Synthesis and In Silico Evaluation of Piperazine-Substituted 2,3-Dichloro-5,8-dihydroxy-1,4-naphthoquinone Derivatives as Potential PARP-1 InhibitorsClick to copy article linkArticle link copied!
- Ulviyye NemetovaUlviyye NemetovaEngineering Faculty, Department of Chemistry, Organic Chemistry, Istanbul University-Cerrahpaşa, 34320 Istanbul, TurkeyMore by Ulviyye Nemetova
- Pınar Si̇yah*Pınar Si̇yah*Email: [email protected]Department of Biochemistry, Faculty of Pharmacy, Bahcesehir University, 34353 Istanbul, TurkeyMore by Pınar Si̇yah
- Tuğçe BoranTuğçe BoranFaculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul University-Cerrahpaşa, 34500 Istanbul, TurkeyMore by Tuğçe Boran
- Çiğdem Bi̇lgi̇Çiğdem Bi̇lgi̇Faculty of Pharmacy, Department of Pharmacognosy, Istanbul University-Cerrahpaşa, 34500 Istanbul, TurkeyMore by Çiğdem Bi̇lgi̇
- Mustafa ÖzyürekMustafa ÖzyürekEngineering Faculty, Department of Chemistry, Analytical Chemistry, Istanbul University-Cerrahpaşa, 34320 Istanbul, TurkeyMore by Mustafa Özyürek
- Sibel Şahi̇nler Ayla*Sibel Şahi̇nler Ayla*Email: [email protected]Engineering Faculty, Department of Chemistry, Organic Chemistry, Istanbul University-Cerrahpaşa, 34320 Istanbul, TurkeyMore by Sibel Şahi̇nler Ayla
Abstract
PARP-1 (poly(ADP-ribose)-polymerase 1) inhibitors are vital in synthetic lethality, primarily due to their specificity for PARP-1 over PARP-2 (PARP-1 > PARP-2). This specificity is crucial as it allows precise inhibition of PARP-1 in tumor cells with Breast Cancer 1 protein (BRCA1) or BRCA2 deficiencies. The development of highly specific PARP-1 inhibitors not only meets the therapeutic needs of tumor treatment but also has the potential to minimize the adverse effects associated with nonselective PARP-2 inhibition. In this study, a series of novel 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (DDNO) derivatives were synthesized, characterized, and evaluated regarding their PARP-1 inhibitory and cytotoxic activity. Compound 3 exhibited the highest cytotoxic potential against all cell lines, except for MDA-MB-231 cells. The inhibitory potential of these molecules against PARP-1 was evaluated through in silico molecular docking and molecular dynamics studies. Notably, compounds 5, 9, and 13 exhibited significant inhibitory activity in silico results, interacting with critical amino acids known to be important for PARP-1 inhibition during simulations. These compounds exhibited target-specific and strong binding profiles, with docking scores of −7.17, −7.41, and −7.37 kcal/mol, respectively, and MM/GBSA scores of −52.51, −43.77, and −62.87 kcal/mol, respectively. These novel compounds (DDNO derivatives) hold promise as potential PARP-1 inhibitors for the development of targeted therapeutics against cancer.
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License Summary*
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*Disclaimer
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
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1. Introduction
2. Experimental Section
2.1. General Procedure
2.1.1. 2-Chloro-5,8-dihydroxy-3-thiomorpholinonaphthalene-1,4-dione (3)
2.1.2. 2-Chloro-3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-5,8-dihydroxynaphthalene-1,4-dione (5)
2.1.3. 2-Chloro-3-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-5,8-dihydroxynaphthalene-1,4-dione (7)
2.1.4. 2-Chloro-5,8-dihydroxy-3-(4-(pyridin-2-yl)piperazin-1-yl)naphthalene-1,4-dione (9)
2.1.5. 2-(4-(4-Bromo-2-fluorobenzyl)piperazin-1-yl)-3-chloro-5,8-dihydroxynaphthalene-1,4-dione (11)
2.1.6. 2-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-3-chloro-5,8-dihydroxynaphthalene-1,4-dione (13)
2.2. In Silico Studies
2.2.1. Preparation of the Piperazine-Substituted 2,3-Dichloro-5,8-dihydroxy-1,4-naphthoquinone Derivative Compounds for Molecular Docking
2.2.2. Preparation of PARP-1 Protein for Molecular Docking
2.2.3. Grid Box Generation and Molecular Docking Studies
2.2.4. Molecular Dynamics Simulations
2.2.5. ADME Analysis and Therapeutic-QSAR Models
2.3. Cytotoxicity Assay (In Vitro Studies)
3. Results and Discussion
3.1. Synthesis of Compounds
Figure 1
Figure 1. Synthetic pathway of piperazine-substituted 5,8-dihydroxy 1,4-naphthoquinone compounds.
Figure 2
Figure 2. Three-dimensional structure of the prepared PARP-1 protein (PDB ID: 7ONT) with the active region highlighted.
3.2. In Silico Analysis
PARP-1 (7ONT) | PARP-2 (4TVJ) | |||
---|---|---|---|---|
ligand name | docking score (kcal/mol) | ligand efficiency | docking score (kcal/mol) | ligand efficiency |
compound 9 | –7.41 | –0.274 | –5.82 | –0.215 |
compound 13 | –7.37 | –0.254 | –6.05 | –0.209 |
compound 5 | –7.17 | –0.247 | –4.00 | –0.138 |
compound 3 | –6.52 | –0.310 | –5.46 | –0.260 |
compound 7 | –2.27 | –0.065 | –5.72 | –0.163 |
compound 11 | –2.18 | –0.073 | –6.59 | –0.220 |
nicotinamide | –7.43 | –0.826 | –7.33 | –0.814 |
rucaparib | –7.36 | –0.307 | –6.51 | –0.271 |
niraparib | –7.11 | –0.296 | –7.58 | –0.316 |
olaparib | –5.23 | –0.163 | –13.94 | –0.436 |
Figure 3
Figure 3. Three-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site.
PARP-1 | PARP-2 | ||
---|---|---|---|
ligand name | MM/GBSA score (kcal/mol) | ligand name | MM/GBSA score (kcal/mol) |
olapariba | –66.70 | olaparib | –99.96 |
compound 13b | –62.87 | rucaparib | –63.13 |
niraparib | –55.42 | niraparib | –62.31 |
compound 5 | –52.51 | talazoparib | –61.40 |
rucaparib | –49.67 | compound 7 | –55.62 |
compound 9 | –43.77 | compound 11 | –46.68 |
compound 7 | –36.45 | compound 13 | –46.40 |
compound 11 | –33.90 | compound 9 | –40.37 |
nicotinamide | –30.35 | compound 5 | –38.55 |
talazoparib | N/A | nicotinamide | –38.54 |
Italicized entries represent reference PARP inhibitor drugs.
The synthesized compounds that showed promising results as PARP-1 over PARP-2 selective inhibitors are indicated in bold.
Figure 4
Figure 4. (A) Analysis of the interactions between binding pocket residues of compound 13 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with compound 13 during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.
Figure 5
Figure 5. (A) Analysis of the interactions between binding pocket residues of Olaparib and PARP-1 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of Olaparib at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with Olaparib during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.
(1) | Gly863 (Gly429 in PARP-2) forms two hydrogen bonds with the bi- or tricyclic ring system of each inhibitor in PARP-1, where Gly863’s amide nitrogen acts as an H-bond donor and the carbonyl oxygen serves as an H-bond acceptor. | ||||
(2) | Ser904 (Ser470 in PARP-2) acts as an H-bond donor to a carbonyl in/on the bi- or tricyclic ring system of each inhibitor, contributing to the bidentate interaction of Gly863 and forming the basis for the inhibitor’s mimicry of nicotinamide. | ||||
(3) | Tyr907 (Tyr473 in PARP-2) engages in a π–π interaction with the aromatic bi- or tricyclic ring of each inhibitor, despite not forming a similar interaction with the nicotinamide ring. This interaction significantly enhances PARPi’s affinity compared to nicotinamide and plays a vital role in binding inhibitors with larger aromatic ring structures, such as olaparib, more effectively than those with smaller aromatic rings, like veliparib. |
3.3. Cytotoxicity
IC50b | ||||||
---|---|---|---|---|---|---|
cell line | 3 | 5 | 7 | 9 | 11 | 13 |
HaCaT | 0.11 ± 0.01a | 1.96 ± 0.25 | 0.15 ± 0.02 | 1.29 ± 0.06 | 3.29 ± 1.35 | 2.03 ± 0.08 |
HepG2 | 0.22 ± 0.04 | 3.43 ± 0.49 | 0.48 ± 0.04 | 5.65 ± 1.15 | 4.85 ± 1.31 | 6.53 ± 0.97 |
SH-SY5Y | 0.08 ± 0.02 | 1.72 ± 0.27 | 0.59 ± 0.02 | 8.23 ± 0.35 | 8.23 ± 1.13 | 10.27 ± 0.63 |
A549 | 0.45 ± 0.08 | 9.31 ± 0.98 | >2.5 ± 0.07 | 12.30 ± 0.06 | 9.22 ± 2.33 | 13.96 ± 2.39 |
MCF7 | 0.38 ± 0.07 | 5.64 ± 1.47 | 0.38 ± 0.02 | 1.71 ± 0.25 | 2.72 ± 0.27 | 3.40 ± 0.85 |
MDA-MB-231 | 0.46 ± 0.05 | 3.43 ± 0.49 | 0.36 ± 0.03 | 7.01 ± 1.47 | 10.30 ± 2.58 | 9.45 ± 0.43 |
Data are represented as mean ± standard deviation.
IC50 values expressed as μg/mL.
4. Conclusions
Acknowledgments
The authors gratefully thank the Research Fund of the İstanbul University-Cerrahpaşa for financial support of this work. Project Number: FYL-2020-34351.
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- 22Jamal, S.; Goyal, S.; Shanker, A.; Grover, A. Checking the STEP-Associated Trafficking and Internalization of Glutamate Receptors for Reduced Cognitive Deficits: A Machine Learning Approach-Based Cheminformatics Study and Its Application for Drug Repurposing. PLoS One 2015, 10 (6), e0129370 DOI: 10.1371/journal.pone.0129370Google ScholarThere is no corresponding record for this reference.
- 23Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. J. Comput.-Aided Mol. Des 2013, 27, 221– 234, DOI: 10.1007/s10822-013-9644-8Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmslalu7c%253D&md5=259a6d547ef3e1310e091fb50fe8de16Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichmentsMadhavi Sastry, G.; Adzhigirey, Matvey; Day, Tyler; Annabhimoju, Ramakrishna; Sherman, WoodyJournal of Computer-Aided Molecular Design (2013), 27 (3), 221-234CODEN: JCADEQ; ISSN:0920-654X. (Springer)Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepd. prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove at. clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addn., ligands must be prepd. to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system prepn. is generally accepted in the field, an extensive study of the prepn. steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in prepg. a system for virtual screening. We first explore a large no. of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper prepn. and that neglecting certain steps of the prepn. process produces a systematic degrdn. in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the prepn. that impact database enrichment. While the work presented here was performed with the Protein Prepn. Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
- 24Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J. M.; Lu, C.; Dahlgren, M. K.; Mondal, S.; Chen, W.; Wang, L. OPLS3e: Extending Force Field Coverage for Drug-like Small Molecules. J. Chem. Theory Comput. 2019, 15 (3), 1863– 1874, DOI: 10.1021/acs.jctc.8b01026Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFKlsrs%253D&md5=5c91547ddc0c975f9616cfba56a5454fOPLS3e: Extending Force Field Coverage for Drug-Like Small MoleculesRoos, Katarina; Wu, Chuanjie; Damm, Wolfgang; Reboul, Mark; Stevenson, James M.; Lu, Chao; Dahlgren, Markus K.; Mondal, Sayan; Chen, Wei; Wang, Lingle; Abel, Robert; Friesner, Richard A.; Harder, Edward D.Journal of Chemical Theory and Computation (2019), 15 (3), 1863-1874CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chem. space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chem. specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small mol. conformational propensities, solvation, and protein-ligand binding.
- 25Johannes, J. W.; Balazs, A.; Barratt, D.; Bista, M.; Chuba, M. D.; Cosulich, S.; Critchlow, S. E.; Degorce, S. L.; Di Fruscia, P.; Edmondson, S. D. Discovery of 5-{4-[(7-Ethyl-6-Oxo-5, 6-Dihydro-1, 5-Naphthyridin-3-Yl) Methyl] Piperazin-1-Yl}-N-Methylpyridine-2-Carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs. J. Med. Chem. 2021, 64 (19), 14498– 14512, DOI: 10.1021/acs.jmedchem.1c01012Google ScholarThere is no corresponding record for this reference.
- 26Jacobson, M. P.; Pincus, D. L.; Rapp, C. S.; Day, T. J. F.; Honig, B.; Shaw, D. E.; Friesner, R. A. A Hierarchical Approach to All-atom Protein Loop Prediction. Proteins 2004, 55 (2), 351– 367, DOI: 10.1002/prot.10613Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtFKhsrc%253D&md5=e0eff655eeefb30ea00ae041ea9099c8A hierarchical approach to all-atom protein loop predictionJacobson, Matthew P.; Pincus, David L.; Rapp, Chaya S.; Day, Tyler J. F.; Honig, Barry; Shaw, David E.; Friesner, Richard A.Proteins: Structure, Function, and Bioinformatics (2004), 55 (2), 351-367CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)The application of all-atom force fields (and explicit or implicit solvent models) to protein homol.-modeling tasks such as side-chain and loop prediction remains challenging both because of the expense of the individual energy calcns. and because of the difficulty of sampling the rugged all-atom energy surface. Here the authors address this challenge for the problem of loop prediction through the development of numerous new algorithms, with an emphasis on multiscale and hierarchical techniques. As a first step in evaluating the performance of the authors' loop prediction algorithm, the authors have applied it to the problem of reconstructing loops in native structures; the authors also explicitly include crystal packing to provide a fair comparison with crystal structures. In brief, large nos. of loops are generated by using a dihedral angle-based buildup procedure followed by iterative cycles of clustering, side-chain optimization, and complete energy minimization of selected loop structures. The authors evaluate this method by the largest test set yet used for validation of a loop prediction method, with a total of 833 loops ranging from 4 to 12 residues in length. Av./median backbone root-mean-square deviations (RMSDs) to the native structures (superimposing the body of the protein, not the loop itself) are 0.42/0.24 Å for 5 residue loops, 1.00/0.44 Å for 8 residue loops, and 2.47/1.83 Å for 11 residue loops. Median RMSDs are substantially lower than the avs. because of a small no. of outliers; the causes of these failures are examd. in some detail, and many can be attributed to errors in assignment of protonation states of titratable residues, omission of ligands from the simulation, and, in a few cases, probable errors in the exptl. detd. structures. When these obvious problems in the data sets are filtered out, av. RMSDs to the native structures improve to 0.43 Å for 5 residue loops, 0.84 Å for 8 residue loops, and 1.63 Å for 11 residue loops. In the vast majority of cases, the method locates energy min. that are lower than or equal to that of the minimized native loop, thus indicating that sampling rarely limits prediction accuracy. The overall results are, to the authors' knowledge, the best reported to date, and the authors attribute this success to the combination of an accurate all-atom energy function, efficient methods for loop buildup and side-chain optimization, and, esp. for the longer loops, the hierarchical refinement protocol.
- 27Bas, D. C.; Rogers, D. M.; Jensen, J. H. Very Fast Prediction and Rationalization of PKa Values for Protein–Ligand Complexes. Proteins 2008, 73 (3), 765– 783, DOI: 10.1002/prot.22102Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlCgsbjO&md5=34f63cf947000be5482b745675ff8a8aVery fast prediction and rationalization of pKa values for protein-ligand complexesBas, Delphine C.; Rogers, David M.; Jensen, Jan H.Proteins: Structure, Function, and Bioinformatics (2008), 73 (3), 765-783CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)The PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non-proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to exptl. data for 26 protein-ligand complexes including trypsin, thrombin, three pepsins, HIV-1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been obsd. exptl. for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, resp. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein-ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate detn. of the protonation states of key residues and ligand functional groups within the binding or active site of a protein.
- 28Güngör, T.; Ozleyen, A.; Yılmaz, Y. B.; Siyah, P.; Ay, M.; Durdağı, S.; Tumer, T. B. New Nimesulide Derivatives with Amide/Sulfonamide Moieties: Selective COX-2 Inhibition and Antitumor Effects. Eur. J. Med. Chem. 2021, 221, 113566 DOI: 10.1016/j.ejmech.2021.113566Google ScholarThere is no corresponding record for this reference.
- 29Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47 (7), 1739– 1749, DOI: 10.1021/jm0306430Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFyit74%253D&md5=8cc2f0022318b12dd972e9c493375bf9Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracyFriesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
- 30Siyah, P.; Durdagi, S.; Aksoydan, B. Discovery of Potential PD-L1 Small Molecule Inhibitors as Novel Cancer Therapeutics Using Machine Learning-Based QSAR Models: A Virtual Drug Repurposing Study. Biophys. J. 2023, 122 (3), 144a, DOI: 10.1016/j.bpj.2022.11.942Google ScholarThere is no corresponding record for this reference.
- 31Siyah, P.; Akgol, S.; Durdagi, S.; Kocabas, F. Identification of First-in-Class Plasmodium OTU Inhibitors with Potent Anti-Malarial Activity. Biochem. J. 2021, 478 (18), 3445– 3466, DOI: 10.1042/BCJ20210481Google ScholarThere is no corresponding record for this reference.
- 32Nilov, D.; Maluchenko, N.; Kurgina, T.; Pushkarev, S.; Lys, A.; Kutuzov, M.; Gerasimova, N.; Feofanov, A.; Švedas, V.; Lavrik, O.; Studitsky, V. M. Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine. Int. J. Mol. Sci. 2020, 21 (6), 2159, DOI: 10.3390/ijms21062159Google ScholarThere is no corresponding record for this reference.
- 33Rudolph, J.; Jung, K.; Luger, K. Inhibitors of PARP: Number Crunching and Structure Gazing. Proc. Natl. Acad. Sci. U.S.A. 2022, 119 (11), e2121979119 DOI: 10.1073/pnas.2121979119Google ScholarThere is no corresponding record for this reference.
- 34Ferraris, D. V. Evolution of Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic. J. Med. Chem. 2010, 53 (12), 4561– 4584, DOI: 10.1021/jm100012mGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkt1WksLs%253D&md5=6c093238562c908d45dfcd2f3055457dEvolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to ClinicFerraris, Dana V.Journal of Medicinal Chemistry (2010), 53 (12), 4561-4584CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Poly(ADP-ribose) polymerase-1 (PARP-1) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the "guardian angel of DNA", this abundant nuclear enzyme has been the focus of over 20 medicinal chem. programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, and diabetes. Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clin. trials. Recent results from several PARP-1 inhibitors in phase II clin. trials for cancer therapy have attracted the attention of national media. Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the crit. PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP- 1 received so much attention in the late 1990s and early 2000s followed by the slight decline in the medicinal chem. efforts today.
- 35Li, J.; Zhou, N.; Cai, P.; Bao, J. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment. Int. J. Mol. Sci. 2016, 17 (2), 258, DOI: 10.3390/ijms17020258Google ScholarThere is no corresponding record for this reference.
- 36Zhao, C.; Tang, X.; Chen, X.; Jiang, Z. Multifaceted Carbonized Metal–Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy. ACS Nano 2024, 18 (27), 17852– 17868, DOI: 10.1021/acsnano.4c04022Google ScholarThere is no corresponding record for this reference.
- 37Liu, K.; Jiang, Z.; Zhao, F.; Wang, W.; Jäkle, F.; Wang, N.; Tang, X.; Yin, X.; Chen, P. Triarylboron-Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low Phototoxicity. Adv. Mater. 2022, 34 (49), 2206594 DOI: 10.1002/adma.202206594Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivVGjsrbE&md5=b5c0c4d2bff4a38a286e2ac540fd5f35Triarylboron-Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low PhototoxicityLiu, Kanglei; Jiang, Zhenqi; Zhao, Fenggui; Wang, Weizhi; Jakle, Frieder; Wang, Nan; Tang, Xiaoying; Yin, Xiaodong; Chen, PangkuanAdvanced Materials (Weinheim, Germany) (2022), 34 (49), 2206594CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)The development of efficient org. sonosensitizers is crucial for sonodynamic therapy (SDT) in the field of cancer treatment. Herein, a new strategy for the development of efficient org. sonosensitizers based on triarylboron-doped acenethiophene scaffolds is presented. The attachment of boron to the linear acenethiophenes lowers the LUMO (LUMO) energy, resulting in red shifted absorptions and emissions. After encapsulation with the amphiphilic polymer DSPE-mPEG2000, it is found that the nanostructured BAnTh-NPs and BTeTh-NPs (nanoparticles of BAnTh and BTeTh) shows efficient hydroxyl radical (•OH) generation under ultrasound (US) irradn. in aq. soln. with almost no phototoxicity, which can overcome the shortcomings of O2-dependent SDT and avoid the potential cutaneous phototoxicity issue. In vitro and in vivo therapeutic results validate that boron-doped acenethiophenes as sonosensitizers enable high SDT efficiency with low phototoxicity and good biocompatibility, indicating that boron-functionalization of acenes is a promising strategy toward org. sonosensitizers for SDT.
- 38Zhou, Y.; Li, Q.; Pan, R.; Wang, Q.; Zhu, X.; Yuan, C.; Cai, F.; Gao, Y.; Cui, Y. Regulatory Roles of Three MiRNAs on Allergen MRNA Expression in Tyrophagus Putrescentiae. Allergy 2022, 77 (2), 469– 482, DOI: 10.1111/all.15111Google ScholarThere is no corresponding record for this reference.
- 39Zhu, J.; Jiang, X.; Luo, X.; Zhao, R.; Li, J.; Cai, H.; Ye, X. Y.; Bai, R.; Xie, T. Combination of Chemotherapy and Gaseous Signaling Molecular Therapy: Novel β-Elemene Nitric Oxide Donor Derivatives against Leukemia. Drug Dev. Res. 2023, 84 (4), 718, DOI: 10.1002/ddr.22051Google ScholarThere is no corresponding record for this reference.
- 40Shen, X.; Wang, Y.; Han, X.; Sheng, L.; Wu, F.; Liu, X. Design, Synthesis and Anticancer Activity of Naphthoquinone Derivatives. J. Enzyme Inhib. Med. Chem. 2020, 35 (1), 1740693 DOI: 10.1080/14756366.2020.1740693Google ScholarThere is no corresponding record for this reference.
- 41Long, H.; Hu, X.; Wang, B.; Wang, Q.; Wang, R.; Liu, S.; Xiong, F.; Jiang, Z.; Zhang, X.-Q.; Ye, W.-C.; Wang, H. Discovery of Novel Apigenin–Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer. J. Med. Chem. 2021, 64 (16), 12089– 12108, DOI: 10.1021/acs.jmedchem.1c00735Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvVSqs73J&md5=acbdd99492d0b2315d3222cc2269f1a8Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of CancerLong, Huan; Hu, Xiaolong; Wang, Baolin; Wang, Quan; Wang, Rong; Liu, Shumeng; Xiong, Fei; Jiang, Zhenzhou; Zhang, Xiao-Qi; Ye, Wen-Cai; Wang, HaoJournal of Medicinal Chemistry (2021), 64 (16), 12089-12108CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivs. (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), resp. Among these compds., 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Mol. dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compd. for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- 42Hong, Y.; Liao, Z.-C.; Chen, J.-J.; Liu, J.; Liu, Y.-L.; Li, J.-H.; Sun, Q.; Chen, S.-L.; Wang, S.-W.; Tang, S. Radical 1, 2-Nitrogen Migration Cascades of β-Bromo α-Amino Acid Esters to Access β-Amino Acid Motifs Enabled by Cooperative Ni/Diboron Catalysis. ACS Catal. 2024, 14 (8), 5491– 5502, DOI: 10.1021/acscatal.4c01034Google ScholarThere is no corresponding record for this reference.
- 43Hu, S.; Jiang, S.; Qi, X.; Bai, R.; Ye, X. Y.; Xie, T. Races of Small Molecule Clinical Trials for the Treatment of COVID-19: An up-to-Date Comprehensive Review. Drug Dev. Res. 2022, 83, 16, DOI: 10.1002/ddr.21895Google ScholarThere is no corresponding record for this reference.
- 44Dilipkumar, S.; Karthik, V.; Dk, S.; Gowramma, B.; Lakshmanan, K. In-Silico Screening and Molecular Dynamics Simulation of Quinazolinone Derivatives as PARP1 and STAT3 Dual Inhibitors: A Novel DML Approaches. J. Biomol. Struct. Dyn. 2023, 1– 11, DOI: 10.1080/07391102.2023.2259476Google ScholarThere is no corresponding record for this reference.
- 45Zhou, J.; Ji, M.; Wang, X.; Zhao, H.; Cao, R.; Jin, J.; Li, Y.; Chen, X.; Sheng, L.; Chen, X.; Xu, B. Discovery of Quinazoline-2,4(1 H,3 H)-Dione Derivatives Containing 3-Substituted Piperizines as Potent PARP-1/2 Inhibitors-Design, Synthesis, in Vivo Antitumor Activity, and X-Ray Crystal Structure Analysis. J. Med. Chem. 2021, 64 (22), 16711, DOI: 10.1021/acs.jmedchem.1c01522Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. Synthetic pathway of piperazine-substituted 5,8-dihydroxy 1,4-naphthoquinone compounds.
Figure 2
Figure 2. Three-dimensional structure of the prepared PARP-1 protein (PDB ID: 7ONT) with the active region highlighted.
Figure 3
Figure 3. Three-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site.
Figure 4
Figure 4. (A) Analysis of the interactions between binding pocket residues of compound 13 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of compound 13 at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with compound 13 during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.
Figure 5
Figure 5. (A) Analysis of the interactions between binding pocket residues of Olaparib and PARP-1 throughout the MD simulations. (B) Two-dimensional ligand interaction diagram of Olaparib at the PARP-1 binding site. (C) Interaction percentages of residues in the binding pocket of PARP-1 with Olaparib during the MD simulations. The findings present statistical outcomes based on 100 trajectory frames collected over 10 ns MD simulations.
References
This article references 45 other publications.
- 1Kerns, R. J.; Rybak, M. J.; Kaatz, G. W.; Vaka, F.; Cha, R.; Grucz, R. G.; Diwadkar, V. U. Structural Features of Piperazinyl-Linked Ciprofloxacin Dimers Required for Activity against Drug-Resistant Strains of Staphylococcus Aureus. Bioorg. Med. Chem. Lett. 2003, 13 (13), 2109– 2112, DOI: 10.1016/S0960-894X(03)00376-71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXksVaktro%253D&md5=b6c7e118a6ccc3c0bce58e029b7b9fa8Structural features of piperazinyl-linked ciprofloxacin dimers required for activity against drug-resistant strains of Staphylococcus aureusKerns, Robert J.; Rybak, Michael J.; Kaatz, Glenn W.; Vaka, Flamur; Cha, Raymond; Grucz, Richard G.; Diwadkar, Veena U.Bioorganic & Medicinal Chemistry Letters (2003), 13 (13), 2109-2112CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)It was previously demonstrated that piperazinyl-linked fluoroquinolone dimers possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus. A series of incomplete dimers were prepd. and evaluated toward ascertaining structural features of piperazinyl-linked ciprofloxacin dimers that render these agents refractory to fluoroquinolone-resistance mechanisms in Staphylococcus aureus.
- 2Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D. A.; Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C. Targeting the DNA Repair Defect in BRCA Mutant Cells as a Therapeutic Strategy. Nature 2005, 434 (7035), 917– 921, DOI: 10.1038/nature034452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtFOmsrc%253D&md5=03b5ba0adc21a5627fe17ae535f45078Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyFarmer, Hannah; McCabe, Nuala; Lord, Christopher J.; Tutt, Andrew N. J.; Johnson, Damian A.; Richardson, Tobias B.; Santarosa, Manuela; Dillon, Krystyna J.; Hickson, Ian; Knights, Charlotte; Martin, Niall M. B.; Jackson, Stephen P.; Smith, Graeme C. M.; Ashworth, AlanNature (London, United Kingdom) (2005), 434 (7035), 917-921CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. The authors show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
- 3Ashworth, A.; Lord, C. J.; Reis-Filho, J. S. Genetic Interactions in Cancer Progression and Treatment. Cell 2011, 145 (1), 30– 38, DOI: 10.1016/j.cell.2011.03.020There is no corresponding record for this reference.
- 4Lord, C. J.; Ashworth, A. PARP Inhibitors: The First Synthetic Lethal Targeted Therapy. Science 2017, 355 (6330), eaam7344, DOI: 10.1126/science.aam7344There is no corresponding record for this reference.
- 5Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T. Specific Killing of BRCA2-Deficient Tumours with Inhibitors of Poly (ADP-Ribose) Polymerase. Nature 2005, 434 (7035), 913– 917, DOI: 10.1038/nature034435https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjtFOmsrY%253D&md5=44631eba667cf75ef99c31d011d6db44Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose) polymeraseBryant, Helen E.; Schultz, Niklas; Thomas, Huw D.; Parker, Kayan M.; Flower, Dan; Lopez, Elena; Kyle, Suzanne; Meuth, Mark; Curtin, Nicola J.; Helleday, ThomasNature (London, United Kingdom) (2005), 434 (7035), 913-917CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumors. Here, the authors show that PARP inhibitors trigger γ-H2AX and RAD51 foci formation. The authors propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, the authors show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. The authors exploit this requirement in order to kill BRCA2-deficient tumors by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumor specific, because only the tumors (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumor, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
- 6Jain, P. G.; Patel, B. D. Medicinal Chemistry Approaches of Poly ADP-Ribose Polymerase 1 (PARP1) Inhibitors as Anticancer Agents-A Recent Update. Eur. J. Med. Chem. 2019, 165, 198– 215, DOI: 10.1016/j.ejmech.2019.01.024There is no corresponding record for this reference.
- 7Goldberg, M. S.; Xing, D.; Ren, Y.; Orsulic, S.; Bhatia, S. N.; Sharp, P. A. Nanoparticle-Mediated Delivery of SiRNA Targeting Parp1 Extends Survival of Mice Bearing Tumors Derived from Brca1-Deficient Ovarian Cancer Cells. Proc. Natl. Acad. Sci. U.S.A. 2011, 108 (2), 745– 750, DOI: 10.1073/pnas.1016538108There is no corresponding record for this reference.
- 8Yu, J.; Luo, L.; Hu, T.; Cui, Y.; Sun, X.; Gou, W.; Hou, W.; Li, Y.; Sun, T. Structure-Based Design, Synthesis, and Evaluation of Inhibitors with High Selectivity for PARP-1 over PARP-2. Eur. J. Med. Chem. 2022, 227, 113898 DOI: 10.1016/j.ejmech.2021.1138988https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitlWksrfN&md5=659fdebe7ca8ad7cbeb75c1dd45fb384Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2Yu, Jiang; Luo, Lingling; Hu, Tong; Cui, Yating; Sun, Xiao; Gou, Wenfeng; Hou, Wenbin; Li, Yiliang; Sun, TieminEuropean Journal of Medicinal Chemistry (2022), 227 (), 113898CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. A few selected compds. (labeled Y17, Y29, Y31 and Y49) showed excellent PARP-1 inhibition, and their IC50 values were 0.61, 0.66, 0.41 and 0.96 nM, resp. Then, Y49 (PARP-1 IC50 = 0.96 nM, PARP-2 IC50 = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compds. Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.
- 9Chen, L.; Jiang, Z.; Yang, L.; Fang, Y.; Lu, S.; Akakuru, O. U.; Huang, S.; Li, J.; Ma, S.; Wu, A. HPDA/Zn as a CREB Inhibitor for Ultrasound Imaging and Stabilization of Atherosclerosis Plaque. Chin. J. Chem. 2023, 41 (2), 2200406 DOI: 10.1002/cjoc.202200406There is no corresponding record for this reference.
- 10Straub, J. S.; Nowotarski, M. S.; Lu, J.; Sheth, T.; Jiao, S.; Fisher, M. P. A.; Shell, M. S.; Helgeson, M. E.; Jerschow, A.; Han, S. Phosphates Form Spectroscopically Dark State Assemblies in Common Aqueous Solutions. Proc. Natl. Acad. Sci. U.S.A. 2023, 120 (1), e2206765120 DOI: 10.1073/pnas.2206765120There is no corresponding record for this reference.
- 11Sampson, J. J., III; Donkor, I. O.; Huang, T. L.; Adunyah, S. E. Novel Piperazine Induces Apoptosis in U937 Cells. Int. J. Biochem. Mol. Biol. 2011, 2 (1), 78There is no corresponding record for this reference.
- 12Zhou, H.; Li, M.; Liu, H.; Liu, Z.; Wang, X.; Wang, S. Design, Synthesis, and Biological Evaluation of Piperazine Derivatives Involved in the 5-HT1AR/BDNF/PKA Pathway. J. Enzyme Inhib. Med. Chem. 2024, 39 (1), 2286183 DOI: 10.1080/14756366.2023.2286183There is no corresponding record for this reference.
- 13Ibis, C.; Ayla, S. S.; Bahar, H.; Stasevych, M. V.; Komarovska-Porokhnyavets, O.; Novikov, V. Synthesis, Characterization, and Biological Properties of Novel Piperidinolyl-, Piperidinyl-, and Piperazinyl-Substituted Naphthoquinone Compounds and Their Reactions with Some Thiols. Phosphorus, Sulfur Silicon Relat. Elem. 2015, 190 (9), 1422– 1433, DOI: 10.1080/10426507.2014.986268There is no corresponding record for this reference.
- 14Tandon, V. K.; Chhor, R. B.; Singh, R. V.; Rai, S.; Yadav, D. B. Design, Synthesis and Evaluation of Novel 1, 4-Naphthoquinone Derivatives as Antifungal and Anticancer Agents. Bioorg. Med. Chem. Lett. 2004, 14 (5), 1079– 1083, DOI: 10.1016/j.bmcl.2004.01.002There is no corresponding record for this reference.
- 15Shen, X.; Liang, X.; He, C.; Yin, L.; Xu, F.; Li, H.; Tang, H.; Lv, C. Structural and Pharmacological Diversity of 1, 4-Naphthoquinone Glycosides in Recent 20 Years. Bioorg. Chem. 2023, 138, 106643 DOI: 10.1016/j.bioorg.2023.106643There is no corresponding record for this reference.
- 16Majdi, C.; Duvauchelle, V.; Meffre, P.; Benfodda, Z. An Overview on the Antibacterial Properties of Juglone, Naphthazarin, Plumbagin and Lawsone Derivatives and Their Metal Complexes. Biomed. Pharmacother. 2023, 162, 114690 DOI: 10.1016/j.biopha.2023.11469016https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXnvFGqs7c%253D&md5=5776dc995cd0bdefbdf19d521f4a63ddAn overview on the antibacterial properties of juglone, naphthazarin, plumbagin and lawsone derivatives and their metal complexesMajdi, Chaimae; Duvauchelle, Valentin; Meffre, Patrick; Benfodda, ZohraBiomedicine & Pharmacotherapy (2023), 162 (), 114690CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)A review. Bacterial resistance development represents a serious threat to human health across the globe and has become a very serious clin. problem for many classes of antibiotics. Hence, there is a const. and urgent need for the discovery and development of new effective antibacterial agents to stem the emergence of resistant bacteria. 1,4-naphthoquinones are an important class of natural products and have been known for decades as a privileged scaffold in medicinal chem. regarding their many biol. properties. The significant biol. properties of specific 1,4-naphthoquinones hydroxyderivatives have drawn the attention of researchers in order to find new derivs. with an optimized activity, mainly as antibacterial agents. Based on juglone, naphthazarin, plumbagin and lawsone moieties, structural optimization was realized with the purpose of improving the antibacterial activity. Thereupon, relevant antibacterial activities have been obsd. on different panels of bacterial strains including resistant ones. In this review, we highlight the interest of developing new 1,4-naphthoquinones hydroxyderivatives and some metal complexes as promising antibacterial agents alternatives. Here, we thoroughly report for the first time both the antibacterial activity and the chem. synthesis of four different 1,4-naphthoquinones (juglone, naphthazarin, plumbagin and lawsone) from 2002 to 2022 with an emphasis on the structure-activity relationship, when applicable.
- 17Abel, G.; Amobonye, A.; Bhagwat, P.; Pillai, S. Diversity, Stability and Applications of Mycopigments. Process Biochem. 2023, 133, 270– 284, DOI: 10.1016/j.procbio.2023.09.002There is no corresponding record for this reference.
- 18Rani, R.; Sethi, K.; Kumar, S.; Varma, R. S.; Kumar, R. Natural Naphthoquinones and Their Derivatives as Potential Drug Molecules against Trypanosome Parasites. Chem. Biol. Drug Des. 2022, 100 (6), 786– 817, DOI: 10.1111/cbdd.14122There is no corresponding record for this reference.
- 19Bonifazi, E. L.; Ríos-Luci, C.; León, L. G.; Burton, G.; Padrón, J. M.; Misico, R. I. Antiproliferative Activity of Synthetic Naphthoquinones Related to Lapachol. First Synthesis of 5-Hydroxylapachol. Bioorg. Med. Chem. 2010, 18 (7), 2621– 2630, DOI: 10.1016/j.bmc.2010.02.032There is no corresponding record for this reference.
- 20Ollinger, K.; Brunmark, A. Effect of Hydroxy Substituent Position on 1, 4-Naphthoquinone Toxicity to Rat Hepatocytes. J. Biol. Chem. 1991, 266 (32), 21496– 21503, DOI: 10.1016/S0021-9258(18)54666-4There is no corresponding record for this reference.
- 21Onder, F. C.; Siyah, P.; Durdagi, S.; Ay, M.; Ozpolat, B. Novel Etodolac Derivatives as Eukaryotic Elongation Factor 2 Kinase (EEF2K) Inhibitors for Targeted Cancer Therapy. RSC Med. Chem. 2022, 13 (7), 840– 849, DOI: 10.1039/D2MD00105EThere is no corresponding record for this reference.
- 22Jamal, S.; Goyal, S.; Shanker, A.; Grover, A. Checking the STEP-Associated Trafficking and Internalization of Glutamate Receptors for Reduced Cognitive Deficits: A Machine Learning Approach-Based Cheminformatics Study and Its Application for Drug Repurposing. PLoS One 2015, 10 (6), e0129370 DOI: 10.1371/journal.pone.0129370There is no corresponding record for this reference.
- 23Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. J. Comput.-Aided Mol. Des 2013, 27, 221– 234, DOI: 10.1007/s10822-013-9644-823https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmslalu7c%253D&md5=259a6d547ef3e1310e091fb50fe8de16Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichmentsMadhavi Sastry, G.; Adzhigirey, Matvey; Day, Tyler; Annabhimoju, Ramakrishna; Sherman, WoodyJournal of Computer-Aided Molecular Design (2013), 27 (3), 221-234CODEN: JCADEQ; ISSN:0920-654X. (Springer)Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepd. prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove at. clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addn., ligands must be prepd. to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system prepn. is generally accepted in the field, an extensive study of the prepn. steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in prepg. a system for virtual screening. We first explore a large no. of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper prepn. and that neglecting certain steps of the prepn. process produces a systematic degrdn. in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the prepn. that impact database enrichment. While the work presented here was performed with the Protein Prepn. Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
- 24Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J. M.; Lu, C.; Dahlgren, M. K.; Mondal, S.; Chen, W.; Wang, L. OPLS3e: Extending Force Field Coverage for Drug-like Small Molecules. J. Chem. Theory Comput. 2019, 15 (3), 1863– 1874, DOI: 10.1021/acs.jctc.8b0102624https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFKlsrs%253D&md5=5c91547ddc0c975f9616cfba56a5454fOPLS3e: Extending Force Field Coverage for Drug-Like Small MoleculesRoos, Katarina; Wu, Chuanjie; Damm, Wolfgang; Reboul, Mark; Stevenson, James M.; Lu, Chao; Dahlgren, Markus K.; Mondal, Sayan; Chen, Wei; Wang, Lingle; Abel, Robert; Friesner, Richard A.; Harder, Edward D.Journal of Chemical Theory and Computation (2019), 15 (3), 1863-1874CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chem. space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chem. specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small mol. conformational propensities, solvation, and protein-ligand binding.
- 25Johannes, J. W.; Balazs, A.; Barratt, D.; Bista, M.; Chuba, M. D.; Cosulich, S.; Critchlow, S. E.; Degorce, S. L.; Di Fruscia, P.; Edmondson, S. D. Discovery of 5-{4-[(7-Ethyl-6-Oxo-5, 6-Dihydro-1, 5-Naphthyridin-3-Yl) Methyl] Piperazin-1-Yl}-N-Methylpyridine-2-Carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs. J. Med. Chem. 2021, 64 (19), 14498– 14512, DOI: 10.1021/acs.jmedchem.1c01012There is no corresponding record for this reference.
- 26Jacobson, M. P.; Pincus, D. L.; Rapp, C. S.; Day, T. J. F.; Honig, B.; Shaw, D. E.; Friesner, R. A. A Hierarchical Approach to All-atom Protein Loop Prediction. Proteins 2004, 55 (2), 351– 367, DOI: 10.1002/prot.1061326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtFKhsrc%253D&md5=e0eff655eeefb30ea00ae041ea9099c8A hierarchical approach to all-atom protein loop predictionJacobson, Matthew P.; Pincus, David L.; Rapp, Chaya S.; Day, Tyler J. F.; Honig, Barry; Shaw, David E.; Friesner, Richard A.Proteins: Structure, Function, and Bioinformatics (2004), 55 (2), 351-367CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)The application of all-atom force fields (and explicit or implicit solvent models) to protein homol.-modeling tasks such as side-chain and loop prediction remains challenging both because of the expense of the individual energy calcns. and because of the difficulty of sampling the rugged all-atom energy surface. Here the authors address this challenge for the problem of loop prediction through the development of numerous new algorithms, with an emphasis on multiscale and hierarchical techniques. As a first step in evaluating the performance of the authors' loop prediction algorithm, the authors have applied it to the problem of reconstructing loops in native structures; the authors also explicitly include crystal packing to provide a fair comparison with crystal structures. In brief, large nos. of loops are generated by using a dihedral angle-based buildup procedure followed by iterative cycles of clustering, side-chain optimization, and complete energy minimization of selected loop structures. The authors evaluate this method by the largest test set yet used for validation of a loop prediction method, with a total of 833 loops ranging from 4 to 12 residues in length. Av./median backbone root-mean-square deviations (RMSDs) to the native structures (superimposing the body of the protein, not the loop itself) are 0.42/0.24 Å for 5 residue loops, 1.00/0.44 Å for 8 residue loops, and 2.47/1.83 Å for 11 residue loops. Median RMSDs are substantially lower than the avs. because of a small no. of outliers; the causes of these failures are examd. in some detail, and many can be attributed to errors in assignment of protonation states of titratable residues, omission of ligands from the simulation, and, in a few cases, probable errors in the exptl. detd. structures. When these obvious problems in the data sets are filtered out, av. RMSDs to the native structures improve to 0.43 Å for 5 residue loops, 0.84 Å for 8 residue loops, and 1.63 Å for 11 residue loops. In the vast majority of cases, the method locates energy min. that are lower than or equal to that of the minimized native loop, thus indicating that sampling rarely limits prediction accuracy. The overall results are, to the authors' knowledge, the best reported to date, and the authors attribute this success to the combination of an accurate all-atom energy function, efficient methods for loop buildup and side-chain optimization, and, esp. for the longer loops, the hierarchical refinement protocol.
- 27Bas, D. C.; Rogers, D. M.; Jensen, J. H. Very Fast Prediction and Rationalization of PKa Values for Protein–Ligand Complexes. Proteins 2008, 73 (3), 765– 783, DOI: 10.1002/prot.2210227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlCgsbjO&md5=34f63cf947000be5482b745675ff8a8aVery fast prediction and rationalization of pKa values for protein-ligand complexesBas, Delphine C.; Rogers, David M.; Jensen, Jan H.Proteins: Structure, Function, and Bioinformatics (2008), 73 (3), 765-783CODEN: PSFBAF ISSN:. (Wiley-Liss, Inc.)The PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non-proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to exptl. data for 26 protein-ligand complexes including trypsin, thrombin, three pepsins, HIV-1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been obsd. exptl. for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, resp. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein-ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate detn. of the protonation states of key residues and ligand functional groups within the binding or active site of a protein.
- 28Güngör, T.; Ozleyen, A.; Yılmaz, Y. B.; Siyah, P.; Ay, M.; Durdağı, S.; Tumer, T. B. New Nimesulide Derivatives with Amide/Sulfonamide Moieties: Selective COX-2 Inhibition and Antitumor Effects. Eur. J. Med. Chem. 2021, 221, 113566 DOI: 10.1016/j.ejmech.2021.113566There is no corresponding record for this reference.
- 29Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47 (7), 1739– 1749, DOI: 10.1021/jm030643029https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhsFyit74%253D&md5=8cc2f0022318b12dd972e9c493375bf9Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracyFriesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
- 30Siyah, P.; Durdagi, S.; Aksoydan, B. Discovery of Potential PD-L1 Small Molecule Inhibitors as Novel Cancer Therapeutics Using Machine Learning-Based QSAR Models: A Virtual Drug Repurposing Study. Biophys. J. 2023, 122 (3), 144a, DOI: 10.1016/j.bpj.2022.11.942There is no corresponding record for this reference.
- 31Siyah, P.; Akgol, S.; Durdagi, S.; Kocabas, F. Identification of First-in-Class Plasmodium OTU Inhibitors with Potent Anti-Malarial Activity. Biochem. J. 2021, 478 (18), 3445– 3466, DOI: 10.1042/BCJ20210481There is no corresponding record for this reference.
- 32Nilov, D.; Maluchenko, N.; Kurgina, T.; Pushkarev, S.; Lys, A.; Kutuzov, M.; Gerasimova, N.; Feofanov, A.; Švedas, V.; Lavrik, O.; Studitsky, V. M. Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine. Int. J. Mol. Sci. 2020, 21 (6), 2159, DOI: 10.3390/ijms21062159There is no corresponding record for this reference.
- 33Rudolph, J.; Jung, K.; Luger, K. Inhibitors of PARP: Number Crunching and Structure Gazing. Proc. Natl. Acad. Sci. U.S.A. 2022, 119 (11), e2121979119 DOI: 10.1073/pnas.2121979119There is no corresponding record for this reference.
- 34Ferraris, D. V. Evolution of Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic. J. Med. Chem. 2010, 53 (12), 4561– 4584, DOI: 10.1021/jm100012m34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkt1WksLs%253D&md5=6c093238562c908d45dfcd2f3055457dEvolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to ClinicFerraris, Dana V.Journal of Medicinal Chemistry (2010), 53 (12), 4561-4584CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Poly(ADP-ribose) polymerase-1 (PARP-1) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the "guardian angel of DNA", this abundant nuclear enzyme has been the focus of over 20 medicinal chem. programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, and diabetes. Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clin. trials. Recent results from several PARP-1 inhibitors in phase II clin. trials for cancer therapy have attracted the attention of national media. Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the crit. PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP- 1 received so much attention in the late 1990s and early 2000s followed by the slight decline in the medicinal chem. efforts today.
- 35Li, J.; Zhou, N.; Cai, P.; Bao, J. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment. Int. J. Mol. Sci. 2016, 17 (2), 258, DOI: 10.3390/ijms17020258There is no corresponding record for this reference.
- 36Zhao, C.; Tang, X.; Chen, X.; Jiang, Z. Multifaceted Carbonized Metal–Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy. ACS Nano 2024, 18 (27), 17852– 17868, DOI: 10.1021/acsnano.4c04022There is no corresponding record for this reference.
- 37Liu, K.; Jiang, Z.; Zhao, F.; Wang, W.; Jäkle, F.; Wang, N.; Tang, X.; Yin, X.; Chen, P. Triarylboron-Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low Phototoxicity. Adv. Mater. 2022, 34 (49), 2206594 DOI: 10.1002/adma.20220659437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivVGjsrbE&md5=b5c0c4d2bff4a38a286e2ac540fd5f35Triarylboron-Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low PhototoxicityLiu, Kanglei; Jiang, Zhenqi; Zhao, Fenggui; Wang, Weizhi; Jakle, Frieder; Wang, Nan; Tang, Xiaoying; Yin, Xiaodong; Chen, PangkuanAdvanced Materials (Weinheim, Germany) (2022), 34 (49), 2206594CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)The development of efficient org. sonosensitizers is crucial for sonodynamic therapy (SDT) in the field of cancer treatment. Herein, a new strategy for the development of efficient org. sonosensitizers based on triarylboron-doped acenethiophene scaffolds is presented. The attachment of boron to the linear acenethiophenes lowers the LUMO (LUMO) energy, resulting in red shifted absorptions and emissions. After encapsulation with the amphiphilic polymer DSPE-mPEG2000, it is found that the nanostructured BAnTh-NPs and BTeTh-NPs (nanoparticles of BAnTh and BTeTh) shows efficient hydroxyl radical (•OH) generation under ultrasound (US) irradn. in aq. soln. with almost no phototoxicity, which can overcome the shortcomings of O2-dependent SDT and avoid the potential cutaneous phototoxicity issue. In vitro and in vivo therapeutic results validate that boron-doped acenethiophenes as sonosensitizers enable high SDT efficiency with low phototoxicity and good biocompatibility, indicating that boron-functionalization of acenes is a promising strategy toward org. sonosensitizers for SDT.
- 38Zhou, Y.; Li, Q.; Pan, R.; Wang, Q.; Zhu, X.; Yuan, C.; Cai, F.; Gao, Y.; Cui, Y. Regulatory Roles of Three MiRNAs on Allergen MRNA Expression in Tyrophagus Putrescentiae. Allergy 2022, 77 (2), 469– 482, DOI: 10.1111/all.15111There is no corresponding record for this reference.
- 39Zhu, J.; Jiang, X.; Luo, X.; Zhao, R.; Li, J.; Cai, H.; Ye, X. Y.; Bai, R.; Xie, T. Combination of Chemotherapy and Gaseous Signaling Molecular Therapy: Novel β-Elemene Nitric Oxide Donor Derivatives against Leukemia. Drug Dev. Res. 2023, 84 (4), 718, DOI: 10.1002/ddr.22051There is no corresponding record for this reference.
- 40Shen, X.; Wang, Y.; Han, X.; Sheng, L.; Wu, F.; Liu, X. Design, Synthesis and Anticancer Activity of Naphthoquinone Derivatives. J. Enzyme Inhib. Med. Chem. 2020, 35 (1), 1740693 DOI: 10.1080/14756366.2020.1740693There is no corresponding record for this reference.
- 41Long, H.; Hu, X.; Wang, B.; Wang, Q.; Wang, R.; Liu, S.; Xiong, F.; Jiang, Z.; Zhang, X.-Q.; Ye, W.-C.; Wang, H. Discovery of Novel Apigenin–Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer. J. Med. Chem. 2021, 64 (16), 12089– 12108, DOI: 10.1021/acs.jmedchem.1c0073541https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvVSqs73J&md5=acbdd99492d0b2315d3222cc2269f1a8Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of CancerLong, Huan; Hu, Xiaolong; Wang, Baolin; Wang, Quan; Wang, Rong; Liu, Shumeng; Xiong, Fei; Jiang, Zhenzhou; Zhang, Xiao-Qi; Ye, Wen-Cai; Wang, HaoJournal of Medicinal Chemistry (2021), 64 (16), 12089-12108CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivs. (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), resp. Among these compds., 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Mol. dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compd. for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- 42Hong, Y.; Liao, Z.-C.; Chen, J.-J.; Liu, J.; Liu, Y.-L.; Li, J.-H.; Sun, Q.; Chen, S.-L.; Wang, S.-W.; Tang, S. Radical 1, 2-Nitrogen Migration Cascades of β-Bromo α-Amino Acid Esters to Access β-Amino Acid Motifs Enabled by Cooperative Ni/Diboron Catalysis. ACS Catal. 2024, 14 (8), 5491– 5502, DOI: 10.1021/acscatal.4c01034There is no corresponding record for this reference.
- 43Hu, S.; Jiang, S.; Qi, X.; Bai, R.; Ye, X. Y.; Xie, T. Races of Small Molecule Clinical Trials for the Treatment of COVID-19: An up-to-Date Comprehensive Review. Drug Dev. Res. 2022, 83, 16, DOI: 10.1002/ddr.21895There is no corresponding record for this reference.
- 44Dilipkumar, S.; Karthik, V.; Dk, S.; Gowramma, B.; Lakshmanan, K. In-Silico Screening and Molecular Dynamics Simulation of Quinazolinone Derivatives as PARP1 and STAT3 Dual Inhibitors: A Novel DML Approaches. J. Biomol. Struct. Dyn. 2023, 1– 11, DOI: 10.1080/07391102.2023.2259476There is no corresponding record for this reference.
- 45Zhou, J.; Ji, M.; Wang, X.; Zhao, H.; Cao, R.; Jin, J.; Li, Y.; Chen, X.; Sheng, L.; Chen, X.; Xu, B. Discovery of Quinazoline-2,4(1 H,3 H)-Dione Derivatives Containing 3-Substituted Piperizines as Potent PARP-1/2 Inhibitors-Design, Synthesis, in Vivo Antitumor Activity, and X-Ray Crystal Structure Analysis. J. Med. Chem. 2021, 64 (22), 16711, DOI: 10.1021/acs.jmedchem.1c01522There is no corresponding record for this reference.