Chemical Society Reviews (2014), 43 (19), 6727-6749CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Multiple abnormalities occur in the homeostasis of essential endogenous brain biometals in age-related neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As a result, metals both accumulate in microscopic proteinopathies, and can be deficient in cells or cellular compartments. Therefore, bulk measurement of metal content in brain tissue samples reveal only the "tip of the iceberg", with most of the important changes occurring on a microscopic and biochem. level. Each of the major proteins implicated in these disorders interacts with biol. transition metals. Tau and the amyloid protein precursor have important roles in normal neuronal iron homeostasis. Changes in metal distribution, cellular deficiencies, or sequestration in proteinopathies all present abnormalities that can be cor. in animal models by small mols. These biochem. targets are more complex than the simple excess of metals that are targeted by chelators. In this review we illustrate some of the richness in the science that has developed in the study of metals in neurodegeneration, and explore its novel pharmacol.
- 17Folk, D. S.; Franz, K. J. A prochelator activated by β-secretase inhibits Aβ aggregation and suppresses copper-induced reactive oxygen species formation. J. Am. Chem. Soc. 2010, 132, 4994– 4995, DOI: 10.1021/ja100943rGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjsFSlsb8%253D&md5=7fc9ab4fec5cc285d06904eb241bc643A Prochelator Activated by β-Secretase Inhibits Aβ Aggregation and Suppresses Copper-Induced Reactive Oxygen Species FormationFolk, Drew S.; Franz, Katherine J.Journal of the American Chemical Society (2010), 132 (14), 4994-4995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The intersection of the amyloid cascade hypothesis and the implication of metal ions in Alzheimer's disease progression has sparked an interest in using metal-binding compds. as potential therapeutic agents. In the present work, we describe a prochelator SWH that is enzymically activated by β-secretase to produce a high affinity copper chelator CP. Because β-secretase is responsible for the amyloidogenic processing of the amyloid precursor protein, this prochelator strategy imparts disease specificity toward copper chelation not possible with general metal chelators. Furthermore, once activated, CP efficiently sequesters copper from amyloid-β, prevents and disassembles copper-induced amyloid-β aggregation, and diminishes copper-promoted reactive oxygen species formation.
- 18Lincoln, K. M.; Richardson, T. E.; Rutter, L.; Gonzalez, P.; Simpkins, J. W.; Green, K. N. An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation. ACS Chem. Neurosci. 2012, 3, 919– 927, DOI: 10.1021/cn300060vGoogle Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ymsr%252FF&md5=420f45288c46cef2b3953e3c4c3f955bAn N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid DisaggregationLincoln, Kimberly M.; Richardson, Timothy E.; Rutter, Lauren; Gonzalez, Paulina; Simpkins, James W.; Green, Kayla N.ACS Chemical Neuroscience (2012), 3 (11), 919-927CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (Aβ) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and SEM imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu2+ induced AB1-40 aggregation. The pyridine backbone of 1 engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this arom. feature. Finally, 1 prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using d. functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity obsd.
- 19Lee, S.; Zheng, X.; Krishnamoorthy, J.; Savelieff, M. G.; Park, H. M.; Brender, J. R.; Kim, J. H.; Derrick, J. S.; Kochi, A.; Lee, H. J.; Kim, C.; Ramamoorthy, A.; Bowers, M. T.; Lim, M. H. Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer’s disease. J. Am. Chem. Soc. 2014, 136, 299– 310, DOI: 10.1021/ja409801pGoogle Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVWnsL3I&md5=808d231c5dca419453c176265d16bfe3Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer's DiseaseLee, Sanghyun; Zheng, Xueyun; Krishnamoorthy, Janarthanan; Savelieff, Masha G.; Park, Hyun Min; Brender, Jeffrey R.; Kim, Jin Hoon; Derrick, Jeffrey S.; Kochi, Akiko; Lee, Hyuck Jin; Kim, Cheal; Ramamoorthy, Ayyalusamy; Bowers, Michael T.; Lim, Mi HeeJournal of the American Chemical Society (2014), 136 (1), 299-310CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Alzheimer's disease (AD) is characterized by multiple, intertwined pathol. features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. The authors report a novel compd. (ML) prototype of a rationally designed mol. obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single mol. Chem., biochem., ion mobility mass spectrometric, and NMR studies indicate that the compd. ML targets metal-free and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)-phenol (DAP) and (8-aminoquinolin-2-yl)-methanol ) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-sol. and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, the authors demonstrate that a rational structure-based design strategy can generate a small mol. that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.
- 20Gonzalez, P.; da Costa, V. C. P.; Hyde, K.; Wu, Q.; Annunziata, O.; Rizo, J.; Akkaraju, G.; Green, K. N. Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer’s disease. Metallomics 2014, 6, 2072– 2082, DOI: 10.1039/C4MT00161CGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSiu7zN&md5=5ec498b5921b13847ba44dd531801c70Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's diseaseGonzalez, Paulina; da Costa, Viviana C. P.; Hyde, Kimberly; Wu, Qiong; Annunziata, Onofrio; Rizo, Josep; Akkaraju, Giridhar; Green, Kayla N.Metallomics (2014), 6 (11), 2072-2082CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the prodn. of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small mol., lipoic cyclen, which has been designed to target mol. features of AD. This construct utilizes the biol. compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused mol. as a potential strategy for the development of lead compds. for the treatment of neurodegenerative disorders.
- 21Derrick, J. S.; Lim, M. H. Tools of the trade: investigations into design strategies of small molecules to target components in Alzheimer’s disease. ChemBioChem 2015, 16, 887– 898, DOI: 10.1002/cbic.201402718Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVWrtbk%253D&md5=7d41b07f4f349aafed8bd2dee2a164abTools of the Trade: Investigations into Design Strategies of Small Molecules to Target Components in Alzheimer's DiseaseDerrick, Jeffrey S.; Lim, Mi HeeChemBioChem (2015), 16 (6), 887-898CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The growing prevalence of Alzheimer's disease (AD) has warranted the development of effective therapeutic methods. Current available drugs for AD (i.e., acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) have only offered brief symptomatic relief. Considering that the nos. affected by AD are projected to substantially rise, long-term strategies are urgently needed. The multiple series of small mols. to combat AD have been expanded, with current methods taking aim at factors, such as misfolded protein accumulation, metal ion dyshomeostasis, and oxidative stress. This concept article focuses on describing the design of compds. to target various components of AD and underlining recent advances that have been made.
- 22Derrick, J. S.; Kerr, R. A.; Nam, Y.; Oh, S. B.; Lee, H. J.; Earnest, K. G.; Suh, N.; Peck, K. L.; Ozbil, M.; Korshavn, K. J.; Ramamoorthy, A.; Prabhakar, R.; Merino, E. J.; Shearer, J.; Lee, J.-Y.; Ruotolo, B. T.; Lim, M. H. A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: in vitro and in vivo efficacy and molecular mechanisms. J. Am. Chem. Soc. 2015, 137, 14785– 14797, DOI: 10.1021/jacs.5b10043Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGmt7fL&md5=f95a3cad02c9a2752ea0389e69820943A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular MechanismsDerrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; Oh, Shin Bi; Lee, Hyuck Jin; Earnest, Kaylin G.; Suh, Nayoung; Peck, Kristy L.; Ozbil, Mehmet; Korshavn, Kyle J.; Ramamoorthy, Ayyalusamy; Prabhakar, Rajeev; Merino, Edward J.; Shearer, Jason; Lee, Joo-Yong; Ruotolo, Brandon T.; Lim, Mi HeeJournal of the American Chemical Society (2015), 137 (46), 14785-14797CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Chem. reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, the authors report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small mol. (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addn., for the first time, biochem., biophys., and mol. dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small mol. (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramol. crosslinking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathol. and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small mol. (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of sol. Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, the authors' in vitro and in vivo studies of DMPD toward Aβ with the first mol.-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compds. without the structural complexity as next-generation chem. tools for amyloid management.
- 23Beck, M. W.; Derrick, J. S.; Kerr, R. A.; Oh, S. B.; Cho, W. J.; Lee, S. J. C.; Ji, Y.; Han, J.; Tehrani, Z. A.; Suh, N.; Kim, S.; Larsen, S. D.; Kim, K. S.; Lee, J.-Y.; Ruotolo, B. T.; Lim, M. H. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease. Nat. Commun. 2016, 7, 13115, DOI: 10.1038/ncomms13115Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSitb3P&md5=c92d00abedc661f493e496ba21f20879Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's diseaseBeck, Michael W.; Derrick, Jeffrey S.; Kerr, Richard A.; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C.; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D.; Kim, Kwang S.; Lee, Joo-Yong; Ruotolo, Brandon T.; Lim, Mi HeeNature Communications (2016), 7 (), 13115CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted etiol. Because of the lack of chem. tools to identify pathol. factors, investigations into AD pathogenesis have also been insubstantial. Here we report chem. regulators that demonstrate distinct specificity towards targets linked to AD pathol., including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free org. radicals. We obtained these chem. regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small mols. for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathol., and improving cognitive deficits. Our chem. tools show promise for deciphering AD pathogenesis and discovering effective drugs.
- 24Jones, M. R.; Mathieu, E.; Dyrager, C.; Faissner, S.; Vaillancourt, Z.; Korshavn, K. J.; Lim, M. H.; Ramamoorthy, A.; Wee Yong, V.; Tsutsui, S.; Stys, P. K.; Storr, T. Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer’s disease. Chem. Sci. 2017, 8, 5636– 5643, DOI: 10.1039/C7SC01269AGoogle Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1yitL0%253D&md5=c70d2f489b8d762cfc246c0dc1428f1aMulti-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's diseaseJones, Michael R.; Mathieu, Emilie; Dyrager, Christine; Faissner, Simon; Vaillancourt, Zavier; Korshavn, Kyle J.; Lim, Mi Hee; Ramamoorthy, Ayyalusamy; Wee Yong, V.; Tsutsui, Shigeki; Stys, Peter K.; Storr, TimChemical Science (2017), 8 (8), 5636-5643CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aβ peptide oligomers are all considered to contribute to the etiol. of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aβ peptide and modulation of Aβ peptide aggregation, and the ability to limit Aβ1-42-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated via click chem., highlights the influence of R-group modification on ligand-Aβ interactions and neuroprotective effects. Overall, this study demonstrates that the phenol-triazole ligand scaffold can target multiple factors assocd. with AD, thus warranting further therapeutic development.
- 25Han, J.; Lee, H. J.; Kim, K. Y.; Lee, S. J. C.; Suh, J.-M.; Cho, J.; Chae, J.; Lim, M. H. Tuning structures and properties for developing novel chemical tools toward distinct pathogenic elements in Alzheimer’s disease. ACS Chem. Neurosci. 2018, 9, 800– 808, DOI: 10.1021/acschemneuro.7b00454Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVCjsLfI&md5=3384d8f9a25a4f323b250258f516ef22Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's DiseaseHan, Jiyeon; Lee, Hyuck Jin; Kim, Kyu Yeon; Lee, Shin Jung C.; Suh, Jong-Min; Cho, Jaeheung; Chae, Junghyun; Lim, Mi HeeACS Chemical Neuroscience (2018), 9 (4), 800-808CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal-Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathol. elements in AD, chem. tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathol. factors, however, it has been challenging to invent such chem. tools. Herein, the authors report novel small mols. as chem. tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chem. properties (e.g., oxidn. potentials) of the mols. and their coverage of reactivities toward the pathol. targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among the three compds., I with the lowest oxidn. potential is able to noticeably modify the aggregation of both metal-free Aβ and metal-Aβ, as well as scavenge free radicals. Compd. II with the moderate oxidn. potential significantly alters the aggregation of Cu(II)-Aβ42. The hardly oxidizable compd., III, relative to I and II, indicates no noticeable interactions with all pathogenic factors, including metal-free Aβ, metal-Aβ, and free radicals. Overall, the studies demonstrate that the design of small mols. as chem. tools able to control distinct pathol. components could be achieved via fine-tuning of structures and properties.
- 26Gomes, L. M. F.; Mahammed, A.; Prosser, K. E.; Smith, J. R.; Silverman, M. A.; Walsby, C. J.; Gross, Z.; Storr, T. A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation. Chem. Sci. 2019, 10, 1634– 1643, DOI: 10.1039/C8SC04660CGoogle Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlOku7rF&md5=c81d88ecd31c5145b863db455609060bA catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generationGomes, Luiza M. F.; Mahammed, Atif; Prosser, Kathleen E.; Smith, Jason R.; Silverman, Michael A.; Walsby, Charles J.; Gross, Zeev; Storr, TimChemical Science (2019), 10 (6), 1634-1643CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Alzheimer's disease (AD) is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-beta (Aβ) aggregates. In this work we report the large affinity binding of the iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the Aβ peptide (Kd ∼ 10-7) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(II) ions. Specific findings are that: (a) an Abeta histidine residue binds axially to FeL1; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high mol. wt. peptide aggregates. UV-Vis and ESR (EPR) studies show that although the binding of FeL1 does not influence the Abeta-Cu(II) interaction (Kd 10-10), bound FeL1 still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from Abeta-Cu. Overall, FeL1 is shown to bind to the Abeta-peptide, and modulate peptide aggregation. In addn., FeL1 forms a ternary species with Abeta-Cu(II) and impedes ROS generation, thus showing the promise of discrete metal complexes to limit the toxicity pathways of the Abeta peptide.
- 27Miller, J. J.; Blanchet, A.; Orvain, C.; Nouchikian, L.; Reviriot, Y.; Clarke, R. M.; Martelino, D.; Wilson, D.; Gaiddon, C.; Storr, T. Bifunctional ligand design for modulating mutant p53 aggregation in cancer. Chem. Sci. 2019, 10, 10802– 10814, DOI: 10.1039/C9SC04151FGoogle Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFWrs77L&md5=4c927ea13fc06e09a6cdd3666b43545dBifunctional ligand design for modulating mutant p53 aggregation in cancerMiller, Jessica J.; Blanchet, Anais; Orvain, Christophe; Nouchikian, Lucienne; Reviriot, Yasmin; Clarke, Ryan M.; Martelino, Diego; Wilson, Derek; Gaiddon, Christian; Storr, TimChemical Science (2019), 10 (46), 10802-10814CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Protein misfolding and aggregation contributes to development of wide range of diseases. P53 mutations also frequently result in alteration or loss of zinc at DNA-binding site, which increases aggregation via nucleation with zinc-bound p53. We designed two novel bifunctional ligands, LI and LH, to modulate mutant p53 aggregation and restore zinc binding using a metallochaperone approach. Incorporation of iodine function in LI resulted in modulation of mutant p53 aggregation, both in recombinant and cellular environments. Native mass spectrometry shows a protein-ligand interaction for LI, as opposed to LH, which is hypothesized to lead to p53 aggregation profile. Incorporation of a di-2-picolylamine binding unit into the ligand design provided efficient intracellular zinc uptake, resulting in metallochaperone capability for both LI and LH. The ability of LI to reduce mutant p53 aggregation results in increased restoration of p53 transcriptional function and mediates both caspase-dependent and -independent cell death pathways. We further demonstrate that LI exhibits minimal toxicity in non-cancerous organoids, and that it is well tolerated in mice. Iodination of our ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation and highlights LI as a suitable candidate for comprehensive in vivo anticancer preclin. evaluations.
- 28Beck, M. W.; Derrick, J. S.; Suh, J.-M.; Kim, M.; Korshavn, K. J.; Kerr, R. A.; Cho, W. J.; Larsen, S. D.; Ruotolo, B. T.; Ramamoorthy, A.; Lim, M. H. Minor structural variations of small molecules tune regulatory activities toward pathological factors in Alzheimer’s disease. ChemMedChem 2017, 12, 1828– 1838, DOI: 10.1002/cmdc.201700456Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Wrur%252FM&md5=9d621ac940142ae6f6c35edb47a8a490Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's DiseaseBeck, Michael W.; Derrick, Jeffrey S.; Suh, Jong-Min; Kim, Mingeun; Korshavn, Kyle J.; Kerr, Richard A.; Cho, Woo Jong; Larsen, Scott D.; Ruotolo, Brandon T.; Ramamoorthy, Ayyalusamy; Lim, Mi HeeChemMedChem (2017), 12 (22), 1828-1838CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Chem. tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chem. tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chem. tool were found to drastically det. the tool's reactivities toward multiple pathol. facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small mols. vary toward different targets as a result of minor structural modifications. These compds. were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aβ, reactive oxygen species (ROS), and free org. radicals. Our results show that although small mols. are structurally similar, they can interact with multiple factors assocd. with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chem. tools capable of regulating individual or interrelated pathol. features in AD.
- 29Lauw, S. J. L.; Xu, X.; Webster, R. D. Primary-colored electrochromism of 1,4-phenylenediamines. ChemPlusChem 2015, 80, 1288– 1297, DOI: 10.1002/cplu.201500247Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOrtbnM&md5=182273d12b49ab26e39690c1a29b68f3Primary-Colored Electrochromism of 1,4-PhenylenediaminesLauw, Sherman J. L.; Xu, Xiuhui; Webster, Richard D.ChemPlusChem (2015), 80 (8), 1288-1297CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)Ten 1,4-phenylenediamines were studied using electrochem. techniques (voltammetry and controlled potential electrolysis) and UV/Vis spectroscopy under ambient conditions. All compds. demonstrated vibrant color changes upon one-electron electrochem. oxidn. in acetonitrile, with most displaying a primary color (red, green, blue, or yellow) in their oxidized state. The four electrochromes that exhibited the most intense color changes were examd. by using a gold micromesh electrode laminated inside a polymer film to det. their electrochromic properties in soln. (contrast ratios, chromatic efficiency, and cycle life). Their colored radical cations were also characterized by ESR spectroscopy as well as monitored for color retention over a period of 24 h. Notably, only relatively small potentials were required to initiate the chromatic changes and the oxidized forms of the compds. were long-lived and unaffected by atm. oxygen or moisture.
- 30Fan, Y.; Liu, J.-H.; Yang, C.-P.; Yu, M.; Liu, P. Graphene–polyaniline composite film modified electrode for voltammetric determination of 4-aminophenol. Sens. Actuators, B 2011, 157, 669– 674, DOI: 10.1016/j.snb.2011.05.053Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvF2mtrc%253D&md5=5d2919bc8425a2296a82cd1a10176a66Graphene-polyaniline composite film modified electrode for voltammetric determination of 4-aminophenolFan, Yang; Liu, Jin-Hang; Yang, Chun-Peng; Yu, Meng; Liu, PengSensors and Actuators, B: Chemical (2011), 157 (2), 669-674CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)An electrochem. sensor based on graphene-polyaniline (GR-PANI) nanocomposite for voltammetric detn. of 4-aminophenol (4-AP) is presented. The electrochem. behavior of 4-AP at the GR-PANI composite film modified glassy carbon electrode (GCE) was investigated by cyclic voltammetry. 4-AP exhibits enhanced voltammetric response at GR-PANI modified GCE. This electrochem. sensor shows a favorable anal. performance for 4-AP detection with a detection limit of 6.5 × 10-8 M and high sensitivity of 604.2 μA mM-1. Moreover, 4-AP and paracetamol can be detected simultaneously without interference of each other in a large dynamic range.
- 31Marcus, M. F.; Hawley, M. D. The electrochemical oxidation of p-dimethylaminophenol in aqueous solution. J. Electroanal. Chem. Interfacial Electrochem. 1968, 18, 175– 183, DOI: 10.1016/S0022-0728(68)80172-XGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXkt1CjsLg%253D&md5=8f13adb0104a64a70d4be366c32057efThe electrochemical oxidation of p-dimethylaminophenol in aqueous solutionMarcus, Mark F.; Hawley, M. D.Journal of Electroanalytical Chemistry and Interfacial Electrochemistry (1968), 18 (1-2), 175-83CODEN: JEIEBC; ISSN:0022-0728.The electrochem. behavior of p-dimethylaminophenol (I) as the HCl salt was studied as a function of pH by chronoamperometry and chronopotentiometry by using a carbon paste working electrode and a Pt auxiliary electrode and by controlled-potential electrolysis using a Hg pool working electrode and a salt bridge as auxiliary electrode; for all expts., a S.C.E. was used as reference. McIlvaine buffers were used for pH 3-8 and carbonate buffers for pH 9-10. Cyclic voltammograms of 2mM I in 2M H2SO4 at different scan rates show 2 anodic waves and 1 cathodic wave which suggests that a chem. reaction precedes electron transfer and both of the indicated oxidns. are kinetically controlled; also the 2 electroactive species are in equil. At pH 3, 2-electron oxidn. of I occurs to yield p-N,N-dimethylbenzoquinone imine (II) at 0.4 v. and the redn. of II to I on the cathodic sweep. Controlled-potential electrolysis confirms the 2-electron interpretation. However, after exhaustive electrolysis, a 2nd redn. wave appears due to redn. of benzoquinone. At pH 6-7, 3 cathodic waves are obtained corresponding to redn. of unhydrolyzed II to I, redn. of benzoquinone, and redn. of I and benzoquinone. The latter together with the anodic wave due to formation of 2,4-bis(dimethylamino)phenol by the Michael 1,4-addn. of a hydrolysis product, dimethylamine, to II, forms a 3rd redox couple. The oxidn. of I at pH 6-9 is a 4-electron process which yields 2-dimethylamino-p-benzoquinone. At pH 8, an inflection in the I oxidn. is observed. At pH 9-10, the main oxidn. wave is split due to a 1-electron oxidn. yielding phenoxy radical and then to a 1-electron oxidn. of quinone imine.
- 32McCormick, M. C.; Keijzer, K.; Polavarapu, A.; Schultz, F. A.; Baik, M.-H. Understanding intrinsically irreversible, non-Nernstian, two-electron redox processes: a combined experimental and computational study of the electrochemical activation of platinum(IV) antitumor prodrugs. J. Am. Chem. Soc. 2014, 136, 8992– 9000, DOI: 10.1021/ja5029765Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVOns7Y%253D&md5=b0fc997db4db81cbee546fbb8e08c4f5Understanding intrinsically irreversible, non-Nernstian, two-electron redox processes: a combined experimental and computational study of the electrochemical activation of platinum(IV) antitumor prodrugsMcCormick, Meghan C.; Keijzer, Karlijn; Polavarapu, Abhigna; Schultz, Franklin A.; Baik, Mu-HyunJournal of the American Chemical Society (2014), 136 (25), 8992-9000CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Six-coordinate Pt(IV)-complexes are prominent prodrug candidates for the treatment of various cancers where, upon two-electron redn. and loss of two axial ligands, they form more familiar, pharmacol. active four-coordinate Pt(II) drugs. A series of electrochem. expts. coupled with extensive d. functional calcns. has been employed to elucidate the mechanism for the two-electron redn. of PtIV(NH3)2Cl2L2 to PtII(NH3)2Cl2 (L = CH3COO-, 1; L = CHCl2COO-, 2; L = Cl-, 3). A reliable est. for the normal redn. potential Eo is derived for the electrochem. irreversible Pt(IV) redn. and is compared directly to the quantum chem. calcd. redn. potentials. The process of electron transfer and Pt-L bond cleavage is found to occur in a stepwise fashion, suggesting that a metastable six-coordinate Pt(III) intermediate is formed upon addn. of a single electron, and the loss of both axial ligands is assocd. with the second electron transfer. The quantum chem. calcd. redn. potentials are in excellent agreement with exptl. detd. values that are notably more pos. than peak potentials reported previously for 1-3.
- 33Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A. Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 10566– 10571, DOI: 10.1073/pnas.93.20.10566Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtVOlsLs%253D&md5=eefa9720687d7c963df75782fcbbb604Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guideMecozzi, Sandro; West, Anthony P., Jr.; Dougherty, Dennis A.Proceedings of the National Academy of Sciences of the United States of America (1996), 93 (20), 10566-10571CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The cation-π interaction is an important, general force for mol. recognition in biol. receptors. Through the sidechains of arom. amino acids, novel binding sites for cationic ligands such as acetylcholine can be constructed. The authors report here a no. of calcns. on prototypical cation-π systems, emphasizing structures of relevance to biol. receptors and prototypical heterocycles of the type often of importance in medicinal chem. Trends in the data can be rationalized using a relatively simple model that emphasizes the electrostatic component of the cation-π interaction. In particular, plots of the electrostatic potential surfaces of the relevant aroms. provide useful guidelines for predicting cation-π interactions in new systems.
- 34Walter, R. I. Substituent effects on the properties of stable aromatic free radicals. The criterion for non-Hammett behavior. J. Am. Chem. Soc. 1966, 88, 1923– 1930, DOI: 10.1021/ja00961a014Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhtVensb8%253D&md5=8bb985e9ac14e856bc207e25ab294dc4Substituent effects on the properties of stable aromatic free radicals. The criterion for non-Hammett behaviorWalter, Robert I.Journal of the American Chemical Society (1966), 88 (9), 1923-30CODEN: JACSAT; ISSN:0002-7863.Substitution in the para positions of the aryl groups of the triarylaminum salt and the 1-picryl-2,2-diarylhydrazyl free radicals strongly affects the optical and E.S.R. spectra of these substances. In the aminium salt series, either donor or acceptor substituents alter each type of absorption in the same direction. In the hydrazyl series, donor and acceptor substituents shift each type of absorption in opposite directions. These observations can be interpreted in terms of the contributions of structures which place only an unpaired electron, or either an unpaired electron or an unshared electron pair, on the atom to which is attached the aromatic rings which contain the substituents in the mols. Generalization of these ideas affords a structural basis for predicting the nature of substituent effects in other types of stable free radicals. Those unsubstituted radicals for which one can write both structures G-C6H4-X• with an unpaired electron, and G-C6H4-X• with an unshared electron pair, on the atom para to the site of substitution, belong to class O. Those radicals for which only the first structure can be written for the unsubstituted radical are assigned to class S. Class O (for opposite) radicals exhibit Hammett-like behavior, with donor and acceptor substituents shifting observed properties in opposite directions, but properties of class S (for same) radicals are shifted in the same direction by either donor or acceptor substituents. Known types of stable free radicals are classified on the basis of this structural criterion, and the classifications are shown to be consistent with the available data on these systems.
- 35van den Berg, R.; Haenen, G. R. M. M.; van den Berg, H.; Bast, A. Applicability of an improved Trolox equivalent antioxidant capacity (TEAC) assay for evaluation of antioxidant capacity measurements of mixtures. Food Chem. 1999, 66, 511– 517, DOI: 10.1016/S0308-8146(99)00089-8Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktFWnt7Y%253D&md5=bc6602190f07d7d683c366d77a0c1235Applicability of an improved Trolox equivalent antioxidant capacity (TEAC) assay for evaluation of antioxidant capacity measurements of mixturesVan den Berg, Robin; Haenen, Guido R. M. M.; Van den Berg, Henk; Bast, AaltFood Chemistry (1999), 66 (4), 511-517CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Science Ltd.)The TEAC (Trolox equiv. antioxidant capacity) assay is based on scavenging of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) radical anions (ABTS-). In this report we describe a modification based on pre-generation of the ABTS radical anions with a thermolabile azo compd., 2,2'-azobis(2-amidinopropane)-2HCl (ABAP). This modification makes the assay less susceptible to artifacts, e.g. influence on the radical generation process. For most antioxidants tested, a biphasic reaction pattern was seen, i.e. a fast and slow scavenging rate. We evaluated application of the assay with both lipophilic and hydrophilic compds. with antioxidant capacity. Several org. solvents, compatible with water, were tested with α-tocopherol, quercetin and β-carotene. It was found that the TEACs differed in various solvents. Under standardized conditions additivity of TEACs obtained from individual antioxidants could be demonstrated. This might enable application of the assay for the identification of "unknown" antioxidants.
- 36Rao, P. S.; Hayon, E. Oxidation of aromatic amines and diamines by OH radicals. Formation and ionization constants of amine cation radicals in water. J. Phys. Chem. 1975, 79, 1063– 1066, DOI: 10.1021/j100578a005Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXkt1Ohtrc%253D&md5=350607f571d0712f2cf46626dbfbe44eOxidation of aromatic amines and diamines by hydroxyl radicals. Formation and ionization constants of amine cation radicals in waterRao, P. S.; Hayon, E.Journal of Physical Chemistry (1975), 79 (11), 1063-6CODEN: JPCHAX; ISSN:0022-3654.The one-electron oxidn. by hydroxyl radicals of arom. amines and diamines in water initially gives radical adducts which decay by 1st-order kinetics and have lifetimes of ∼5-50μ sec. The decay products are cation radicals and are long-lived in the absence of O. The pKa values of the cation radicals are detd.
- 37Benmehdi, H.; Behilil, A.; Memmou, F.; Amrouche, A. Free radical scavenging activity, kinetic behaviour and phytochemical constituents of Aristolochia clematitis L. roots. Arabian J. Chem. 2017, 10, S1402– S1408, DOI: 10.1016/j.arabjc.2013.04.015Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVymsbc%253D&md5=74113933c9a435b91f74f22605b4bfc5Free radical scavenging activity, kinetic behaviour and phytochemical constituents of Aristolochia clematitis L. rootsBenmehdi, Houcine; Behilil, Asma; Memmou, Faiza; Amrouche, AbdelillahArabian Journal of Chemistry (2017), 10 (Suppl._1), S1402-S1408CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)Nowadays there is an increasing demand of natural antioxidants. Imbalanced prodn. and consumption of reactive oxygen species, lead to many diseases such as cancer, arteriosclerosis and ageing processes. The protective effects of plants have long been attributed to their antioxidant compds., like polyphenols, flavonoids, carotenoids, and vitamins C and E. Therefore, the present study was designed to evaluate the antioxidant activity of tannins and crude methanolic exts. of Aristolochia clematitis L. by two complementary test systems (DPPH free radical scavenging and bioautog. HPTLC). Besides, phytochem. screening was carried out on roots of A. clematitis and showed the presence of tannins, alkaloids and essential oils. High performance thin layer chromatog. (HPTLC) screening provided qual. the antioxidant effect of exts. under study. Furthermore, it was found that the tannins and methanolic crude exts. from A. clematitis had a potent DPPH scavenging potency with IC50 values of 0.196 and 0.142 mg/mL, resp. Besides, the kinetic behavior of DPPH radical scavenging activity of exts. under study allowed us to det. the half life t1/2, time reaction (t) and the remaining DPPH· percent.
- 38Lee, S. J. C.; Nam, E.; Lee, H. J.; Savelieff, M. G.; Lim, M. H. Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors. Chem. Soc. Rev. 2017, 46, 310– 323, DOI: 10.1039/C6CS00731GGoogle Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFCisr7F&md5=ce85df9dd5a10a5f0a39a1c97d8c0eabTowards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitorsLee, Shin Jung C.; Nam, Eunju; Lee, Hyuck Jin; Savelieff, Masha G.; Lim, Mi HeeChemical Society Reviews (2017), 46 (2), 310-323CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Alzheimer's disease (AD) is characterized by an imbalance between prodn. and clearance of amyloid-β (Aβ) species. Aβ peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among the various Aβ species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aβ oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers' assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic Aβ oligomers could be a valid approach to regulate Aβ-assocd. toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of Aβ oligomers' assembly, structural properties, and toxicity, along with inhibitors against Aβ aggregation, including oligomerization.
- 39Kotler, S. A.; Walsh, P.; Brender, J. R.; Ramamoorthy, A. Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer’s disease. Chem. Soc. Rev. 2014, 43, 6692– 6700, DOI: 10.1039/C3CS60431DGoogle Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsV2mt7nI&md5=2c2a4fbf2b471b4800edfff6872182a3Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer's diseaseKotler, Samuel A.; Walsh, Patrick; Brender, Jeffrey R.; Ramamoorthy, AyyalusamyChemical Society Reviews (2014), 43 (19), 6692-6700CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. The assocn. of the amyloid-β (Aβ) peptide with cellular membranes is hypothesized to be the underlying phenomenon of neurotoxicity in Alzheimer's disease. Misfolding of proteins and peptides, as is the case with Aβ, follows a progression from a monomeric state, through intermediates, ending at long, unbranched amyloid fibers. This tutorial review offers a perspective on the assocn. of toxic Aβ structures with membranes as well as details of membrane-assocd. mechanisms of toxicity.
- 40Smith, D. P.; Ciccotosto, G. D.; Tew, D. J.; Fodero-Tavoletti, M. T.; Johanssen, T.; Masters, C. L.; Barnham, K. J.; Cappai, R. Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer’s disease amyloid-β peptide. Biochemistry 2007, 46, 2881– 2891, DOI: 10.1021/bi0620961Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsFOlurg%253D&md5=1398370fb29dac05b0641c8017d91fe3Concentration Dependent Cu2+ Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β PeptideSmith, David P.; Ciccotosto, Giuseppe D.; Tew, Deborah J.; Fodero-Tavoletti, Michelle T.; Johanssen, Timothy; Masters, Colin L.; Barnham, Kevin J.; Cappai, RobertoBiochemistry (2007), 46 (10), 2881-2891CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)The Amyloid β peptide (Aβ) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline assocd. with the disease. Cu2+ ions can induce the de novo aggregation of the Aβ peptide into non-amyloidogenic aggregates and the prodn. of a toxic species. The mechanism by which Cu2+ mediates the change from amyloid material toward Cu2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of Aβ1-42 at neutral pH is governed by the Cu2+:peptide molar ratio. By probing amyloid content and total aggregation, we obsd. a distinct Cu2+ switching effect centered at equimolar Cu2+:peptide ratios. At sub-equimolar Cu2+:peptide molar ratios, Aβ1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu2+:peptide molar ratios, Aβ1-42 forms both small spherical oligomers approx. 10-20 nm in size and large amorphous aggregates. We demonstrate that these insol. aggregates form spontaneously via a sol. species without the presence of an observable lag phase. In seeding expts., the Cu2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu2+ induced aggregates are toxic when compared to Aβ1-42 aged in the absence of Cu2+. Importantly, the formation of dityrosine crosslinked Aβ, by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu2+ induced aggregates. These results define the role Cu2+ plays in modulating the aggregation state and toxicity of Aβ1-42.
- 41Noy, D.; Solomonov, I.; Sinkevich, O.; Arad, T.; Kjaer, K.; Sagi, I. Zinc-amyloid β interactions on a millisecond time-scale stabilize non-fibrillar Alzheimer-related species. J. Am. Chem. Soc. 2008, 130, 1376– 1383, DOI: 10.1021/ja076282lGoogle Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivFyqtw%253D%253D&md5=7f38fc8e05a2a4a26ff324c8e089e4b9Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related SpeciesNoy, Dror; Solomonov, Inna; Sinkevich, Ory; Arad, Talmon; Kjaer, Kristian; Sagi, IritJournal of the American Chemical Society (2008), 130 (4), 1376-1383CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The role of zinc, an essential element for normal brain function, in the pathol. of Alzheimer's disease (AD) is poorly understood. On one hand, physiol. and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid β-protein (Aβ) in senile plaques. On the other hand, levels of extracellular ("free") zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing Aβ aggregation. Remarkably, the release of transient high local concns. of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting Aβ aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concns., immediately interacts with Aβ 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of Aβ fibrils (more benign species) presumably by interfering with the self-assembly process of Aβ. These in vitro results strongly suggest a significant role for zinc pulses in Aβ pathol. We further propose that by interfering with Aβ self-assembly, which leads to insol., non-pathol. fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of mol. pathogens that effectively perturb the self-assembly of benign Aβ fibrils, and stabilize harmful non-fibrillar forms.
- 42Tougu, V.; Karafin, A.; Zovo, K.; Chung, R. S.; Howells, C.; West, A. K.; Palumaa, P. Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1–42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators. J. Neurochem. 2009, 110, 1784– 1795, DOI: 10.1111/j.1471-4159.2009.06269.xGoogle Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFOgsrnI&md5=765c41f2d8d34e4380613a3792d44977Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelatorsTougu, Vello; Karafin, Ann; Zovo, Kairit; Chung, Roger S.; Howells, Claire; West, Adrian K.; Palumaa, PeepJournal of Neurochemistry (2009), 110 (6), 1784-1795CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)Aggregation of amyloid-β (Aβ) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Aβ aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Aβ42 fibrillization and initiate formation of non-fibrillar Aβ42 aggregates, and that the inhibitory effect of Zn(II) (IC50 = 1.8 μM) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced Aβ42 aggregation. Moreover, their addn. to preformed aggregates initiated fast Aβ42 fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of Aβ42. H13A and H14A mutations in Aβ42 reduced the inhibitory effect of metal ions, whereas an H6A mutation had no significant impact. We suggest that metal binding by H13 and H14 prevents the formation of a cross-β core structure within region 10-23 of the amyloid fibril. Cu(II)-Aβ42 aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-Aβ42 aggregates were non-toxic. Disturbed metal homeostasis in the vicinity of zinc-enriched neurons might pre-dispose formation of metal-induced Aβ aggregates, subsequent fibrillization of which can lead to amyloid formation. The mol. background underlying metal-chelating therapies for Alzheimer's disease is discussed in this light.
- 43Pedersen, J. T.; Ostergaard, J.; Rozlosnik, N.; Gammelgaard, B.; Heegaard, N. H. H. Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-β peptides. J. Biol. Chem. 2011, 286, 26952– 26963, DOI: 10.1074/jbc.M111.220863Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpt1Krs7Y%253D&md5=33d3e04c0d770c42c222ea1da6fc2e5dCu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β PeptidesPedersen, Jeppe T.; Oestergaard, Jesper; Rozlosnik, Noemi; Gammelgaard, Bente; Heegaard, Niels H. H.Journal of Biological Chemistry (2011), 286 (30), 26952-26963, S26952/1-S26952/12CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-β (Aβ) peptide. Elucidating the underlying Cu(II)-induced Aβ aggregation is paramount for understanding the role of Cu(II) in the pathol. of Alzheimer disease. The aim of this study was to characterize the qual. and quant. influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphol. of Aβ1-40 using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):Aβ ratio in soln. has a major influence on (i) the aggregation kinetics/mechanism of Aβ, because three different kinetic scenarios were obsd. depending on the Cu(II):Aβ ratio; (ii) the metal:peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):Aβ ratio; and (iii) the morphol. of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):Aβ ratios. We obsd. dynamic morphol. changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphol. end point independent on the Cu(II) concn. Expts. with Aβ1-42 were compatible with the conclusions for Aβ1-40 even though the low soly. of Aβ1-42 precluded examn. under the same conditions as for the Aβ1-40. Expts. with Aβ1-16 and Aβ1-28 showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced Aβ aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of Aβ1-40 depending on the Cu(II):Aβ ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-assocd. aggregation or toxicity in Alzheimer disease.
- 44Felice, F. G. D.; Vieira, M. N. N.; Saraiva, L. M.; Figueroa-villar, J. D.; Garcia-abreu, J.; Liu, R.; Chang, L.; Klein, W. L.; Ferreira, S. T. Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aβ oligomerization. FASEB J. 2004, 18, 1366– 1372, DOI: 10.1096/fj.04-1764comGoogle ScholarThere is no corresponding record for this reference.
- 45Meek, A. R.; Simms, G. A.; Weaver, D. F. In silico search for an endogenous anti-Alzheimer’s molecule — Screening amino acid metabolic pathways. Can. J. Chem. 2012, 90, 865– 873, DOI: 10.1139/v2012-074Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eiurfE&md5=2d47d8c3b97fb06ad3f185c41c7c9d14In silico search for an endogenous anti-Alzheimer's molecule - Screening amino acid metabolic pathwaysMeek, Autumn R.; Simms, Gordon A.; Weaver, Donald F.Canadian Journal of Chemistry (2012), 90 (10), 865-873CODEN: CJCHAG; ISSN:0008-4042. (Canadian Science Publishing)Alzheimer's disease (AD) is a neurodegenerative disorder arising from abnormal aggregation of β-amyloid (Aβ) and progressing at different rates from person to person. There may exist endogenous compds. within the brain that playa role in inhibiting aggregation. We have devised a unique in silico screening strategy of endogenous mols. within the human brain, with special emphasis on amino acid metabolic pathways, to identify compds. with the potential to inhibit Aβ aggregation. Metabolites of tryptophan were computationally identified through this screening as potential therapeutics and were optimized via mol. modeling to det. their capacity to bind to Aβ. The most successful mol. identified was 3-hydroxyanthranilic acid (3-HAA). This endogenous mol. was then computationally explored to design novel analogs of 3-HAA with the goal of improving Aβ anti-aggregant activity. These combined in silico methods of screening, identifying, and successfully "analoguing" an endogenous mol. of the brain as an AD therapeutic has yielded pos. results and a novel approach to computer-aided drug design.
- 46Chung, Y.-C.; Su, Y. O. Effects of phenyl- and methyl-substituents on p-phenylenediamine, an electrochemical and spectral study. J. Chin. Chem. Soc. 2009, 56, 493– 503, DOI: 10.1002/jccs.200900074Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVKmt7zO&md5=9de4094ec3a35e9f5036d4de85970cf5Effects of phenyl- and methyl-substituents on p-phenylenediamine, an electrochemical and spectral studyChung, Yi-Chun; Su, Yuhlong OliverJournal of the Chinese Chemical Society (Taipei, Taiwan) (2009), 56 (3), 493-503CODEN: JCCTAC; ISSN:0009-4536. (Chinese Chemical Society)Two series of substituted p-phenylenediamines have been studied for their electronic effects on redox potential and spectral properties. P-Phenylenediamines and N,N,N',N'-tetramethyl-p-phenylenediamine substituted with different nos. of Ph groups have been synthesized and their cyclic voltammograms have been obtained. The correlation between the substituent no. and the redox potential appears linear. The slope reflects the additive effect of electron-donating Me and electron-withdrawing Ph groups. The absorption spectra of the cation radicals indicate that phenyl-substituted ones have broad intervalence-charge transfer bands. The p-phenylenediamines exhibit different properties from triphenylamines in that the oxidized forms are more stable in CH3CN then those in CH2Cl2. Some of the cation radicals or dications could undergo follow-up chem. reactions and form products that are more easily oxidized.
- 47Bai, Y.-H.; Li, J.-Y.; Zhu, Y.-h.; Xu, J.-J.; Chen, H.-Y. Selective detection of p-phenylenediamine in hair dyes based on a special CE mechanism using MnO2 nanowires. Electroanalysis 2010, 22, 1239– 1247, DOI: 10.1002/elan.200900576Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvVGms7k%253D&md5=c921f894cc3ebddab4ecb7ec97fa7eacSelective Detection of p-Phenylenediamine in Hair Dyes Based on a Special CE Mechanism Using MnO2 NanowiresBai, Yu-Hui; Li, Jin-Yi; Zhu, Yu-hua; Xu, Jing-Juan; Chen, Hong-YuanElectroanalysis (2010), 22 (11), 1239-1247CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)We report a novel approach for selective detn. of p-phenylenediamine in hair dyes using β-MnO2 nanowires modified glassy carbon (GC) electrodes through an electrochem. co-deposition process with chitosan hydrogel. A special CE (chem. reaction and electron transfer) process on the surface of β-MnO2 nanowires modified GC electrode is proposed and proved by cyclic voltammetry and UV-Vis spectroscopy in the presence of p-phenylenediamine. P-Phenylenediamine can react with MnO2 nanowires to produce diimine and the equil. of the 2-electron and 2-proton redox process of p-phenylenediamine on the electrode is changed, and consequently the reductive current is enhanced significantly. At a const. potential of 0 V vs. SCE, other main components of hair dyes including o-, m-phenylenediamine, catechol, resorcinol, and p-dihydroxybenzene do not interfere in the detn. of p-phenylenediamine in the amperometric measurement because of their much lower chem. reaction activities with MnO2 nanowires. It shows a detn. range of 0.2-150 μM and a low detection limit of 50 nM to response p-phenylenediamine. This modified electrode is successfully used to analyze the amt. of p-phenylenediamine in hair dyes without presepn. procedures.
- 48Meyer, A.; Fischer, K. Oxidative transformation processes and products of para-phenylenediamine (PPD) and para-toluenediamine (PTD)—a review. Environ. Sci. Eur. 2015, 27, 11– 26, DOI: 10.1186/s12302-015-0044-7Google ScholarThere is no corresponding record for this reference.
- 49Lerner, L. Identity of a purple dye formed by peroxidic oxidation of p-aminophenol at low pH. J. Phys. Chem. A 2011, 115, 9901– 9910, DOI: 10.1021/jp2045806Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVagsLzM&md5=7d9544a9310e7726b970b42dc567d1bbIdentity of a Purple Dye Formed by Peroxidic Oxidation of p-Aminophenol at Low pHLerner, L.Journal of Physical Chemistry A (2011), 115 (35), 9901-9910CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The structure of a colored intermediate commonly formed in the oxidn. of p-aminophenol at low pH is established by anal. of 1H NMR and UV-vis spectra, kinetics, and mol. modeling, following a new method for synthesizing the dye in high concns. The chromogen is shown to consist of two compds. with absorption maxima at 540-560 and 375-385 nm. The 2,6-di-Me and 3,5-di-Me analogs of p-aminophenol are found to undergo N- rather than C-substitution under similar conditions.
- 50Eyer, P.; Lengfelder, E. Radical formation during autoxidation of 4-dimethylaminophenol and some properties of the reaction products. Biochem. Pharmacol. 1984, 33, 1005– 1013, DOI: 10.1016/0006-2952(84)90507-0Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXkvVGjtrs%253D&md5=a2e895d42d40c90eb0a6ec33c866ff63Radical formation during autoxidation of 4-dimethylaminophenol and some properties of the reaction productsEyer, P.; Lengfelder, E.Biochemical Pharmacology (1984), 33 (7), 1005-13CODEN: BCPCA6; ISSN:0006-2952.4-Dimethylaminophenol (I) [619-60-3], after i.v. injection, rapidly formed ferriHb and was successfully used in the treatment of cyanide poisoning. Since I produced many equiv. of ferriHb, it was of interest to obtain further insight into this catalytic process. I autoxidized readily at pH regions above neutrality, a process which was markedly accelerated by oxyHb. The resulting red-colored product was identified as 4-(N,N-dimethylamino)phenoxyl (II) [19052-61-0]. II was also produced by pulse radiolysis and oxidn. with K ferricyanide. II was quite unstable and decayed in a pseudo-1st order reaction with the formation of p-benzoquinone [106-51-4] and dimethylamine [124-40-3]. This obsd. decay rate was identical with the rate of hydrolysis of N-dimethylquinonimine [619-60-3]. When a soln. contg. II was extd. with ether, half the stoichiometric amt. of I was recovered. Hence, it was apparent that II decayed by disproportionation yielding I and N,N-dimethylquinonimine. The latter product then quickly hydrolyzed. The equil. of this disproportionation reaction was far towards the radical side, and the pseudo-1st order hydrolysis controlled the radical decay rate. p-Benzoquinone rapidly reacted with I with the formation of II and the semiquinone radical [20217-26-9]. Thus, the autocatalytic II formation during autoxidn. of I. I was not oxidized by H2O2 or O, but II was rapidly reduced by O. In addn., II was quickly reduced by NAD(P)H [53-57-6] or GSH [70-18-8] with the formation of NAD(P) [53-59-8] or GSSG [27025-41-8]. Since I was also able to reduce 2 equiv of ferriHb (provided that the ferroHb produced is trapped by CO) electrophilic addn. reactions of II seem unimportant in contrast to N,N-dimethylquinonimine. Hence, during the catalytic ferriHb formation, I is oxidized by O which is activated by Hb, and II oxidizes ferroHb. This catalytic process is terminated by covalent binding of N,N-dimethylquinonimine to SH groups of Hb (and GSH in red cells).
- 51Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 2009, 30, 2785– 2791, DOI: 10.1002/jcc.21256Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GitrnK&md5=679ce22fc50e9291c9aa16e7a1855845AutoDock and AutoDockTools: Automated docking with selective receptor flexibilityMorris, Garrett M.; Huey, Ruth; Lindstrom, William; Sanner, Michel F.; Belew, Richard K.; Goodsell, David S.; Olson, Arthur J.Journal of Computational Chemistry (2009), 30 (16), 2785-2791CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking expt. with 188 diverse ligand-protein complexes and a cross-docking expt. using flexible sidechains in 87 HIV protease complexes. We also report its utility in anal. of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009.
- 52Vivekanandan, S.; Brender, J. R.; Lee, S. Y.; Ramamoorthy, A. A partially folded structure of amyloid-beta(1–40) in an aqueous environment. Biochem. Biophys. Res. Commun. 2011, 411, 312– 316, DOI: 10.1016/j.bbrc.2011.06.133Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXps1arsrs%253D&md5=dcaf756dcb5b5fcdc484d7f9596271bfA partially folded structure of amyloid-beta(1-40) in an aqueous environmentVivekanandan, Subramanian; Brender, Jeffrey R.; Lee, Shirley Y.; Ramamoorthy, AyyalusamyBiochemical and Biophysical Research Communications (2011), 411 (2), 312-316CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Aggregation of the Aβ1-40 peptide is linked to the development of extracellular plaques characteristic of Alzheimer's disease. While previous studies commonly show the Aβ1-40 is largely unstructured in soln., we show that Aβ1-40 can adopt a compact, partially folded structure. In this structure (PDB ID: 2LFM), the central hydrophobic region of the peptide forms a 310 helix from H13 to D23 and the N- and C-termini collapse against the helix due to the clustering of hydrophobic residues. Helical intermediates have been predicted to be crucial on-pathway intermediates in amyloid fibrillogenesis, and the structure presented here presents a new target for investigation of early events in Aβ1-40 fibrillogenesis.
- 53Vogt, W. Oxidation of methionyl residues in proteins: tools, targets, and reversal. Free Radical Biol. Med. 1995, 18, 93– 105, DOI: 10.1016/0891-5849(94)00158-GGoogle Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjtVequ7g%253D&md5=b046a8d4e8b32282f3b98a278fc970f3Oxidation of methionyl residues in proteins: tools, targets, and reversalVogt, WaltherFree Radical Biology & Medicine (1995), 18 (1), 93-105CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)A review with 136 refs. Methionine (Met) is one of the most readily oxidized amino acid constituents of proteins. It is attacked by H2O2, hydroxyl radicals, hypochlorite, chloramines, and peroxynitrite, all these oxidants being produced in biol. systems. The oxidn. product, Met sulfoxide, can be reduced back to Met by Met sulfoxide reductase. Numerous proteins lose functional activity by Met oxidn. However, functional activation of proteins by Met oxidn. has also been obsd. Functional changes by Met oxidn. in a given protein appear to have pathophysiol. significance in some cases. Considering the reversibility of Met oxidn. and the functional changes assocd. with the oxidn., it seems possible that Met oxidn./redn. in proteins may be one means to control homeostasis in biologicals systems.
- 54Davies, M. J. Protein oxidation and peroxidation. Biochem. J. 2016, 473, 805– 825, DOI: 10.1042/BJ20151227Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvFClsLg%253D&md5=fd1192a5ac27edeb8583228d439afca9Protein oxidation and peroxidationDavies, Michael J.Biochemical Journal (2016), 473 (7), 805-825CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Proteins are major targets for radicals and two-electron oxidants in biol. systems due to their abundance and high rate consts. for reaction. With highly reactive radicals damage occurs at multiple side-chain and backbone sites. Less reactive species show greater selectivity with regard to the residues targeted and their spatial location. Modification can result in increased side-chain hydrophilicity, side-chain and backbone fragmentation, aggregation via covalent crosslinking or hydrophobic interactions, protein unfolding and altered conformation, altered interactions with biol. partners and modified turnover. In the presence of O2, high yields of peroxyl radicals and peroxides (protein peroxidn.) are formed; the latter account for up to 70% of the initial oxidant flux. Protein peroxides can oxidize both proteins and other targets. One-electron redn. results in addnl. radicals and chain reactions with alcs. and carbonyls as major products; the latter are commonly used markers of protein damage. Direct oxidn. of cysteine (and less commonly) methionine residues is a major reaction; this is typically faster than with H2O2, and results in altered protein activity and function. Unlike H2O2, which is rapidly removed by protective enzymes, protein peroxides are only slowly removed, and catabolism is a major fate. Although turnover of modified proteins by proteasomal and lysosomal enzymes, and other proteases (e.g. mitochondrial Lon), can be efficient, protein hydroperoxides inhibit these pathways and this may contribute to the accumulation of modified proteins in cells. Available evidence supports an assocn. between protein oxidn. and multiple human pathologies, but whether this link is causal remains to be established.
- 55Munday, R. Generation of superoxide radical, hydrogen peroxide and hydroxyl radical during the autoxidation of N,N,N’,N’-tetramethyl-p-phenylenediamine. Chem.-Biol. Interact. 1988, 65, 133– 143, DOI: 10.1016/0009-2797(88)90050-6Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktFylsbc%253D&md5=289aae92f507fa771a331237ca479f3fGeneration of superoxide radical, hydrogen peroxide and hydroxyl radical during the autoxidation of N,N,N',N'-tetramethyl-p-phenylenediamineMunday, R.Chemico-Biological Interactions (1988), 65 (2), 133-43CODEN: CBINA8; ISSN:0009-2797.The autoxidn. of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) at neutral pH generates superoxide radical and H2O2. The rate of formation of these species was increased in the presence of certain Fe and Cu compds.; in the presence of Fe complexed with EDTA, hydroxyl radical was also produced. H2O2 was detected in erythrocytes incubated with TMPD and these cells suffered oxidative damage as reflected by metHb formation and glutathione depletion; the 1-electron oxidn. product of TMPD, Wurster's Blue, was equally effective in producing such changes in erythrocytes. N-Methylated p-phenylenediamines are known to be mutagenic and myotoxic, and it is suggested that active O species may be involved in the initiation of these harmful effects.
- 56Stadtman, E. R.; Levine, R. L. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids 2003, 25, 207– 218, DOI: 10.1007/s00726-003-0011-2Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpsFOntL8%253D&md5=8d16642d300ae1e55932881e5d02b886Free radical-mediated oxidation of free amino acids and amino acid residues in proteinsStadtman, E. R.; Levine, R. L.Amino Acids (2003), 25 (3-4), 207-218CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag Wien)A review. We summarize here results of studies designed to elucidate basic mechanisms of reactive oxygen (ROS)-mediated oxidn. of proteins and free amino acids. These studies have shown that oxidn. of proteins can lead to hydroxylation of arom. groups and aliph. amino acid side chains, nitration of arom. amino acid residues, nitrosylation of sulfhydryl groups, sulfoxidn. of methionine residues, chlorination of arom. groups and primary amino groups, and to conversion of some amino acid residues to carbonyl derivs. Oxidn. can lead also to cleavage of the polypeptide chain and to formation of cross-linked protein aggregates. Furthermore, functional groups of proteins can react with oxidn. products of polyunsatd. fatty acids and with carbohydrate derivs. (glycation/glycoxidn.) to produce inactive derivs. Highly specific methods have been developed for the detection and assay of the various kinds of protein modifications. Because the generation of carbonyl derivs. occurs by many different mechanisms, the level of carbonyl groups in proteins is widely used as a marker of oxidative protein damage. The level of oxidized proteins increases with aging and in a no. of age-related diseases. However, the accumulation of oxidized protein is a complex function of the rates of ROS formation, antioxidant levels, and the ability to proteolytically eliminate oxidized forms of proteins. Thus, the accumulation of oxidized proteins is also dependent upon genetic factors and individual life styles. It is noteworthy that surface-exposed methionine and cysteine residues of proteins are particularly sensitive to oxidn. by almost all forms of ROS; however, unlike other kinds of oxidn. the oxidn. of these sulfur-contg. amino acid residues is reversible. It is thus evident that the cyclic oxidn. and redn. of the sulfur-contg. amino acids may serve as an important antioxidant mechanism, and also that these reversible oxidns. may provide an important mechanism for the regulation of some enzyme functions.
- 57McNaney, C. A.; Drexler, D. M.; Hnatyshyn, S. Y.; Zvyaga, T. A.; Knipe, J. O.; Belcastro, J. V.; Sanders, M. An automated liquid chromatography-mass spectrometry process to determine metabolic stability half-life and intrinsic clearance of drug candidates by substrate depletion. Assay Drug Dev. Technol. 2008, 6, 121– 129, DOI: 10.1089/adt.2007.103Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtFKqtbs%253D&md5=3833f7d7c4be366bc2d4b3e656ef4ae2An Automated Liquid Chromatography-Mass Spectrometry Process to Determine Metabolic Stability Half-Life and Intrinsic Clearance of Drug Candidates by Substrate DepletionMcNaney, Colleen A.; Drexler, Dieter M.; Hnatyshyn, Serhiy Y.; Zvyaga, Tatyana A.; Knipe, Jay O.; Belcastro, James V.; Sanders, MarkAssay and Drug Development Technologies (2008), 6 (1), 121-129CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)An automated process is described for the detailed assessment of the in vitro metabolic stability properties of drug candidates in support of pharmaceutical property profiling. Compds. are incubated with liver microsomes using a robotic liq. handler. Aliquots are taken at various time points, and the resulting samples are quant. analyzed by liq. chromatog.-mass spectrometry utilizing ion trap mass spectrometers to det. the amt. of compd. remaining. From these data metab. rates can be calcd. A high degree of automation is achieved through custom software, which is employed for instrument setup, data processing, and results reporting. The assay setup is highly configurable, allowing for any combination of up to six user-selected time points, variable substrate concn., and microsomes or other biol. active media. The data, based on relative substrate depletion, affords an est. of metabolic stability through the calcn. of half-life (t1/2) and intrinsic clearance, which are used to differentiate and rank order drug leads. In general, t1/2 is the time necessary for the metab., following first-order kinetics, of 50 of the initial compd. Intrinsic clearance is the proportionality const. between rate of metab. of a compd. and its concn. at the enzyme site. Described here is the setup of the assay, and data from assay test compds. are presented.
- 58Di, L.; Kerns, E. H.; Hong, Y.; Kleintop, T. A.; Mcconnell, O. J.; Huryn, D. M. Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates. J. Biomol. Screening 2003, 8, 453– 462, DOI: 10.1177/1087057103255988Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntlWrtbo%253D&md5=0a576434f52b90073d67b81aa4dd3b92Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidatesDi, Li; Kerns, Edward H.; Hong, Yan; Kleintop, Teresa A.; McConnell, Oliver J.; Huryn, Donna M.Journal of Biomolecular Screening (2003), 8 (4), 453-462CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)Metabolic stability plays an important role in the success of drug candidates. First-pass metab. is one of the major causes of poor oral bioavailability and short half-life. Traditionally, metabolic stability was evaluated at a later stage of drug discovery and required laborious manual manipulations. With the advance of high-throughput screening, combinatorial chem., and early profiling of drug-like properties, automated and rapid stability assays are needed to meet the increasing demand of throughput, speed, and reproducibility at earlier stages of drug discovery. The authors describe optimization of a simple, robust, high-throughput microsomal stability assay developed in a 96-well format. The assay consists of 2 automated components: robotic sample prepn. for incubation and cleanup and rapid liq. chromatog./mass spectrometry/mass spectrometry (LC/MS/MS) anal. to det. percent remaining of the parent compd. The reagent solns. and procedural steps were optimized for automation. Variables affecting assay results were investigated. The variability introduced by microsome prepns. from different sources (various vendors and batches) was studied and indicates the need for careful control. Quality control and normalization of the stability results are crit. when applying the screening data, generated at different times or research sites, to discovery projects.
- 59Oakley, H.; Cole, S. L.; Logan, S.; Maus, E.; Shao, P.; Craft, J.; Guillozet-Bongaarts, A.; Ohno, M.; Disterhoft, J.; Van Eldik, L.; Berry, R.; Vassar, R. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 2006, 26, 10129– 10140, DOI: 10.1523/JNEUROSCI.1202-06.2006Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVymurbK&md5=a47a3bedd25b37812f9172ebca81fb1dIntraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formationOakley, Holly; Cole, Sarah L.; Logan, Sreemathi; Maus, Erika; Shao, Pei; Craft, Jeffery; Guillozet-Bongaarts, Angela; Ohno, Masuo; Disterhoft, John; Van Eldik, Linda; Berry, Robert; Vassar, RobertJournal of Neuroscience (2006), 26 (40), 10129-10140CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase prodn. of β-amyloid 42 (Aβ42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ42 and exhibit amyloid plaque pathol. similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ42 prodn. 5XFAD mice generate Aβ42 almost exclusively and rapidly accumulate massive cerebral Aβ42 levels. Amyloid deposition (and gliosis) begins at 2 mo and reaches a very large burden, esp. in subiculum and deep cortical layers. Intraneuronal Aβ42 accumulates in 5XFAD brain starting at 1.5 mo of age (before plaques form), is aggregated (as detd. by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphol. abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic d.-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addn., levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 mo in 5XFAD brain, although an upward trend is obsd. by 3 mo of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathol. and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloid plaque formation.
- 60Vorhees, C. V.; Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 2006, 1, 848– 858, DOI: 10.1038/nprot.2006.116Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s3gsVWmsQ%253D%253D&md5=236edc21e2a0444deaf77ebef3885e8fMorris water maze: procedures for assessing spatial and related forms of learning and memoryVorhees Charles V; Williams Michael TNature protocols (2006), 1 (2), 848-58 ISSN:.The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed across repeated trials and reference memory is determined by preference for the platform area when the platform is absent. Reversal and shift trials enhance the detection of spatial impairments. Trial-dependent, latent and discrimination learning can be assessed using modifications of the basic protocol. Search-to-platform area determines the degree of reliance on spatial versus non-spatial strategies. Cued trials determine whether performance factors that are unrelated to place learning are present. Escape from water is relatively immune from activity or body mass differences, making it ideal for many experimental models. The MWM has proven to be a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and NMDA receptor function. We present protocols for performing variants of the MWM test, from which results can be obtained from individual animals in as few as 6 days.
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Abstract
Figure 1
Figure 1. Overview of a rational strategy of designing compact aromatic molecules with multiple reactivities against pathological factors found in the AD-affected brain and the chemical series studied in this work. (a) Structures of 1–4 (Group-I) and 5–10 (Group-II). 1, benzene-1,4-diamine; 2, 4-aminophenol; 3, N1,N1,N4,N4-tetramethylbenzene-1,4-diamine; 4, 4-(dimethylamino)phenol; 5, aniline; 6, 4-aminobenzoic acid; 7, pyridine-4-amine; 8, N,N-dimethylaniline; 9, 4-(dimethylamino)benzoic acid; 10, N,N-dimethylpyridine-4-amine. (b) Summary of the multiple targets and the desired effects in vitro and in vivo.
Figure 2
Figure 2. Redox behaviors of 1–10 and vitamin C measured by cyclic voltammetry. (a) Cyclic voltammograms of 1–4 in CH3CN with 1% v/v DMSO. (b) Values of Epa1 and E1/2 at the scan rate of 250 mV/s. aQuasi-reversible redox behavior was indicated for 2. Conditions: [compound] = 1 mM; [TBAPF6] = 100 mM (for supporting electrolyte and reference electrode); [AgNO3] = 10 mM (for reference electrode); N2(g); scan rates = 25, 50, 100, 150, 200, and 250 mV/s; three electrodes: glassy carbon working electrode, Ag/Ag(I) reference electrode, and platinum counter electrode; room temperature.
Figure 3
Figure 3. Scavenging capability of 1–10 and vitamin C against free organic radicals determined by the TEAC assay in cell lysates. The TEAC values are relative to that of an analogue of vitamin E, Trolox (6-hydroxy-2,5,7,8-tetramethlychroman-2-carboxylic acid). The error bars indicate the standard error from four independent experiments. *TEAC values of 5–10 were not obtained because they showed no measurable capacity to quench free radicals.
Figure 4
Figure 4. Effects of 1–5 on the formation of metal-free or metal-treated Aβ40 aggregates. (a) Scheme of the inhibition experiments. (b–d) Gel/Western blots (an anti-Aβ antibody, 6E10) of the Aβ40 species generated in the (b) absence and (c and d) presence of metal ions. Lanes: (c) Aβ40; (1) Aβ40 + 1; (2) Aβ40 + 2; (3) Aβ40 + 3; (4) Aβ40 + 4; (5) Aβ40 + 5. (e) Quantification of Aβ40 species visualized in the gel by the ImageJ software. The intensity of the gel from the sample was normalized to that from the corresponding control (ISample/IControl). (f) TEM images of the samples obtained from (b) metal-free Aβ40 and Aβ40 with 1 equiv of (c) Cu(II) and (d) Zn(II). Conditions: [Aβ40] = 25 μM; [Cu(II) or Zn(II)] = 12.5, 25, and 50 μM; [compound] = 50 μM; 20 mM HEPES, pH 7.4 [for metal-free or Zn(II)-containing samples] or pH 6.6 [for Cu(II)-added samples], 150 mM NaCl; 37 °C; 24 h; constant agitation. Scale bar = 200 nm.
Figure 5
Figure 5. Analyses of 1’s transformation and interactions with metal-free Aβ40 or Cu(II)-added Aβ40. (a) Oxidative transformation of 1 in the presence of Aβ40 with or without Cu(II) detected by UV–vis spectroscopy. Conditions: [Aβ40] = 25 μM; [Cu(II)] = 25 μM; [1] = 50 μM; 20 mM HEPES, pH 7.4 (for metal-free samples) or pH 6.6 [for Cu(II)-added samples], 150 mM NaCl; 37 °C; 0–24 h; no agitation. (b–d) Interactions of 1 with metal-free Aβ40 and Cu(II)-treated Aβ40 monitored by ESI-MS, ESI-MS2, and MALDI-MS. Aβ40 monomer incubated with 1 in the (b and d) absence and (d) presence of Cu(II) was analyzed by (b) ESI-MS or (d) MALDI-MS. The oxidized Aβ40 and the BQ–Aβ40 adduct are indicated with red and blue circles, respectively. The covalent bond with Aβ40 (green circle) was only observed from 1-treated samples. (c) ESI-MS2 spectrum of the singly oxidized Aβ403+ produced upon addition of 1. Conditions (for ESI-MS studies): [Aβ40] = 50 μM; [1] = 100 μM; 1 mM ammonium acetate, pH 7.4; 37 °C; 24 h; constant agitation. The samples were diluted by 10-fold with ddH2O before injection to the mass spectrometer. Conditions (for MALDI-MS measurements): [Aβ40] = 25 μM; [Cu(II)] = 25 μM; [1] = 50 μM; pH 7.4 (for metal-free samples) or pH 6.6 [for Cu(II)-added samples]; 37 °C; 24 h; constant agitation.
Figure 6
Figure 6. Analysis of the amounts of Aβ species in 1- or BQ-treated 5×FAD mice. (a) Levels of soluble Aβ42, insoluble Aβ42, total Aβ42, and oligomeric Aβ measured in triplicate per sample by ELISA. Soluble phosphate buffered saline (PBS)- and sodium dodecyl sulfate (SDS)-soluble fractions (for soluble Aβ42), formic acid (FA)-soluble fractions (for insoluble Aβ42), and the sum of PBS-, SDS-, and FA-soluble fractions (for total Aβ42) were analyzed. Lanes: (Vehicle) 5×FAD + vehicle; (BQ) 5×FAD + BQ; (1) 5×FAD + 1. (b) Loads of amyloid deposits and plaques in the brain expressed as the percent area of 4G8-immunoreactive deposits or the number of congophilic plaques per mm2 of a region of interest, which was taken from hippocampal (hip), cortical (ctx), and thalamic (tlm) areas. (c) Representative images of 4G8-immunoreactive (1st row) or Congo red-positive (2nd and 3rd rows) amyloid deposits or plaques in hip and ctx (1st and 3rd rows) or tlm (2nd row) regions in the brains of vehicle- (1st column), BQ- (2nd column), or 1-treated (3rd column) 5×FAD mice are shown. Congo red-stained brain sections were also counter-stained with hematoxylin to differentiate the nuclei of neural cells (2nd and 3rd rows). Subiculum (sub), corpus callosum (cc), and fornix (fx). Scale bars = 500 μm (white) or 200 μm (black). The measurements were performed in five sagittal sections taken every 200 μm from midline per animal. Bars denote mean ± standard errors of mean (s.e.m.) (animal numbers; n = 19 for vehicle-treated 5×FAD mice; n = 9 for BQ-treated 5×FAD mice; n = 12 for 1-treated 5×FAD mice). *P < 0.05 or **P < 0.01 by unpaired two-tail t-test.
Figure 7
Figure 7. Measurement of spatial learning and memory improvements in 1- or BQ-administrated 5×FAD mice. (a) Escape latency time daily assessed for 5 days from the day of the 30th compound treatment in the MWM test. From the second training trial to the fifth trial, the latency time became significantly shorter in nontransgenic wild-type mice [WT; P = 0.012 by one-way analysis of variance (ANOVA) with Student–Newman–Keuls post hoc test] or 1-treated 5×FAD mice (1; P = 0.0017) but not in vehicle- (Vehicle; P = 0.054) or BQ-treated (BQ; P = 0.40) 5×FAD mice. (b) After the MWM test, the probe trials were performed in the same water pool without the escape platform. All images present the representative paths of the mice to search for the previous platform location [the small circle area in the gray, northwest (NW) target quadrant] for 60 s (from point S to point E). (c–f) In the probe test, we recorded (c) the path distance to first enter the target quadrant, (d) the latency time to touch the previous location of the platform, (e) the crossing frequency to traverse across the target platform, and (f) the times spent in the target quadrant to search for the platform. Lanes: (WT) wild-type; (Vehicle) 5×FAD + vehicle; (BQ) 5×FAD + BQ; (1) 5×FAD + 1. The statistical comparisons were performed between vehicle-treated 5×FAD and their wild-type littermate mice (*) or between vehicle- and 1-treated 5×FAD mice (#). Bars denote mean ± s.e.m. Animal number: n = 17 for wild-type mice; n = 19 for vehicle-treated 5×FAD mice; n = 9 for BQ-treated 5×FAD mice; n = 12 for 1-treated 5×FAD mice. *,#P < 0.05, **,##P < 0.01, or ***,###P < 0.001 by unpaired two-tail t-test.
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- 10Martins, R. N.; Villemagne, V.; Sohrabi, H. R.; Chatterjee, P.; Shah, T. M.; Verdile, G.; Fraser, P.; Taddei, K.; Gupta, V. B.; Rainey-Smith, S. R.; Hone, E.; Pedrini, S.; Lim, W. L.; Martins, I.; Frost, S.; Gupta, S.; O’Bryant, S.; Rembach, A.; Ames, D.; Ellis, K.; Fuller, S. J.; Brown, B.; Gardener, S. L.; Fernando, B.; Bharadwaj, P.; Burnham, S.; Laws, S. M.; Barron, A. M.; Goozee, K.; Wahjoepramono, E. J.; Asih, P. R.; Doecke, J. D.; Salvado, O.; Bush, A. I.; Rowe, C. C.; Gandy, S. E.; Masters, C. L. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies. J. Alzheimer's Dis. 2018, 62, 965– 992, DOI: 10.3233/JAD-17114510https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXks1ygsrc%253D&md5=4763da2ac699e78b6800d3976a6af52bAlzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort StudiesMartins, Ralph N.; Villemagne, Victor; Sohrabi, Hamid R.; Chatterjee, Pratishtha; Shah, Tejal M.; Verdile, Giuseppe; Fraser, Paul; Taddei, Kevin; Gupta, Veer B.; Rainey-Smith, Stephanie R.; Hone, Eugene; Pedrini, Steve; Lim, Wei Ling; Martins, Ian; Frost, Shaun; Gupta, Sunil; O'Bryant, Sid; Rembach, Alan; Ames, David; Ellis, Kathryn; Fuller, Stephanie J.; Brown, Belinda; Gardener, Samantha L.; Fernando, Binosha; Bharadwaj, Prashant; Burnham, Samantha; Laws, Simon M.; Barron, Anna M.; Goozee, Kathryn; Wahjoepramono, Eka J.; Asih, Prita R.; Doecke, James D.; Salvado, Olivier; Bush, Ashley I.; Rowe, Christopher C.; Gandy, Samuel E.; Masters, Colin L.Journal of Alzheimer's Disease (2018), 62 (3), 965-992CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Worldwide there are over 46 million people living with dementia, and this no. is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extd. from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clin. AD using PET amyloid tracers, a method now serving as the gold std. for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E .vepsiln.4, as well as better understanding the role of lifestyle factors particularly diet, phys. activity and sleep to cognitive decline and the accumulation of cerebral Aβ.
- 11Mecocci, P.; Polidori, M. C. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim. Biophys. Acta, Mol. Basis Dis. 2012, 1822, 631– 638, DOI: 10.1016/j.bbadis.2011.10.00611https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1GrtbY%253D&md5=516667c4e9e8840318acc5f92cf325a6Antioxidant clinical trials in mild cognitive impairment and Alzheimer's diseaseMecocci, Patrizia; Polidori, Maria CristinaBiochimica et Biophysica Acta, Molecular Basis of Disease (2012), 1822 (5), 631-638CODEN: BBADEX; ISSN:0925-4439. (Elsevier B. V.)A review. Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing no. of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclin. phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clin. trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clin. trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clin. benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
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- 14Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018, 14, 450– 464, DOI: 10.1016/j.redox.2017.10.01414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslans73L&md5=f61600ab9e355cd49838961d26de5c4fOxidative stress and the amyloid beta peptide in Alzheimer's diseaseCheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F.Redox Biology (2018), 14 (), 450-464CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)A review. Oxidative stress is known to play an important role in the pathogenesis of a no. of diseases. In particular, it is linked to the etiol. of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathol. hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the prodn. of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding mol. (proteins, lipids, ...). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding mols. in terms of oxidative damage. In addn., the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS prodn. are discussed, along with both in vitro and in vivo oxidn. of the Aβ peptide, at the mol. level.
- 15Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297, 353– 356, DOI: 10.1126/science.107299415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Cju7s%253D&md5=f7b8db1bc6f13e85f887b73f3042e86eThe amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeuticsHardy, John; Selkoe, Dennis J.Science (Washington, DC, United States) (2002), 297 (5580), 353-356CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review. It has been more than 10 yr since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles contg. tau protein, is proposed to result from an imbalance between Aβ prodn. and Aβ clearance.
- 16Barnham, K. J.; Bush, A. I. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem. Soc. Rev. 2014, 43, 6727– 6749, DOI: 10.1039/C4CS00138A16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12msLrK&md5=59061ef7a1462599c78d5ec47fb3ceb0Biological metals and metal-targeting compounds in major neurodegenerative diseasesBarnham, Kevin J.; Bush, Ashley I.Chemical Society Reviews (2014), 43 (19), 6727-6749CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Multiple abnormalities occur in the homeostasis of essential endogenous brain biometals in age-related neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As a result, metals both accumulate in microscopic proteinopathies, and can be deficient in cells or cellular compartments. Therefore, bulk measurement of metal content in brain tissue samples reveal only the "tip of the iceberg", with most of the important changes occurring on a microscopic and biochem. level. Each of the major proteins implicated in these disorders interacts with biol. transition metals. Tau and the amyloid protein precursor have important roles in normal neuronal iron homeostasis. Changes in metal distribution, cellular deficiencies, or sequestration in proteinopathies all present abnormalities that can be cor. in animal models by small mols. These biochem. targets are more complex than the simple excess of metals that are targeted by chelators. In this review we illustrate some of the richness in the science that has developed in the study of metals in neurodegeneration, and explore its novel pharmacol.
- 17Folk, D. S.; Franz, K. J. A prochelator activated by β-secretase inhibits Aβ aggregation and suppresses copper-induced reactive oxygen species formation. J. Am. Chem. Soc. 2010, 132, 4994– 4995, DOI: 10.1021/ja100943r17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjsFSlsb8%253D&md5=7fc9ab4fec5cc285d06904eb241bc643A Prochelator Activated by β-Secretase Inhibits Aβ Aggregation and Suppresses Copper-Induced Reactive Oxygen Species FormationFolk, Drew S.; Franz, Katherine J.Journal of the American Chemical Society (2010), 132 (14), 4994-4995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The intersection of the amyloid cascade hypothesis and the implication of metal ions in Alzheimer's disease progression has sparked an interest in using metal-binding compds. as potential therapeutic agents. In the present work, we describe a prochelator SWH that is enzymically activated by β-secretase to produce a high affinity copper chelator CP. Because β-secretase is responsible for the amyloidogenic processing of the amyloid precursor protein, this prochelator strategy imparts disease specificity toward copper chelation not possible with general metal chelators. Furthermore, once activated, CP efficiently sequesters copper from amyloid-β, prevents and disassembles copper-induced amyloid-β aggregation, and diminishes copper-promoted reactive oxygen species formation.
- 18Lincoln, K. M.; Richardson, T. E.; Rutter, L.; Gonzalez, P.; Simpkins, J. W.; Green, K. N. An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation. ACS Chem. Neurosci. 2012, 3, 919– 927, DOI: 10.1021/cn300060v18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ymsr%252FF&md5=420f45288c46cef2b3953e3c4c3f955bAn N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid DisaggregationLincoln, Kimberly M.; Richardson, Timothy E.; Rutter, Lauren; Gonzalez, Paulina; Simpkins, James W.; Green, Kayla N.ACS Chemical Neuroscience (2012), 3 (11), 919-927CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (Aβ) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and SEM imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu2+ induced AB1-40 aggregation. The pyridine backbone of 1 engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this arom. feature. Finally, 1 prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using d. functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity obsd.
- 19Lee, S.; Zheng, X.; Krishnamoorthy, J.; Savelieff, M. G.; Park, H. M.; Brender, J. R.; Kim, J. H.; Derrick, J. S.; Kochi, A.; Lee, H. J.; Kim, C.; Ramamoorthy, A.; Bowers, M. T.; Lim, M. H. Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer’s disease. J. Am. Chem. Soc. 2014, 136, 299– 310, DOI: 10.1021/ja409801p19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVWnsL3I&md5=808d231c5dca419453c176265d16bfe3Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer's DiseaseLee, Sanghyun; Zheng, Xueyun; Krishnamoorthy, Janarthanan; Savelieff, Masha G.; Park, Hyun Min; Brender, Jeffrey R.; Kim, Jin Hoon; Derrick, Jeffrey S.; Kochi, Akiko; Lee, Hyuck Jin; Kim, Cheal; Ramamoorthy, Ayyalusamy; Bowers, Michael T.; Lim, Mi HeeJournal of the American Chemical Society (2014), 136 (1), 299-310CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Alzheimer's disease (AD) is characterized by multiple, intertwined pathol. features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. The authors report a novel compd. (ML) prototype of a rationally designed mol. obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single mol. Chem., biochem., ion mobility mass spectrometric, and NMR studies indicate that the compd. ML targets metal-free and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)-phenol (DAP) and (8-aminoquinolin-2-yl)-methanol ) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-sol. and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, the authors demonstrate that a rational structure-based design strategy can generate a small mol. that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.
- 20Gonzalez, P.; da Costa, V. C. P.; Hyde, K.; Wu, Q.; Annunziata, O.; Rizo, J.; Akkaraju, G.; Green, K. N. Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer’s disease. Metallomics 2014, 6, 2072– 2082, DOI: 10.1039/C4MT00161C20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSiu7zN&md5=5ec498b5921b13847ba44dd531801c70Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's diseaseGonzalez, Paulina; da Costa, Viviana C. P.; Hyde, Kimberly; Wu, Qiong; Annunziata, Onofrio; Rizo, Josep; Akkaraju, Giridhar; Green, Kayla N.Metallomics (2014), 6 (11), 2072-2082CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the prodn. of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small mol., lipoic cyclen, which has been designed to target mol. features of AD. This construct utilizes the biol. compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused mol. as a potential strategy for the development of lead compds. for the treatment of neurodegenerative disorders.
- 21Derrick, J. S.; Lim, M. H. Tools of the trade: investigations into design strategies of small molecules to target components in Alzheimer’s disease. ChemBioChem 2015, 16, 887– 898, DOI: 10.1002/cbic.20140271821https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVWrtbk%253D&md5=7d41b07f4f349aafed8bd2dee2a164abTools of the Trade: Investigations into Design Strategies of Small Molecules to Target Components in Alzheimer's DiseaseDerrick, Jeffrey S.; Lim, Mi HeeChemBioChem (2015), 16 (6), 887-898CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The growing prevalence of Alzheimer's disease (AD) has warranted the development of effective therapeutic methods. Current available drugs for AD (i.e., acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists) have only offered brief symptomatic relief. Considering that the nos. affected by AD are projected to substantially rise, long-term strategies are urgently needed. The multiple series of small mols. to combat AD have been expanded, with current methods taking aim at factors, such as misfolded protein accumulation, metal ion dyshomeostasis, and oxidative stress. This concept article focuses on describing the design of compds. to target various components of AD and underlining recent advances that have been made.
- 22Derrick, J. S.; Kerr, R. A.; Nam, Y.; Oh, S. B.; Lee, H. J.; Earnest, K. G.; Suh, N.; Peck, K. L.; Ozbil, M.; Korshavn, K. J.; Ramamoorthy, A.; Prabhakar, R.; Merino, E. J.; Shearer, J.; Lee, J.-Y.; Ruotolo, B. T.; Lim, M. H. A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: in vitro and in vivo efficacy and molecular mechanisms. J. Am. Chem. Soc. 2015, 137, 14785– 14797, DOI: 10.1021/jacs.5b1004322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVGmt7fL&md5=f95a3cad02c9a2752ea0389e69820943A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular MechanismsDerrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; Oh, Shin Bi; Lee, Hyuck Jin; Earnest, Kaylin G.; Suh, Nayoung; Peck, Kristy L.; Ozbil, Mehmet; Korshavn, Kyle J.; Ramamoorthy, Ayyalusamy; Prabhakar, Rajeev; Merino, Edward J.; Shearer, Jason; Lee, Joo-Yong; Ruotolo, Brandon T.; Lim, Mi HeeJournal of the American Chemical Society (2015), 137 (46), 14785-14797CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Chem. reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, the authors report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small mol. (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addn., for the first time, biochem., biophys., and mol. dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small mol. (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramol. crosslinking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathol. and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small mol. (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of sol. Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, the authors' in vitro and in vivo studies of DMPD toward Aβ with the first mol.-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compds. without the structural complexity as next-generation chem. tools for amyloid management.
- 23Beck, M. W.; Derrick, J. S.; Kerr, R. A.; Oh, S. B.; Cho, W. J.; Lee, S. J. C.; Ji, Y.; Han, J.; Tehrani, Z. A.; Suh, N.; Kim, S.; Larsen, S. D.; Kim, K. S.; Lee, J.-Y.; Ruotolo, B. T.; Lim, M. H. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease. Nat. Commun. 2016, 7, 13115, DOI: 10.1038/ncomms1311523https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSitb3P&md5=c92d00abedc661f493e496ba21f20879Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's diseaseBeck, Michael W.; Derrick, Jeffrey S.; Kerr, Richard A.; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C.; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D.; Kim, Kwang S.; Lee, Joo-Yong; Ruotolo, Brandon T.; Lim, Mi HeeNature Communications (2016), 7 (), 13115CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted etiol. Because of the lack of chem. tools to identify pathol. factors, investigations into AD pathogenesis have also been insubstantial. Here we report chem. regulators that demonstrate distinct specificity towards targets linked to AD pathol., including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free org. radicals. We obtained these chem. regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small mols. for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathol., and improving cognitive deficits. Our chem. tools show promise for deciphering AD pathogenesis and discovering effective drugs.
- 24Jones, M. R.; Mathieu, E.; Dyrager, C.; Faissner, S.; Vaillancourt, Z.; Korshavn, K. J.; Lim, M. H.; Ramamoorthy, A.; Wee Yong, V.; Tsutsui, S.; Stys, P. K.; Storr, T. Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer’s disease. Chem. Sci. 2017, 8, 5636– 5643, DOI: 10.1039/C7SC01269A24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1yitL0%253D&md5=c70d2f489b8d762cfc246c0dc1428f1aMulti-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's diseaseJones, Michael R.; Mathieu, Emilie; Dyrager, Christine; Faissner, Simon; Vaillancourt, Zavier; Korshavn, Kyle J.; Lim, Mi Hee; Ramamoorthy, Ayyalusamy; Wee Yong, V.; Tsutsui, Shigeki; Stys, Peter K.; Storr, TimChemical Science (2017), 8 (8), 5636-5643CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aβ peptide oligomers are all considered to contribute to the etiol. of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aβ peptide and modulation of Aβ peptide aggregation, and the ability to limit Aβ1-42-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated via click chem., highlights the influence of R-group modification on ligand-Aβ interactions and neuroprotective effects. Overall, this study demonstrates that the phenol-triazole ligand scaffold can target multiple factors assocd. with AD, thus warranting further therapeutic development.
- 25Han, J.; Lee, H. J.; Kim, K. Y.; Lee, S. J. C.; Suh, J.-M.; Cho, J.; Chae, J.; Lim, M. H. Tuning structures and properties for developing novel chemical tools toward distinct pathogenic elements in Alzheimer’s disease. ACS Chem. Neurosci. 2018, 9, 800– 808, DOI: 10.1021/acschemneuro.7b0045425https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVCjsLfI&md5=3384d8f9a25a4f323b250258f516ef22Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's DiseaseHan, Jiyeon; Lee, Hyuck Jin; Kim, Kyu Yeon; Lee, Shin Jung C.; Suh, Jong-Min; Cho, Jaeheung; Chae, Junghyun; Lim, Mi HeeACS Chemical Neuroscience (2018), 9 (4), 800-808CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal-Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathol. elements in AD, chem. tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathol. factors, however, it has been challenging to invent such chem. tools. Herein, the authors report novel small mols. as chem. tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chem. properties (e.g., oxidn. potentials) of the mols. and their coverage of reactivities toward the pathol. targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among the three compds., I with the lowest oxidn. potential is able to noticeably modify the aggregation of both metal-free Aβ and metal-Aβ, as well as scavenge free radicals. Compd. II with the moderate oxidn. potential significantly alters the aggregation of Cu(II)-Aβ42. The hardly oxidizable compd., III, relative to I and II, indicates no noticeable interactions with all pathogenic factors, including metal-free Aβ, metal-Aβ, and free radicals. Overall, the studies demonstrate that the design of small mols. as chem. tools able to control distinct pathol. components could be achieved via fine-tuning of structures and properties.
- 26Gomes, L. M. F.; Mahammed, A.; Prosser, K. E.; Smith, J. R.; Silverman, M. A.; Walsby, C. J.; Gross, Z.; Storr, T. A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation. Chem. Sci. 2019, 10, 1634– 1643, DOI: 10.1039/C8SC04660C26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlOku7rF&md5=c81d88ecd31c5145b863db455609060bA catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generationGomes, Luiza M. F.; Mahammed, Atif; Prosser, Kathleen E.; Smith, Jason R.; Silverman, Michael A.; Walsby, Charles J.; Gross, Zeev; Storr, TimChemical Science (2019), 10 (6), 1634-1643CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Alzheimer's disease (AD) is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-beta (Aβ) aggregates. In this work we report the large affinity binding of the iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the Aβ peptide (Kd ∼ 10-7) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(II) ions. Specific findings are that: (a) an Abeta histidine residue binds axially to FeL1; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high mol. wt. peptide aggregates. UV-Vis and ESR (EPR) studies show that although the binding of FeL1 does not influence the Abeta-Cu(II) interaction (Kd 10-10), bound FeL1 still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from Abeta-Cu. Overall, FeL1 is shown to bind to the Abeta-peptide, and modulate peptide aggregation. In addn., FeL1 forms a ternary species with Abeta-Cu(II) and impedes ROS generation, thus showing the promise of discrete metal complexes to limit the toxicity pathways of the Abeta peptide.
- 27Miller, J. J.; Blanchet, A.; Orvain, C.; Nouchikian, L.; Reviriot, Y.; Clarke, R. M.; Martelino, D.; Wilson, D.; Gaiddon, C.; Storr, T. Bifunctional ligand design for modulating mutant p53 aggregation in cancer. Chem. Sci. 2019, 10, 10802– 10814, DOI: 10.1039/C9SC04151F27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFWrs77L&md5=4c927ea13fc06e09a6cdd3666b43545dBifunctional ligand design for modulating mutant p53 aggregation in cancerMiller, Jessica J.; Blanchet, Anais; Orvain, Christophe; Nouchikian, Lucienne; Reviriot, Yasmin; Clarke, Ryan M.; Martelino, Diego; Wilson, Derek; Gaiddon, Christian; Storr, TimChemical Science (2019), 10 (46), 10802-10814CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Protein misfolding and aggregation contributes to development of wide range of diseases. P53 mutations also frequently result in alteration or loss of zinc at DNA-binding site, which increases aggregation via nucleation with zinc-bound p53. We designed two novel bifunctional ligands, LI and LH, to modulate mutant p53 aggregation and restore zinc binding using a metallochaperone approach. Incorporation of iodine function in LI resulted in modulation of mutant p53 aggregation, both in recombinant and cellular environments. Native mass spectrometry shows a protein-ligand interaction for LI, as opposed to LH, which is hypothesized to lead to p53 aggregation profile. Incorporation of a di-2-picolylamine binding unit into the ligand design provided efficient intracellular zinc uptake, resulting in metallochaperone capability for both LI and LH. The ability of LI to reduce mutant p53 aggregation results in increased restoration of p53 transcriptional function and mediates both caspase-dependent and -independent cell death pathways. We further demonstrate that LI exhibits minimal toxicity in non-cancerous organoids, and that it is well tolerated in mice. Iodination of our ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation and highlights LI as a suitable candidate for comprehensive in vivo anticancer preclin. evaluations.
- 28Beck, M. W.; Derrick, J. S.; Suh, J.-M.; Kim, M.; Korshavn, K. J.; Kerr, R. A.; Cho, W. J.; Larsen, S. D.; Ruotolo, B. T.; Ramamoorthy, A.; Lim, M. H. Minor structural variations of small molecules tune regulatory activities toward pathological factors in Alzheimer’s disease. ChemMedChem 2017, 12, 1828– 1838, DOI: 10.1002/cmdc.20170045628https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Wrur%252FM&md5=9d621ac940142ae6f6c35edb47a8a490Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's DiseaseBeck, Michael W.; Derrick, Jeffrey S.; Suh, Jong-Min; Kim, Mingeun; Korshavn, Kyle J.; Kerr, Richard A.; Cho, Woo Jong; Larsen, Scott D.; Ruotolo, Brandon T.; Ramamoorthy, Ayyalusamy; Lim, Mi HeeChemMedChem (2017), 12 (22), 1828-1838CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Chem. tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chem. tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chem. tool were found to drastically det. the tool's reactivities toward multiple pathol. facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small mols. vary toward different targets as a result of minor structural modifications. These compds. were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aβ, reactive oxygen species (ROS), and free org. radicals. Our results show that although small mols. are structurally similar, they can interact with multiple factors assocd. with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chem. tools capable of regulating individual or interrelated pathol. features in AD.
- 29Lauw, S. J. L.; Xu, X.; Webster, R. D. Primary-colored electrochromism of 1,4-phenylenediamines. ChemPlusChem 2015, 80, 1288– 1297, DOI: 10.1002/cplu.20150024729https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOrtbnM&md5=182273d12b49ab26e39690c1a29b68f3Primary-Colored Electrochromism of 1,4-PhenylenediaminesLauw, Sherman J. L.; Xu, Xiuhui; Webster, Richard D.ChemPlusChem (2015), 80 (8), 1288-1297CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)Ten 1,4-phenylenediamines were studied using electrochem. techniques (voltammetry and controlled potential electrolysis) and UV/Vis spectroscopy under ambient conditions. All compds. demonstrated vibrant color changes upon one-electron electrochem. oxidn. in acetonitrile, with most displaying a primary color (red, green, blue, or yellow) in their oxidized state. The four electrochromes that exhibited the most intense color changes were examd. by using a gold micromesh electrode laminated inside a polymer film to det. their electrochromic properties in soln. (contrast ratios, chromatic efficiency, and cycle life). Their colored radical cations were also characterized by ESR spectroscopy as well as monitored for color retention over a period of 24 h. Notably, only relatively small potentials were required to initiate the chromatic changes and the oxidized forms of the compds. were long-lived and unaffected by atm. oxygen or moisture.
- 30Fan, Y.; Liu, J.-H.; Yang, C.-P.; Yu, M.; Liu, P. Graphene–polyaniline composite film modified electrode for voltammetric determination of 4-aminophenol. Sens. Actuators, B 2011, 157, 669– 674, DOI: 10.1016/j.snb.2011.05.05330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvF2mtrc%253D&md5=5d2919bc8425a2296a82cd1a10176a66Graphene-polyaniline composite film modified electrode for voltammetric determination of 4-aminophenolFan, Yang; Liu, Jin-Hang; Yang, Chun-Peng; Yu, Meng; Liu, PengSensors and Actuators, B: Chemical (2011), 157 (2), 669-674CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)An electrochem. sensor based on graphene-polyaniline (GR-PANI) nanocomposite for voltammetric detn. of 4-aminophenol (4-AP) is presented. The electrochem. behavior of 4-AP at the GR-PANI composite film modified glassy carbon electrode (GCE) was investigated by cyclic voltammetry. 4-AP exhibits enhanced voltammetric response at GR-PANI modified GCE. This electrochem. sensor shows a favorable anal. performance for 4-AP detection with a detection limit of 6.5 × 10-8 M and high sensitivity of 604.2 μA mM-1. Moreover, 4-AP and paracetamol can be detected simultaneously without interference of each other in a large dynamic range.
- 31Marcus, M. F.; Hawley, M. D. The electrochemical oxidation of p-dimethylaminophenol in aqueous solution. J. Electroanal. Chem. Interfacial Electrochem. 1968, 18, 175– 183, DOI: 10.1016/S0022-0728(68)80172-X31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXkt1CjsLg%253D&md5=8f13adb0104a64a70d4be366c32057efThe electrochemical oxidation of p-dimethylaminophenol in aqueous solutionMarcus, Mark F.; Hawley, M. D.Journal of Electroanalytical Chemistry and Interfacial Electrochemistry (1968), 18 (1-2), 175-83CODEN: JEIEBC; ISSN:0022-0728.The electrochem. behavior of p-dimethylaminophenol (I) as the HCl salt was studied as a function of pH by chronoamperometry and chronopotentiometry by using a carbon paste working electrode and a Pt auxiliary electrode and by controlled-potential electrolysis using a Hg pool working electrode and a salt bridge as auxiliary electrode; for all expts., a S.C.E. was used as reference. McIlvaine buffers were used for pH 3-8 and carbonate buffers for pH 9-10. Cyclic voltammograms of 2mM I in 2M H2SO4 at different scan rates show 2 anodic waves and 1 cathodic wave which suggests that a chem. reaction precedes electron transfer and both of the indicated oxidns. are kinetically controlled; also the 2 electroactive species are in equil. At pH 3, 2-electron oxidn. of I occurs to yield p-N,N-dimethylbenzoquinone imine (II) at 0.4 v. and the redn. of II to I on the cathodic sweep. Controlled-potential electrolysis confirms the 2-electron interpretation. However, after exhaustive electrolysis, a 2nd redn. wave appears due to redn. of benzoquinone. At pH 6-7, 3 cathodic waves are obtained corresponding to redn. of unhydrolyzed II to I, redn. of benzoquinone, and redn. of I and benzoquinone. The latter together with the anodic wave due to formation of 2,4-bis(dimethylamino)phenol by the Michael 1,4-addn. of a hydrolysis product, dimethylamine, to II, forms a 3rd redox couple. The oxidn. of I at pH 6-9 is a 4-electron process which yields 2-dimethylamino-p-benzoquinone. At pH 8, an inflection in the I oxidn. is observed. At pH 9-10, the main oxidn. wave is split due to a 1-electron oxidn. yielding phenoxy radical and then to a 1-electron oxidn. of quinone imine.
- 32McCormick, M. C.; Keijzer, K.; Polavarapu, A.; Schultz, F. A.; Baik, M.-H. Understanding intrinsically irreversible, non-Nernstian, two-electron redox processes: a combined experimental and computational study of the electrochemical activation of platinum(IV) antitumor prodrugs. J. Am. Chem. Soc. 2014, 136, 8992– 9000, DOI: 10.1021/ja502976532https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVOns7Y%253D&md5=b0fc997db4db81cbee546fbb8e08c4f5Understanding intrinsically irreversible, non-Nernstian, two-electron redox processes: a combined experimental and computational study of the electrochemical activation of platinum(IV) antitumor prodrugsMcCormick, Meghan C.; Keijzer, Karlijn; Polavarapu, Abhigna; Schultz, Franklin A.; Baik, Mu-HyunJournal of the American Chemical Society (2014), 136 (25), 8992-9000CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Six-coordinate Pt(IV)-complexes are prominent prodrug candidates for the treatment of various cancers where, upon two-electron redn. and loss of two axial ligands, they form more familiar, pharmacol. active four-coordinate Pt(II) drugs. A series of electrochem. expts. coupled with extensive d. functional calcns. has been employed to elucidate the mechanism for the two-electron redn. of PtIV(NH3)2Cl2L2 to PtII(NH3)2Cl2 (L = CH3COO-, 1; L = CHCl2COO-, 2; L = Cl-, 3). A reliable est. for the normal redn. potential Eo is derived for the electrochem. irreversible Pt(IV) redn. and is compared directly to the quantum chem. calcd. redn. potentials. The process of electron transfer and Pt-L bond cleavage is found to occur in a stepwise fashion, suggesting that a metastable six-coordinate Pt(III) intermediate is formed upon addn. of a single electron, and the loss of both axial ligands is assocd. with the second electron transfer. The quantum chem. calcd. redn. potentials are in excellent agreement with exptl. detd. values that are notably more pos. than peak potentials reported previously for 1-3.
- 33Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A. Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 10566– 10571, DOI: 10.1073/pnas.93.20.1056633https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmtVOlsLs%253D&md5=eefa9720687d7c963df75782fcbbb604Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guideMecozzi, Sandro; West, Anthony P., Jr.; Dougherty, Dennis A.Proceedings of the National Academy of Sciences of the United States of America (1996), 93 (20), 10566-10571CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The cation-π interaction is an important, general force for mol. recognition in biol. receptors. Through the sidechains of arom. amino acids, novel binding sites for cationic ligands such as acetylcholine can be constructed. The authors report here a no. of calcns. on prototypical cation-π systems, emphasizing structures of relevance to biol. receptors and prototypical heterocycles of the type often of importance in medicinal chem. Trends in the data can be rationalized using a relatively simple model that emphasizes the electrostatic component of the cation-π interaction. In particular, plots of the electrostatic potential surfaces of the relevant aroms. provide useful guidelines for predicting cation-π interactions in new systems.
- 34Walter, R. I. Substituent effects on the properties of stable aromatic free radicals. The criterion for non-Hammett behavior. J. Am. Chem. Soc. 1966, 88, 1923– 1930, DOI: 10.1021/ja00961a01434https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XhtVensb8%253D&md5=8bb985e9ac14e856bc207e25ab294dc4Substituent effects on the properties of stable aromatic free radicals. The criterion for non-Hammett behaviorWalter, Robert I.Journal of the American Chemical Society (1966), 88 (9), 1923-30CODEN: JACSAT; ISSN:0002-7863.Substitution in the para positions of the aryl groups of the triarylaminum salt and the 1-picryl-2,2-diarylhydrazyl free radicals strongly affects the optical and E.S.R. spectra of these substances. In the aminium salt series, either donor or acceptor substituents alter each type of absorption in the same direction. In the hydrazyl series, donor and acceptor substituents shift each type of absorption in opposite directions. These observations can be interpreted in terms of the contributions of structures which place only an unpaired electron, or either an unpaired electron or an unshared electron pair, on the atom to which is attached the aromatic rings which contain the substituents in the mols. Generalization of these ideas affords a structural basis for predicting the nature of substituent effects in other types of stable free radicals. Those unsubstituted radicals for which one can write both structures G-C6H4-X• with an unpaired electron, and G-C6H4-X• with an unshared electron pair, on the atom para to the site of substitution, belong to class O. Those radicals for which only the first structure can be written for the unsubstituted radical are assigned to class S. Class O (for opposite) radicals exhibit Hammett-like behavior, with donor and acceptor substituents shifting observed properties in opposite directions, but properties of class S (for same) radicals are shifted in the same direction by either donor or acceptor substituents. Known types of stable free radicals are classified on the basis of this structural criterion, and the classifications are shown to be consistent with the available data on these systems.
- 35van den Berg, R.; Haenen, G. R. M. M.; van den Berg, H.; Bast, A. Applicability of an improved Trolox equivalent antioxidant capacity (TEAC) assay for evaluation of antioxidant capacity measurements of mixtures. Food Chem. 1999, 66, 511– 517, DOI: 10.1016/S0308-8146(99)00089-835https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktFWnt7Y%253D&md5=bc6602190f07d7d683c366d77a0c1235Applicability of an improved Trolox equivalent antioxidant capacity (TEAC) assay for evaluation of antioxidant capacity measurements of mixturesVan den Berg, Robin; Haenen, Guido R. M. M.; Van den Berg, Henk; Bast, AaltFood Chemistry (1999), 66 (4), 511-517CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Science Ltd.)The TEAC (Trolox equiv. antioxidant capacity) assay is based on scavenging of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) radical anions (ABTS-). In this report we describe a modification based on pre-generation of the ABTS radical anions with a thermolabile azo compd., 2,2'-azobis(2-amidinopropane)-2HCl (ABAP). This modification makes the assay less susceptible to artifacts, e.g. influence on the radical generation process. For most antioxidants tested, a biphasic reaction pattern was seen, i.e. a fast and slow scavenging rate. We evaluated application of the assay with both lipophilic and hydrophilic compds. with antioxidant capacity. Several org. solvents, compatible with water, were tested with α-tocopherol, quercetin and β-carotene. It was found that the TEACs differed in various solvents. Under standardized conditions additivity of TEACs obtained from individual antioxidants could be demonstrated. This might enable application of the assay for the identification of "unknown" antioxidants.
- 36Rao, P. S.; Hayon, E. Oxidation of aromatic amines and diamines by OH radicals. Formation and ionization constants of amine cation radicals in water. J. Phys. Chem. 1975, 79, 1063– 1066, DOI: 10.1021/j100578a00536https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXkt1Ohtrc%253D&md5=350607f571d0712f2cf46626dbfbe44eOxidation of aromatic amines and diamines by hydroxyl radicals. Formation and ionization constants of amine cation radicals in waterRao, P. S.; Hayon, E.Journal of Physical Chemistry (1975), 79 (11), 1063-6CODEN: JPCHAX; ISSN:0022-3654.The one-electron oxidn. by hydroxyl radicals of arom. amines and diamines in water initially gives radical adducts which decay by 1st-order kinetics and have lifetimes of ∼5-50μ sec. The decay products are cation radicals and are long-lived in the absence of O. The pKa values of the cation radicals are detd.
- 37Benmehdi, H.; Behilil, A.; Memmou, F.; Amrouche, A. Free radical scavenging activity, kinetic behaviour and phytochemical constituents of Aristolochia clematitis L. roots. Arabian J. Chem. 2017, 10, S1402– S1408, DOI: 10.1016/j.arabjc.2013.04.01537https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVymsbc%253D&md5=74113933c9a435b91f74f22605b4bfc5Free radical scavenging activity, kinetic behaviour and phytochemical constituents of Aristolochia clematitis L. rootsBenmehdi, Houcine; Behilil, Asma; Memmou, Faiza; Amrouche, AbdelillahArabian Journal of Chemistry (2017), 10 (Suppl._1), S1402-S1408CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)Nowadays there is an increasing demand of natural antioxidants. Imbalanced prodn. and consumption of reactive oxygen species, lead to many diseases such as cancer, arteriosclerosis and ageing processes. The protective effects of plants have long been attributed to their antioxidant compds., like polyphenols, flavonoids, carotenoids, and vitamins C and E. Therefore, the present study was designed to evaluate the antioxidant activity of tannins and crude methanolic exts. of Aristolochia clematitis L. by two complementary test systems (DPPH free radical scavenging and bioautog. HPTLC). Besides, phytochem. screening was carried out on roots of A. clematitis and showed the presence of tannins, alkaloids and essential oils. High performance thin layer chromatog. (HPTLC) screening provided qual. the antioxidant effect of exts. under study. Furthermore, it was found that the tannins and methanolic crude exts. from A. clematitis had a potent DPPH scavenging potency with IC50 values of 0.196 and 0.142 mg/mL, resp. Besides, the kinetic behavior of DPPH radical scavenging activity of exts. under study allowed us to det. the half life t1/2, time reaction (t) and the remaining DPPH· percent.
- 38Lee, S. J. C.; Nam, E.; Lee, H. J.; Savelieff, M. G.; Lim, M. H. Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors. Chem. Soc. Rev. 2017, 46, 310– 323, DOI: 10.1039/C6CS00731G38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFCisr7F&md5=ce85df9dd5a10a5f0a39a1c97d8c0eabTowards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitorsLee, Shin Jung C.; Nam, Eunju; Lee, Hyuck Jin; Savelieff, Masha G.; Lim, Mi HeeChemical Society Reviews (2017), 46 (2), 310-323CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Alzheimer's disease (AD) is characterized by an imbalance between prodn. and clearance of amyloid-β (Aβ) species. Aβ peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among the various Aβ species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aβ oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers' assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic Aβ oligomers could be a valid approach to regulate Aβ-assocd. toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of Aβ oligomers' assembly, structural properties, and toxicity, along with inhibitors against Aβ aggregation, including oligomerization.
- 39Kotler, S. A.; Walsh, P.; Brender, J. R.; Ramamoorthy, A. Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer’s disease. Chem. Soc. Rev. 2014, 43, 6692– 6700, DOI: 10.1039/C3CS60431D39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsV2mt7nI&md5=2c2a4fbf2b471b4800edfff6872182a3Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer's diseaseKotler, Samuel A.; Walsh, Patrick; Brender, Jeffrey R.; Ramamoorthy, AyyalusamyChemical Society Reviews (2014), 43 (19), 6692-6700CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. The assocn. of the amyloid-β (Aβ) peptide with cellular membranes is hypothesized to be the underlying phenomenon of neurotoxicity in Alzheimer's disease. Misfolding of proteins and peptides, as is the case with Aβ, follows a progression from a monomeric state, through intermediates, ending at long, unbranched amyloid fibers. This tutorial review offers a perspective on the assocn. of toxic Aβ structures with membranes as well as details of membrane-assocd. mechanisms of toxicity.
- 40Smith, D. P.; Ciccotosto, G. D.; Tew, D. J.; Fodero-Tavoletti, M. T.; Johanssen, T.; Masters, C. L.; Barnham, K. J.; Cappai, R. Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer’s disease amyloid-β peptide. Biochemistry 2007, 46, 2881– 2891, DOI: 10.1021/bi062096140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsFOlurg%253D&md5=1398370fb29dac05b0641c8017d91fe3Concentration Dependent Cu2+ Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β PeptideSmith, David P.; Ciccotosto, Giuseppe D.; Tew, Deborah J.; Fodero-Tavoletti, Michelle T.; Johanssen, Timothy; Masters, Colin L.; Barnham, Kevin J.; Cappai, RobertoBiochemistry (2007), 46 (10), 2881-2891CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)The Amyloid β peptide (Aβ) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline assocd. with the disease. Cu2+ ions can induce the de novo aggregation of the Aβ peptide into non-amyloidogenic aggregates and the prodn. of a toxic species. The mechanism by which Cu2+ mediates the change from amyloid material toward Cu2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of Aβ1-42 at neutral pH is governed by the Cu2+:peptide molar ratio. By probing amyloid content and total aggregation, we obsd. a distinct Cu2+ switching effect centered at equimolar Cu2+:peptide ratios. At sub-equimolar Cu2+:peptide molar ratios, Aβ1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu2+:peptide molar ratios, Aβ1-42 forms both small spherical oligomers approx. 10-20 nm in size and large amorphous aggregates. We demonstrate that these insol. aggregates form spontaneously via a sol. species without the presence of an observable lag phase. In seeding expts., the Cu2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu2+ induced aggregates are toxic when compared to Aβ1-42 aged in the absence of Cu2+. Importantly, the formation of dityrosine crosslinked Aβ, by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu2+ induced aggregates. These results define the role Cu2+ plays in modulating the aggregation state and toxicity of Aβ1-42.
- 41Noy, D.; Solomonov, I.; Sinkevich, O.; Arad, T.; Kjaer, K.; Sagi, I. Zinc-amyloid β interactions on a millisecond time-scale stabilize non-fibrillar Alzheimer-related species. J. Am. Chem. Soc. 2008, 130, 1376– 1383, DOI: 10.1021/ja076282l41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXivFyqtw%253D%253D&md5=7f38fc8e05a2a4a26ff324c8e089e4b9Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related SpeciesNoy, Dror; Solomonov, Inna; Sinkevich, Ory; Arad, Talmon; Kjaer, Kristian; Sagi, IritJournal of the American Chemical Society (2008), 130 (4), 1376-1383CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The role of zinc, an essential element for normal brain function, in the pathol. of Alzheimer's disease (AD) is poorly understood. On one hand, physiol. and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid β-protein (Aβ) in senile plaques. On the other hand, levels of extracellular ("free") zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing Aβ aggregation. Remarkably, the release of transient high local concns. of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting Aβ aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concns., immediately interacts with Aβ 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of Aβ fibrils (more benign species) presumably by interfering with the self-assembly process of Aβ. These in vitro results strongly suggest a significant role for zinc pulses in Aβ pathol. We further propose that by interfering with Aβ self-assembly, which leads to insol., non-pathol. fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of mol. pathogens that effectively perturb the self-assembly of benign Aβ fibrils, and stabilize harmful non-fibrillar forms.
- 42Tougu, V.; Karafin, A.; Zovo, K.; Chung, R. S.; Howells, C.; West, A. K.; Palumaa, P. Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1–42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators. J. Neurochem. 2009, 110, 1784– 1795, DOI: 10.1111/j.1471-4159.2009.06269.x42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFOgsrnI&md5=765c41f2d8d34e4380613a3792d44977Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelatorsTougu, Vello; Karafin, Ann; Zovo, Kairit; Chung, Roger S.; Howells, Claire; West, Adrian K.; Palumaa, PeepJournal of Neurochemistry (2009), 110 (6), 1784-1795CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)Aggregation of amyloid-β (Aβ) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Aβ aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Aβ42 fibrillization and initiate formation of non-fibrillar Aβ42 aggregates, and that the inhibitory effect of Zn(II) (IC50 = 1.8 μM) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced Aβ42 aggregation. Moreover, their addn. to preformed aggregates initiated fast Aβ42 fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of Aβ42. H13A and H14A mutations in Aβ42 reduced the inhibitory effect of metal ions, whereas an H6A mutation had no significant impact. We suggest that metal binding by H13 and H14 prevents the formation of a cross-β core structure within region 10-23 of the amyloid fibril. Cu(II)-Aβ42 aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-Aβ42 aggregates were non-toxic. Disturbed metal homeostasis in the vicinity of zinc-enriched neurons might pre-dispose formation of metal-induced Aβ aggregates, subsequent fibrillization of which can lead to amyloid formation. The mol. background underlying metal-chelating therapies for Alzheimer's disease is discussed in this light.
- 43Pedersen, J. T.; Ostergaard, J.; Rozlosnik, N.; Gammelgaard, B.; Heegaard, N. H. H. Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloid-β peptides. J. Biol. Chem. 2011, 286, 26952– 26963, DOI: 10.1074/jbc.M111.22086343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpt1Krs7Y%253D&md5=33d3e04c0d770c42c222ea1da6fc2e5dCu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β PeptidesPedersen, Jeppe T.; Oestergaard, Jesper; Rozlosnik, Noemi; Gammelgaard, Bente; Heegaard, Niels H. H.Journal of Biological Chemistry (2011), 286 (30), 26952-26963, S26952/1-S26952/12CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-β (Aβ) peptide. Elucidating the underlying Cu(II)-induced Aβ aggregation is paramount for understanding the role of Cu(II) in the pathol. of Alzheimer disease. The aim of this study was to characterize the qual. and quant. influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphol. of Aβ1-40 using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):Aβ ratio in soln. has a major influence on (i) the aggregation kinetics/mechanism of Aβ, because three different kinetic scenarios were obsd. depending on the Cu(II):Aβ ratio; (ii) the metal:peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):Aβ ratio; and (iii) the morphol. of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):Aβ ratios. We obsd. dynamic morphol. changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphol. end point independent on the Cu(II) concn. Expts. with Aβ1-42 were compatible with the conclusions for Aβ1-40 even though the low soly. of Aβ1-42 precluded examn. under the same conditions as for the Aβ1-40. Expts. with Aβ1-16 and Aβ1-28 showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced Aβ aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of Aβ1-40 depending on the Cu(II):Aβ ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-assocd. aggregation or toxicity in Alzheimer disease.
- 44Felice, F. G. D.; Vieira, M. N. N.; Saraiva, L. M.; Figueroa-villar, J. D.; Garcia-abreu, J.; Liu, R.; Chang, L.; Klein, W. L.; Ferreira, S. T. Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aβ oligomerization. FASEB J. 2004, 18, 1366– 1372, DOI: 10.1096/fj.04-1764comThere is no corresponding record for this reference.
- 45Meek, A. R.; Simms, G. A.; Weaver, D. F. In silico search for an endogenous anti-Alzheimer’s molecule — Screening amino acid metabolic pathways. Can. J. Chem. 2012, 90, 865– 873, DOI: 10.1139/v2012-07445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1eiurfE&md5=2d47d8c3b97fb06ad3f185c41c7c9d14In silico search for an endogenous anti-Alzheimer's molecule - Screening amino acid metabolic pathwaysMeek, Autumn R.; Simms, Gordon A.; Weaver, Donald F.Canadian Journal of Chemistry (2012), 90 (10), 865-873CODEN: CJCHAG; ISSN:0008-4042. (Canadian Science Publishing)Alzheimer's disease (AD) is a neurodegenerative disorder arising from abnormal aggregation of β-amyloid (Aβ) and progressing at different rates from person to person. There may exist endogenous compds. within the brain that playa role in inhibiting aggregation. We have devised a unique in silico screening strategy of endogenous mols. within the human brain, with special emphasis on amino acid metabolic pathways, to identify compds. with the potential to inhibit Aβ aggregation. Metabolites of tryptophan were computationally identified through this screening as potential therapeutics and were optimized via mol. modeling to det. their capacity to bind to Aβ. The most successful mol. identified was 3-hydroxyanthranilic acid (3-HAA). This endogenous mol. was then computationally explored to design novel analogs of 3-HAA with the goal of improving Aβ anti-aggregant activity. These combined in silico methods of screening, identifying, and successfully "analoguing" an endogenous mol. of the brain as an AD therapeutic has yielded pos. results and a novel approach to computer-aided drug design.
- 46Chung, Y.-C.; Su, Y. O. Effects of phenyl- and methyl-substituents on p-phenylenediamine, an electrochemical and spectral study. J. Chin. Chem. Soc. 2009, 56, 493– 503, DOI: 10.1002/jccs.20090007446https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVKmt7zO&md5=9de4094ec3a35e9f5036d4de85970cf5Effects of phenyl- and methyl-substituents on p-phenylenediamine, an electrochemical and spectral studyChung, Yi-Chun; Su, Yuhlong OliverJournal of the Chinese Chemical Society (Taipei, Taiwan) (2009), 56 (3), 493-503CODEN: JCCTAC; ISSN:0009-4536. (Chinese Chemical Society)Two series of substituted p-phenylenediamines have been studied for their electronic effects on redox potential and spectral properties. P-Phenylenediamines and N,N,N',N'-tetramethyl-p-phenylenediamine substituted with different nos. of Ph groups have been synthesized and their cyclic voltammograms have been obtained. The correlation between the substituent no. and the redox potential appears linear. The slope reflects the additive effect of electron-donating Me and electron-withdrawing Ph groups. The absorption spectra of the cation radicals indicate that phenyl-substituted ones have broad intervalence-charge transfer bands. The p-phenylenediamines exhibit different properties from triphenylamines in that the oxidized forms are more stable in CH3CN then those in CH2Cl2. Some of the cation radicals or dications could undergo follow-up chem. reactions and form products that are more easily oxidized.
- 47Bai, Y.-H.; Li, J.-Y.; Zhu, Y.-h.; Xu, J.-J.; Chen, H.-Y. Selective detection of p-phenylenediamine in hair dyes based on a special CE mechanism using MnO2 nanowires. Electroanalysis 2010, 22, 1239– 1247, DOI: 10.1002/elan.20090057647https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvVGms7k%253D&md5=c921f894cc3ebddab4ecb7ec97fa7eacSelective Detection of p-Phenylenediamine in Hair Dyes Based on a Special CE Mechanism Using MnO2 NanowiresBai, Yu-Hui; Li, Jin-Yi; Zhu, Yu-hua; Xu, Jing-Juan; Chen, Hong-YuanElectroanalysis (2010), 22 (11), 1239-1247CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)We report a novel approach for selective detn. of p-phenylenediamine in hair dyes using β-MnO2 nanowires modified glassy carbon (GC) electrodes through an electrochem. co-deposition process with chitosan hydrogel. A special CE (chem. reaction and electron transfer) process on the surface of β-MnO2 nanowires modified GC electrode is proposed and proved by cyclic voltammetry and UV-Vis spectroscopy in the presence of p-phenylenediamine. P-Phenylenediamine can react with MnO2 nanowires to produce diimine and the equil. of the 2-electron and 2-proton redox process of p-phenylenediamine on the electrode is changed, and consequently the reductive current is enhanced significantly. At a const. potential of 0 V vs. SCE, other main components of hair dyes including o-, m-phenylenediamine, catechol, resorcinol, and p-dihydroxybenzene do not interfere in the detn. of p-phenylenediamine in the amperometric measurement because of their much lower chem. reaction activities with MnO2 nanowires. It shows a detn. range of 0.2-150 μM and a low detection limit of 50 nM to response p-phenylenediamine. This modified electrode is successfully used to analyze the amt. of p-phenylenediamine in hair dyes without presepn. procedures.
- 48Meyer, A.; Fischer, K. Oxidative transformation processes and products of para-phenylenediamine (PPD) and para-toluenediamine (PTD)—a review. Environ. Sci. Eur. 2015, 27, 11– 26, DOI: 10.1186/s12302-015-0044-7There is no corresponding record for this reference.
- 49Lerner, L. Identity of a purple dye formed by peroxidic oxidation of p-aminophenol at low pH. J. Phys. Chem. A 2011, 115, 9901– 9910, DOI: 10.1021/jp204580649https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVagsLzM&md5=7d9544a9310e7726b970b42dc567d1bbIdentity of a Purple Dye Formed by Peroxidic Oxidation of p-Aminophenol at Low pHLerner, L.Journal of Physical Chemistry A (2011), 115 (35), 9901-9910CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)The structure of a colored intermediate commonly formed in the oxidn. of p-aminophenol at low pH is established by anal. of 1H NMR and UV-vis spectra, kinetics, and mol. modeling, following a new method for synthesizing the dye in high concns. The chromogen is shown to consist of two compds. with absorption maxima at 540-560 and 375-385 nm. The 2,6-di-Me and 3,5-di-Me analogs of p-aminophenol are found to undergo N- rather than C-substitution under similar conditions.
- 50Eyer, P.; Lengfelder, E. Radical formation during autoxidation of 4-dimethylaminophenol and some properties of the reaction products. Biochem. Pharmacol. 1984, 33, 1005– 1013, DOI: 10.1016/0006-2952(84)90507-050https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXkvVGjtrs%253D&md5=a2e895d42d40c90eb0a6ec33c866ff63Radical formation during autoxidation of 4-dimethylaminophenol and some properties of the reaction productsEyer, P.; Lengfelder, E.Biochemical Pharmacology (1984), 33 (7), 1005-13CODEN: BCPCA6; ISSN:0006-2952.4-Dimethylaminophenol (I) [619-60-3], after i.v. injection, rapidly formed ferriHb and was successfully used in the treatment of cyanide poisoning. Since I produced many equiv. of ferriHb, it was of interest to obtain further insight into this catalytic process. I autoxidized readily at pH regions above neutrality, a process which was markedly accelerated by oxyHb. The resulting red-colored product was identified as 4-(N,N-dimethylamino)phenoxyl (II) [19052-61-0]. II was also produced by pulse radiolysis and oxidn. with K ferricyanide. II was quite unstable and decayed in a pseudo-1st order reaction with the formation of p-benzoquinone [106-51-4] and dimethylamine [124-40-3]. This obsd. decay rate was identical with the rate of hydrolysis of N-dimethylquinonimine [619-60-3]. When a soln. contg. II was extd. with ether, half the stoichiometric amt. of I was recovered. Hence, it was apparent that II decayed by disproportionation yielding I and N,N-dimethylquinonimine. The latter product then quickly hydrolyzed. The equil. of this disproportionation reaction was far towards the radical side, and the pseudo-1st order hydrolysis controlled the radical decay rate. p-Benzoquinone rapidly reacted with I with the formation of II and the semiquinone radical [20217-26-9]. Thus, the autocatalytic II formation during autoxidn. of I. I was not oxidized by H2O2 or O, but II was rapidly reduced by O. In addn., II was quickly reduced by NAD(P)H [53-57-6] or GSH [70-18-8] with the formation of NAD(P) [53-59-8] or GSSG [27025-41-8]. Since I was also able to reduce 2 equiv of ferriHb (provided that the ferroHb produced is trapped by CO) electrophilic addn. reactions of II seem unimportant in contrast to N,N-dimethylquinonimine. Hence, during the catalytic ferriHb formation, I is oxidized by O which is activated by Hb, and II oxidizes ferroHb. This catalytic process is terminated by covalent binding of N,N-dimethylquinonimine to SH groups of Hb (and GSH in red cells).
- 51Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 2009, 30, 2785– 2791, DOI: 10.1002/jcc.2125651https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1GitrnK&md5=679ce22fc50e9291c9aa16e7a1855845AutoDock and AutoDockTools: Automated docking with selective receptor flexibilityMorris, Garrett M.; Huey, Ruth; Lindstrom, William; Sanner, Michel F.; Belew, Richard K.; Goodsell, David S.; Olson, Arthur J.Journal of Computational Chemistry (2009), 30 (16), 2785-2791CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking expt. with 188 diverse ligand-protein complexes and a cross-docking expt. using flexible sidechains in 87 HIV protease complexes. We also report its utility in anal. of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009.
- 52Vivekanandan, S.; Brender, J. R.; Lee, S. Y.; Ramamoorthy, A. A partially folded structure of amyloid-beta(1–40) in an aqueous environment. Biochem. Biophys. Res. Commun. 2011, 411, 312– 316, DOI: 10.1016/j.bbrc.2011.06.13352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXps1arsrs%253D&md5=dcaf756dcb5b5fcdc484d7f9596271bfA partially folded structure of amyloid-beta(1-40) in an aqueous environmentVivekanandan, Subramanian; Brender, Jeffrey R.; Lee, Shirley Y.; Ramamoorthy, AyyalusamyBiochemical and Biophysical Research Communications (2011), 411 (2), 312-316CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Aggregation of the Aβ1-40 peptide is linked to the development of extracellular plaques characteristic of Alzheimer's disease. While previous studies commonly show the Aβ1-40 is largely unstructured in soln., we show that Aβ1-40 can adopt a compact, partially folded structure. In this structure (PDB ID: 2LFM), the central hydrophobic region of the peptide forms a 310 helix from H13 to D23 and the N- and C-termini collapse against the helix due to the clustering of hydrophobic residues. Helical intermediates have been predicted to be crucial on-pathway intermediates in amyloid fibrillogenesis, and the structure presented here presents a new target for investigation of early events in Aβ1-40 fibrillogenesis.
- 53Vogt, W. Oxidation of methionyl residues in proteins: tools, targets, and reversal. Free Radical Biol. Med. 1995, 18, 93– 105, DOI: 10.1016/0891-5849(94)00158-G53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjtVequ7g%253D&md5=b046a8d4e8b32282f3b98a278fc970f3Oxidation of methionyl residues in proteins: tools, targets, and reversalVogt, WaltherFree Radical Biology & Medicine (1995), 18 (1), 93-105CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)A review with 136 refs. Methionine (Met) is one of the most readily oxidized amino acid constituents of proteins. It is attacked by H2O2, hydroxyl radicals, hypochlorite, chloramines, and peroxynitrite, all these oxidants being produced in biol. systems. The oxidn. product, Met sulfoxide, can be reduced back to Met by Met sulfoxide reductase. Numerous proteins lose functional activity by Met oxidn. However, functional activation of proteins by Met oxidn. has also been obsd. Functional changes by Met oxidn. in a given protein appear to have pathophysiol. significance in some cases. Considering the reversibility of Met oxidn. and the functional changes assocd. with the oxidn., it seems possible that Met oxidn./redn. in proteins may be one means to control homeostasis in biologicals systems.
- 54Davies, M. J. Protein oxidation and peroxidation. Biochem. J. 2016, 473, 805– 825, DOI: 10.1042/BJ2015122754https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvFClsLg%253D&md5=fd1192a5ac27edeb8583228d439afca9Protein oxidation and peroxidationDavies, Michael J.Biochemical Journal (2016), 473 (7), 805-825CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Proteins are major targets for radicals and two-electron oxidants in biol. systems due to their abundance and high rate consts. for reaction. With highly reactive radicals damage occurs at multiple side-chain and backbone sites. Less reactive species show greater selectivity with regard to the residues targeted and their spatial location. Modification can result in increased side-chain hydrophilicity, side-chain and backbone fragmentation, aggregation via covalent crosslinking or hydrophobic interactions, protein unfolding and altered conformation, altered interactions with biol. partners and modified turnover. In the presence of O2, high yields of peroxyl radicals and peroxides (protein peroxidn.) are formed; the latter account for up to 70% of the initial oxidant flux. Protein peroxides can oxidize both proteins and other targets. One-electron redn. results in addnl. radicals and chain reactions with alcs. and carbonyls as major products; the latter are commonly used markers of protein damage. Direct oxidn. of cysteine (and less commonly) methionine residues is a major reaction; this is typically faster than with H2O2, and results in altered protein activity and function. Unlike H2O2, which is rapidly removed by protective enzymes, protein peroxides are only slowly removed, and catabolism is a major fate. Although turnover of modified proteins by proteasomal and lysosomal enzymes, and other proteases (e.g. mitochondrial Lon), can be efficient, protein hydroperoxides inhibit these pathways and this may contribute to the accumulation of modified proteins in cells. Available evidence supports an assocn. between protein oxidn. and multiple human pathologies, but whether this link is causal remains to be established.
- 55Munday, R. Generation of superoxide radical, hydrogen peroxide and hydroxyl radical during the autoxidation of N,N,N’,N’-tetramethyl-p-phenylenediamine. Chem.-Biol. Interact. 1988, 65, 133– 143, DOI: 10.1016/0009-2797(88)90050-655https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktFylsbc%253D&md5=289aae92f507fa771a331237ca479f3fGeneration of superoxide radical, hydrogen peroxide and hydroxyl radical during the autoxidation of N,N,N',N'-tetramethyl-p-phenylenediamineMunday, R.Chemico-Biological Interactions (1988), 65 (2), 133-43CODEN: CBINA8; ISSN:0009-2797.The autoxidn. of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) at neutral pH generates superoxide radical and H2O2. The rate of formation of these species was increased in the presence of certain Fe and Cu compds.; in the presence of Fe complexed with EDTA, hydroxyl radical was also produced. H2O2 was detected in erythrocytes incubated with TMPD and these cells suffered oxidative damage as reflected by metHb formation and glutathione depletion; the 1-electron oxidn. product of TMPD, Wurster's Blue, was equally effective in producing such changes in erythrocytes. N-Methylated p-phenylenediamines are known to be mutagenic and myotoxic, and it is suggested that active O species may be involved in the initiation of these harmful effects.
- 56Stadtman, E. R.; Levine, R. L. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids 2003, 25, 207– 218, DOI: 10.1007/s00726-003-0011-256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpsFOntL8%253D&md5=8d16642d300ae1e55932881e5d02b886Free radical-mediated oxidation of free amino acids and amino acid residues in proteinsStadtman, E. R.; Levine, R. L.Amino Acids (2003), 25 (3-4), 207-218CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag Wien)A review. We summarize here results of studies designed to elucidate basic mechanisms of reactive oxygen (ROS)-mediated oxidn. of proteins and free amino acids. These studies have shown that oxidn. of proteins can lead to hydroxylation of arom. groups and aliph. amino acid side chains, nitration of arom. amino acid residues, nitrosylation of sulfhydryl groups, sulfoxidn. of methionine residues, chlorination of arom. groups and primary amino groups, and to conversion of some amino acid residues to carbonyl derivs. Oxidn. can lead also to cleavage of the polypeptide chain and to formation of cross-linked protein aggregates. Furthermore, functional groups of proteins can react with oxidn. products of polyunsatd. fatty acids and with carbohydrate derivs. (glycation/glycoxidn.) to produce inactive derivs. Highly specific methods have been developed for the detection and assay of the various kinds of protein modifications. Because the generation of carbonyl derivs. occurs by many different mechanisms, the level of carbonyl groups in proteins is widely used as a marker of oxidative protein damage. The level of oxidized proteins increases with aging and in a no. of age-related diseases. However, the accumulation of oxidized protein is a complex function of the rates of ROS formation, antioxidant levels, and the ability to proteolytically eliminate oxidized forms of proteins. Thus, the accumulation of oxidized proteins is also dependent upon genetic factors and individual life styles. It is noteworthy that surface-exposed methionine and cysteine residues of proteins are particularly sensitive to oxidn. by almost all forms of ROS; however, unlike other kinds of oxidn. the oxidn. of these sulfur-contg. amino acid residues is reversible. It is thus evident that the cyclic oxidn. and redn. of the sulfur-contg. amino acids may serve as an important antioxidant mechanism, and also that these reversible oxidns. may provide an important mechanism for the regulation of some enzyme functions.
- 57McNaney, C. A.; Drexler, D. M.; Hnatyshyn, S. Y.; Zvyaga, T. A.; Knipe, J. O.; Belcastro, J. V.; Sanders, M. An automated liquid chromatography-mass spectrometry process to determine metabolic stability half-life and intrinsic clearance of drug candidates by substrate depletion. Assay Drug Dev. Technol. 2008, 6, 121– 129, DOI: 10.1089/adt.2007.10357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtFKqtbs%253D&md5=3833f7d7c4be366bc2d4b3e656ef4ae2An Automated Liquid Chromatography-Mass Spectrometry Process to Determine Metabolic Stability Half-Life and Intrinsic Clearance of Drug Candidates by Substrate DepletionMcNaney, Colleen A.; Drexler, Dieter M.; Hnatyshyn, Serhiy Y.; Zvyaga, Tatyana A.; Knipe, Jay O.; Belcastro, James V.; Sanders, MarkAssay and Drug Development Technologies (2008), 6 (1), 121-129CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)An automated process is described for the detailed assessment of the in vitro metabolic stability properties of drug candidates in support of pharmaceutical property profiling. Compds. are incubated with liver microsomes using a robotic liq. handler. Aliquots are taken at various time points, and the resulting samples are quant. analyzed by liq. chromatog.-mass spectrometry utilizing ion trap mass spectrometers to det. the amt. of compd. remaining. From these data metab. rates can be calcd. A high degree of automation is achieved through custom software, which is employed for instrument setup, data processing, and results reporting. The assay setup is highly configurable, allowing for any combination of up to six user-selected time points, variable substrate concn., and microsomes or other biol. active media. The data, based on relative substrate depletion, affords an est. of metabolic stability through the calcn. of half-life (t1/2) and intrinsic clearance, which are used to differentiate and rank order drug leads. In general, t1/2 is the time necessary for the metab., following first-order kinetics, of 50 of the initial compd. Intrinsic clearance is the proportionality const. between rate of metab. of a compd. and its concn. at the enzyme site. Described here is the setup of the assay, and data from assay test compds. are presented.
- 58Di, L.; Kerns, E. H.; Hong, Y.; Kleintop, T. A.; Mcconnell, O. J.; Huryn, D. M. Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates. J. Biomol. Screening 2003, 8, 453– 462, DOI: 10.1177/108705710325598858https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntlWrtbo%253D&md5=0a576434f52b90073d67b81aa4dd3b92Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidatesDi, Li; Kerns, Edward H.; Hong, Yan; Kleintop, Teresa A.; McConnell, Oliver J.; Huryn, Donna M.Journal of Biomolecular Screening (2003), 8 (4), 453-462CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)Metabolic stability plays an important role in the success of drug candidates. First-pass metab. is one of the major causes of poor oral bioavailability and short half-life. Traditionally, metabolic stability was evaluated at a later stage of drug discovery and required laborious manual manipulations. With the advance of high-throughput screening, combinatorial chem., and early profiling of drug-like properties, automated and rapid stability assays are needed to meet the increasing demand of throughput, speed, and reproducibility at earlier stages of drug discovery. The authors describe optimization of a simple, robust, high-throughput microsomal stability assay developed in a 96-well format. The assay consists of 2 automated components: robotic sample prepn. for incubation and cleanup and rapid liq. chromatog./mass spectrometry/mass spectrometry (LC/MS/MS) anal. to det. percent remaining of the parent compd. The reagent solns. and procedural steps were optimized for automation. Variables affecting assay results were investigated. The variability introduced by microsome prepns. from different sources (various vendors and batches) was studied and indicates the need for careful control. Quality control and normalization of the stability results are crit. when applying the screening data, generated at different times or research sites, to discovery projects.
- 59Oakley, H.; Cole, S. L.; Logan, S.; Maus, E.; Shao, P.; Craft, J.; Guillozet-Bongaarts, A.; Ohno, M.; Disterhoft, J.; Van Eldik, L.; Berry, R.; Vassar, R. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 2006, 26, 10129– 10140, DOI: 10.1523/JNEUROSCI.1202-06.200659https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVymurbK&md5=a47a3bedd25b37812f9172ebca81fb1dIntraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formationOakley, Holly; Cole, Sarah L.; Logan, Sreemathi; Maus, Erika; Shao, Pei; Craft, Jeffery; Guillozet-Bongaarts, Angela; Ohno, Masuo; Disterhoft, John; Van Eldik, Linda; Berry, Robert; Vassar, RobertJournal of Neuroscience (2006), 26 (40), 10129-10140CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase prodn. of β-amyloid 42 (Aβ42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ42 and exhibit amyloid plaque pathol. similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ42 prodn. 5XFAD mice generate Aβ42 almost exclusively and rapidly accumulate massive cerebral Aβ42 levels. Amyloid deposition (and gliosis) begins at 2 mo and reaches a very large burden, esp. in subiculum and deep cortical layers. Intraneuronal Aβ42 accumulates in 5XFAD brain starting at 1.5 mo of age (before plaques form), is aggregated (as detd. by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphol. abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic d.-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addn., levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 mo in 5XFAD brain, although an upward trend is obsd. by 3 mo of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathol. and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloid plaque formation.
- 60Vorhees, C. V.; Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 2006, 1, 848– 858, DOI: 10.1038/nprot.2006.11660https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2s3gsVWmsQ%253D%253D&md5=236edc21e2a0444deaf77ebef3885e8fMorris water maze: procedures for assessing spatial and related forms of learning and memoryVorhees Charles V; Williams Michael TNature protocols (2006), 1 (2), 848-58 ISSN:.The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed across repeated trials and reference memory is determined by preference for the platform area when the platform is absent. Reversal and shift trials enhance the detection of spatial impairments. Trial-dependent, latent and discrimination learning can be assessed using modifications of the basic protocol. Search-to-platform area determines the degree of reliance on spatial versus non-spatial strategies. Cued trials determine whether performance factors that are unrelated to place learning are present. Escape from water is relatively immune from activity or body mass differences, making it ideal for many experimental models. The MWM has proven to be a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and NMDA receptor function. We present protocols for performing variants of the MWM test, from which results can be obtained from individual animals in as few as 6 days.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b13100.
Experimental Section, Tables S1–S4, and Figures S1–S15 (PDF)
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