Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Cent. Sci. 2016, 2, 1, 27-31

Research ArticleDecember 23, 2015

Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
Click to copy article linkArticle link copied!

View Author Information

Open PDF Supporting Information (3)

ACS Central Science

Cite this: ACS Cent. Sci. 2016, 2, 1, 27–31

Click to copy citationCitation copied!

https://doi.org/10.1021/acscentsci.5b00345

Published December 23, 2015

Request reuse permissions

Abstract

Click to copy section linkSection link copied!

The fungal-derived Taiwanese natural product antroquinonol A has attracted both academic and commercial interest due to its reported exciting biological properties. This reduced quinone is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC) and was recently granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Pending successful completion of human clinical trials, antroquinonol is expected to be commercialized under the trade name Hocena. A synthesis-enabled biological re-examination of this promising natural product, however, reveals minimal in vitro and in vivo antitumor activity in preclinical models.

Subjects

Antroquinonol A (1, Figure 1A) is a quinone-containing natural product reported to have remarkable medicinal potential in the areas of oncology, immunology, and even diabetes. (1) More than ten publications have delineated the exciting activities of 1, and as a consequence, an investigational new drug (IND) application was filed by Golden Biotech Corp. in 2010. (2) It is currently in phase II clinical trials (in the USA and Taiwan) (3) for the treatment of non-small-cell lung cancer (NSCLC; phase II began in January 2014) (3) and has been granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Given the excitement surrounding this natural product (4) coupled with its relative structural simplicity, an effort was launched to pursue its synthesis and biological evaluation as part of the academic–industrial symbiosis between Scripps and Bristol-Myers Squibb (BMS). (5) In this communication, an enantioselective, scalable, and modular synthesis of 1 is reported. Access to copious amounts of pure 1 enabled a detailed biological reevaluation that is in contrast to the reported preclinical efficacy of the compound in a nude mouse model harboring human hepatoma xenografts and may temper the enthusiasm surrounding this natural product.

Figure 1. Graphical summary of retrosynthetic analyses explored for the synthesis of antroquinonol A (1).

At the outset of this project, no synthesis of 1 existed and its isolation from the rare Taiwanese fungus Antrodia camphorata was not a practical means for studying pure antroquinonol at BMS. (6) A set of plans, ranging in level of ambition and precedent, were evaluated (Figure 1) before settling on the substituted quinone 10 as our final starting point. Six representative blueprints are illustrated and can be divided conceptually into approaches that build the hydroxy enone of 1 via cyclization strategies or via the semireduction of a quinone system. Among the ring-building approaches, Danheiser-type annulation (2), (7) stepwise conjugate addition/annulation (3 + 4), (8) and Diels–Alder (5 + 6) (9) strategies were all pursued, leading either to lengthy sequences, low-yielding key steps, or unstable starting materials (4 and 6 rapidly isomerize). Inspired by the related structure of Coenzyme Q3 (7), extensive efforts to controllably reduce such systems were explored, to no avail. (10) Attempted allylic alcohol isomerization (11) by utilizing 1,4-diol 8 was not possible due to the inherent instability of such systems (spontaneous aromatization). Finally, efforts centering on a tandem 1,2-/1,4-addition (12) to silyl-dienone 9 (13) failed due to the tendency of silyl lithium reagents to reduce quinones rather than add to them. Collectively, these failures led us to the simplest possible approach: a conjugate addition to a substituted quinone. Reimagining this quinone as quinone–monoketal 10 gives the starting material “directionality”, allowing selective introduction of the nucleophile and electrophile through a Michael addition and subsequent 1,2-alkylation. (14) This strategy inherently makes the synthesis modular, allowing a host of nucleophiles and electrophiles to be quickly appended to any desired quinone starting material.

Scheme 1 depicts the fully optimized six-step, enantioselective, scalable synthesis of antroquinonol A (1). Each step was meticulously studied (see Supporting Information for tables of screened conditions), and as a result, gram quantities of 1 were generated for biological screening. The synthesis commences with the formation of quinon–monoketal 12 from commercial benzaldehyde 11. Baeyer–Villiger and dearomative oxidations followed by a trans-ketalization gave the desired quinone–monoacetal in an overall yield of 64%. (15) Extensive screening of the identity of the ketal protecting group (see Scheme 1B) and also of enantioselective conjugate addition conditions (16) led to a one-pot procedure that produced the vicinally difunctionalized product 14 with moderate yield and high stereoselectivity. Conjugate addition product 13 was also prepared in order to confirm absolute stereochemistry via X-ray crystallography. L-Selectride proved best in producing the 4,5-cis stereochemistry of the natural product with a dr of 3:1. Hydrolysis turned out to be a significant challenge, with most acidic conditions leading to a complex mixture of elimination products. Montmorillonite K10 clay was a sufficiently mild proton source for hydrolysis of ketal 14, producing enantioenriched (+)-antroquinonol A (1) in an overall yield of 13% and with 96% ee. Over one gram of the natural product has been prepared to date.

Scheme 1. Total Synthesis of (+)-Antroquinonol A (1)^a

With synthetic (+)-1 in hand, we began testing the compound against a panel of human tumor cell lines in vitro, previously reported in the literature for the natural product. As outlined in Table 1, natural antroquinonol (1) is reported to have low micromolar activity against the MDA-MB-231 breast, HepG2 hepatocellular, and LNCaP prostate tumor cell lines and low nanomolar activity versus the Hep 3B hepatocellular carcinoma (HCC) cell line. (1, 17) The reported IC₅₀ value in the lung tumor cell line (A549) for the natural product is 25 μM. (2c) In our hands, 1 is ∼3–70-fold less cytotoxic against these cell lines except for the A549 cell line, where it is ∼4-fold more potent than previously reported. The activity of 1 in the Hep 3B cell line was particularly striking, where it is significantly less potent when compared to the natural product. To be thorough, the enantiomer of 1, (−)-antroquinonol A, was tested in a similar panel, and, much like the natural product, high micromolar activity was seen for the Hep 3B and A549 cell lines (Table S6). The observed and reported high micromolar activity of 1 against a NSCLC cell line (A549) is somewhat puzzling since the natural product is in phase II trials for the treatment of this tumor type. It was indicated in the package submitted to the FDA for phase I studies that “In vivo study in NOD/SCID mice with A549 subcutaneous xenografts consistently showed tumor growth suppression after 2 weeks of oral 30 and 60 mg/kg antroquinonol treatment.” (18) In addition, the natural product is reported to have in vivo activity in a Hep 3B tumor model (vide infra). (19) Because of the promising efficacy in this hepatocellular model and the limited in vitro activity against the A549 cell line, we reasoned that an active metabolite(s) could potentially be contributing to the observed in vivo activity seen with 1.

Table 1. Oncology Panel in Vitro Data

entry	cell line	IC₅₀ μM reported in the lit.^a	IC₅₀ μM for 1^b (72 h)^c,^d	IC₅₀ μM for 15 (72 h)^c,^e
1	MDA-MB-231	2.6 ± 0.05^f	19 ± 1.6	>25
2	HepG2	4.3 ± 0.03^f	>25	>25
3	LNCaP	6.1 ± 0.07^f	22 ± 5.4	>25
4	Hep 3B	0.13 ± 0.02^f	8.9 ± 2.1	>25
5	PANC-1 (48 h)^c	19^g,^h	>25	>25
6	AsPC-1 (48 h)^c	20^g,^h	>25	>25
7	A549 (12 h)^c	25ⁱ	6.7 ± 2.5	10.8 ± 5.8
8	H441	25ⁱ	>25^e	>25

Source of cell line reported in the literature. MDA-MB-231: CCRC-60425. HepG2: BCRC-60025. LNCaP: CCRC-60088. Hep 3B: BCRC-60434. PANC-1: ATCC. AsPC-1: ATCC. A549: KMUH. H441: KMUH.

Source of cell lines reported in this paper: ATCC.

Incubation time.

Triplicate data.

Duplicate data.

Reference 1.

Reference 2f.

SRB assay.

ⁱ

Reference 2c.

When 1 was subjected to metabolite identification/biotransformation studies using human, rat, and mouse liver microsomes, it was rapidly converted to a major metabolite across all three species (Figure 2), (20) the structure of which was tentatively assigned as the acid 15 based on MS/MS and ¹H NMR data.

Figure 2. A. Antroquinonol A metabolite (15) profile in MsLM. X = sample matrix peaks, not parent related. B. Reagents and conditions: (a) LiHMDS (1.5 equiv), HMPA (2.5 equiv), allyl bromide (2.5 equiv), THF, 0 °C, 6 h (44%); (b) L-Selectride (2.0 equiv), toluene, −78 °C to −20 °C, 6 h (74%); (c) Montmorillonite K10 clay (30 wt %), DCM, 23 °C, 2 h (49%); (d) TBAF (2.0 equiv), THF, 23 °C, 2 h (99%); (e) PIDA (1.1 equiv), TEMPO (0.2 equiv), THF, 23 °C, 4 h; (f) NaClO₂ (7 equiv), NaH₂PO₄ (7 equiv), 2-methyl-2-butene (20 equiv), t-BuOH, H₂O, 23 °C, 12 h (58%). MsLM = mouse liver microsomes.

In order to confirm this structure and produce enough material for biological evaluation, a synthesis of 15 was undertaken. As a testament to the modularity of the synthetic route to 1, acid 15 was easily accessed through an identical strategy. Simply replacing farnesyl bromide with an oxidized derivative, followed by alkylation, reduction, and hydrolysis conditions, furnished antroquinonol analogue 17. Not surprisingly, chemoselective oxidation of the primary alcohol in the presence of the partially reduced quinone core of antroquinonol proved challenging. Employing TEMPO as a catalytic oxidant proved successful. (21) Subsequent oxidation of the sensitive aldehyde under Pinnick conditions gave the desired acid metabolite 15, which spectroscopically matched the isolated material from liver microsomes (vide supra).

Compound 15 was subjected to the same tumor cell line panel as 1; however, little to no cytotoxicity was observed. (22) Further metabolism studies where 1 was incubated with human, rat, and mouse hepatocytes showed that compound 15 is most likely rapidly oxidized and degraded to a known inactive metabolite (Met2) most likely via mitochondrial β-oxidation (Figure S2). (23a-23c)

Although the source of the Hep 3B tumor cell lines used in the literature is different from the one described herein (see Table 1 footnote), we decided to conduct an in vivo study with synthetic antroquinonol (1) based on the reported efficacy of the natural product. (19) Before embarking on such a study, a pharmacokinetic (PK) study of 1 in mouse was performed to determine the exposure of the compound when dosed either orally (po) or intraperitoneally (ip). A single 50 mg/kg dose of 1 provided the PK profile depicted in Table 2, in which exposures following oral administration were significantly lower compared to those from ip dosing.

Table 2. Mouse Pharmacokinetic Data

PK parameters	ip dosing^a	po dosing^a
C_max (nM)	457 ± 45	79 ± 52
T_max (h)	4 ± 3	2 ± 1
AUC_last (nM·h)	2290 ± 142	266 ± 88

Corn oil was used as the dosing vehicle.

An in vivo efficacy study was conducted with 1 using Hep 3B HCC tumor xenografts implanted subcutaneously in female NSG mice. Despite literature reports of statistically significant antitumor activity observed with the natural product, (2a, 19) compound 1 was inactive (<70% tumor growth inhibition, TGI) in our hands when administered daily ip for 14 consecutive days (Figure 3). Paclitaxel served as a positive control in this study and was clearly efficacious (79% TGI) when administered on its optimal preclinical dosing regimen (24 mg/kg, qd×5, iv). Compound 1 was generally well-tolerated with no overt signs of toxicity and minimal weight loss (∼4%).

Figure 3. *In vivo* antitumor activity of synthetic antroquinonol in the Hep 3B HCC xenograft model. Last measurement in the control group includes only one animal, since all other mice in this group had to be euthanized due to severe tumor necrosis. Standard error of the mean (SE) is calculated using the average deviation built-in formula in Quantrix spreadsheets as part of IDBS’s EWorkBook Suite.

In summary, a concise, six-step, scalable, enantioselective synthesis of (+)-antroquinonol (1) has enabled an extensive reinvestigation of some of its reported preclinical biological properties. As outlined in this manuscript, compound 1 demonstrated only micromolar activity in a panel of select tumor cell lines. While the reported Hep 3B cytotoxicity data was intriguing, it was significantly less potent in our panel, therefore it was not unexpected that the compound was inactive in the xenograft model derived from this cell line. The modular synthetic route enabled us to prepare and evaluate a major metabolite identified from biotransformation studies; this compound was inactive and therefore unlikely contributing to the reported in vivo activity. Despite differences in the cell lines used for the in vitro assays (24) and the manner in which the in vivo studies were conducted (e.g., the different initial tumor sizes), the lack of efficacy in an in vivo preclinical model would be a cause for concern if the compound were to be advanced into the clinic for treating hepatocellular carcinoma. As indicated earlier, antroquinonol is currently in phase II clinical trials for the treatment of NSCLC. However, the reported in vitro IC₅₀ for antroquinonol A (1) as well as the data with synthetic antroquinonol (Table 1) suggest that the activity of the parent compound 1 for this tumor cell line is in the high micromolar range. Based on the in vitro cytotoxicity data for the A549 cell line, metabolic stability data in microsomes, and mouse PK profile, very high exposures (25) or the presence of a yet unknown active metabolite may be necessary for 1 to show efficacy in treating NSCLC in the clinic.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.5b00345.

Crystallographic data (CIF)
Experimental procedures and analytical data (PDF)
NMR spectra (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!

Corresponding Authors
- T. G. Murali Dhar - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States; Email: [email protected]
- Phil S. Baran - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States; Email: [email protected]
Authors
- Matthew T. Villaume - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Eran Sella - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Garrett Saul - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Robert M. Borzilleri - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
- Joseph Fargnoli - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
- Kathy A. Johnston - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
- Haiying Zhang - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
- Mark P. Fereshteh - Departments of Discovery Chemistry, Oncology Discovery and Leads Discovery & Optimization, Preclinical Optimization, Bristol-Myers Squibb Co., Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
Notes
The authors declare no competing financial interest.

Acknowledgment

Click to copy section linkSection link copied!

Financial support for this work was provided by NSF (predoctoral fellowship to M.T.V.) and George E. Hewitt Foundation (postdoctoral fellowship to E.S.). The authors thank Prof. Arnold L. Rheingold and Dr. Curtis E. Moore for X-ray crystallographic analysis. We thank Dr. Joel C. Barrish for useful discussions, Sarah Traeger for NMR analysis of the metabolite, Robin Moore, Paul Elzinga, and Georgia Cornelius for PK support, and Christopher Mulligan for in vivo support.

References

Click to copy section linkSection link copied!

This article references 25 other publications.

1
Isolation and structural determination of antroquinonol A (1):
Lee, T.; Lee, C.; Tsou, W.; Liu, S.; Kuo, M.; Wen, W. Planta Med. 2007, 73, 1412 DOI: 10.1055/s-2007-990232
Google Scholar
There is no corresponding record for this reference.
2
Biological activity studies of 1:
(a) Chiang, P. C.; Lin, S. C.; Pan, S. L.; Kuo, C. H.; Tsai, I. L.; Kuo, M. T.; Wen, W. C.; Chen, P.; Guh, J. H. Biochem. Pharmacol. 2010, 79, 162 DOI: 10.1016/j.bcp.2009.08.022
Google Scholar
There is no corresponding record for this reference.
(b) Kumar, K. J.; Chu, F. H.; Hsieh, H. W.; Liao, J. W.; Li, W. H.; Lin, J. C.; Shaw, J. F.; Wang, S. Y. J. Ethnopharmacol. 2011, 136, 168 DOI: 10.1016/j.jep.2011.04.030
Google Scholar
There is no corresponding record for this reference.
(c) Kumar, V. B.; Yuan, T. C.; Liou, J. W.; Yang, C. J.; Sung, P. J.; Weng, C. F. Mutat. Res., Fundam. Mol. Mech. Mutagen. 2011, 707, 42 DOI: 10.1016/j.mrfmmm.2010.12.009
Google Scholar
2c
Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles
Kumar, V. Bharath; Yuan, Ta-Chun; Liou, Je-Wen; Yang, Chih-Jen; Sung, Ping-Jyun; Weng, Ching-Feng
Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis (2011), 707 (1-2), 42-52CODEN: MUREAV; ISSN:0027-5107. (Elsevier B.V.)
Antroquinonol a deriv. of Antrodia camphorata has been reported to have antitumor effects against various cancer cells. However, the effect of antroquinonol on cell signalling and survival pathways in non-small cell lung cancer (NSCLC) cells has not been fully demarcated. Here we report that antroquinonol treatment significantly reduced the proliferation of three NSCLC cells. Treatment of A549 cells with antroquinonol increased cell shrinkage, apoptotic vacuoles, pore formation, TUNEL pos. cells and increased Sub-G1 cell population with respect to time and dose dependent manner. Antroquinonol treatment not only increased the Sub-G1 accumulation but also reduced the protein levels of cdc2 without altering the expression of cyclin B1, cdc25C, pcdc2, and pcdc25C. Antroquinonol induced apoptosis was assocd. with disrupted mitochondrial membrane potential and activation of Caspase 3 and PARP cleavage in A549 cells. Moreover, antroquinonol treatment down regulated the expression of Bcl2 proteins, which was correlated with the decreased PI3K and mTOR protein levels without altering pro apoptotic and anti apoptotic proteins. Results from the microarray anal. demonstrated that antroquinonol altered the expression level of miRNAs compared with untreated control in A549 cells. The data collectively suggested the antiproliferative effect of antroquinonol on NSCLC A549 cells, which provides useful information for understanding the anticancer mechanism influenced by antroquinonol and is the first report to suggest that antroquinonol may be a promising chemotherapeutic agent for lung cancer.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlGrsbk%253D&md5=7163125bbb7a4d4317fec7ec570e26b1
(d) Tsai, P. Y.; Ka, S. M.; Chao, T. K.; Chang, J. M.; Lin, S. H.; Li, C. Y.; Kuo, M. T.; Chen, P.; Chen, A. Free Radical Biol. Med. 2011, 50, 1503 DOI: 10.1016/j.freeradbiomed.2011.02.029
Google Scholar
2d
Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice
Tsai, Pei-Yi; Ka, Shuk-Man; Chao, Tai-Kuang; Chang, Jia-Ming; Lin, Shih-Hua; Li, Chen-Yun; Kuo, Mao-Tien; Chen, Peini; Chen, Ann
Free Radical Biology & Medicine (2011), 50 (11), 1503-1516CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compd., is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide prodn. and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-β1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-β1-mediated fibrosis pathways in the kidney.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVWhtL8%253D&md5=2c0557160cdee2f39134cac332274dbb
(e) Tsai, P. Y.; Ka, S. M.; Chang, J. M.; Lai, J. H.; Dai, M. S.; Jheng, H. L.; Kuo, M. T.; Chen, P.; Chen, A. Arthritis Rheum. 2012, 64, 232 DOI: 10.1002/art.33328
Google Scholar
2e
Antroquinonol differentially modulates T cell activity and reduces interleukin-18 production, but enhances Nrf2 activation, in murine accelerated severe lupus nephritis
Tsai, Pei-Yi; Ka, Shuk-Man; Chang, Jia-Ming; Lai, Jenn-Haung; Dai, Ming-Shen; Jheng, Huei-Lin; Kuo, Mao-Tien; Chen, Peini; Chen, Ann
Arthritis & Rheumatism (2012), 64 (1), 232-242CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)
Objective: Accelerated severe lupus nephritis (ASLN), with an acute onset of severe clin. manifestations and histopathol. renal lesions, may represent transformation of mild LN to a severe form of glomerulonephritis. Abnormal activation of T and B cells and/or oxidative stress may play a major role in the pathogenesis of ASLN. This study tested the hypothesis that antroquinonol, a purified compd. and major effective component of Antrodia camphorata with antiinflammatory and antioxidant activities, might prevent the transformation of mild LN into higher-grade (severe) nephritis in a murine lupus model. Methods: Exptl. ASLN was induced in (NZB × NZW)F1 mice by twice weekly i.p. injections of Salmonella-type lipopolysaccharide (LPS). Starting 2 days after the first dose of LPS, mice were treated daily with antroquinonol, administered by gavage, for different durations up to 5 wk. Results: Antroquinonol administration significantly ameliorated the proteinuria, hematuria, impairment of renal function, and development of severe renal lesions, esp. cellular crescent formation, neutrophil infiltration, fibrinoid necrosis, and T cell proliferation in the glomerulus, as well as periglomerular interstitial inflammation. Mechanistic analyses revealed that antroquinonol 1) inhibited T cell activation/proliferation, but enhanced Treg cell suppression and reduced renal prodn. of interleukin-18 (IL-18); 2) inhibited prodn. of reactive oxygen species and nitric oxide, but increased activation of Nrf2 in the kidney; and 3) suppressed renal inflammation via blocking of NF-κB activation. Conclusion : Antroquinonol may have therapeutic potential for the early treatment of ASLN via its differential regulation of T cell function and lowering of IL-18 prodn., but also via the promotion of Nrf2 activation.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs12mtbrK&md5=c14a194282503280afebacd6af5acd2e
(f) Yu, C. C.; Chiang, P. C.; Lu, P. H.; Kuo, M. T.; Wen, W. C.; Chen, P.; Guh, J. H. J. Nutr. Biochem. 2012, 23, 900 DOI: 10.1016/j.jnutbio.2011.04.015
Google Scholar
2f
Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells
Yu, Chia-Chun; Chiang, Po-Cheng; Lu, Pin-Hsuan; Kuo, Mao-Tien; Wen, Wu-Che; Chen, Peini; Guh, Jih-Hwa
Journal of Nutritional Biochemistry (2012), 23 (8), 900-907CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
Pancreatic cancer is a malignant neoplasm of the pancreas. A mutation and constitutive activation of K-ras occurs in more than 90% of pancreatic adenocarcinomas. A successful approach for the treatment of pancreatic cancers is urgent. Antroquinonol, a ubiquinone deriv. isolated from a camphor tree mushroom, Antrodia camphorata, induced a concn.-dependent inhibition of cell proliferation in pancreatic cancer PANC-1 and AsPC-1 cells. Flow cytometric anal. of DNA content by propidium iodide staining showed that antroquinonol induced G1 arrest of the cell cycle and a subsequent apoptosis. Antroquinonol inhibited Akt phosphorylation at Ser473, the phosphorylation site crit. for Akt kinase activity, and blocked the mammalian target of rapamycin (mTOR) phosphorylation at Ser2448, a site dependent on mTOR activity. Several signals responsible for mTOR/p70S6K/4E-BP1 signaling cascades have also been examd. to validate the pathway. Moreover, antroquinonol induced the down-regulation of several cell cycle regulators and mitochondrial antiapoptotic proteins. In contrast, the expressions of K-ras and its phosphorylation were significantly increased. The coimmunopptn. assay showed that the assocn. of K-ras and Bcl-xL was dramatically augmented, which was indicative of apoptotic cell death. Antroquinonol also induced the cross talk between apoptosis, autophagic cell death and accelerated senescence, which was, at least partly, explained by the up-regulation of p21Waf1/Cip1 and K-ras. In summary, the data suggest that antroquinonol induces anticancer activity in human pancreatic cancers through an inhibitory effect on PI3-kinase/Akt/mTOR pathways that in turn down-regulates cell cycle regulators. The translational inhibition causes G1 arrest of the cell cycle and an ultimate mitochondria-dependent apoptosis. Moreover, autophagic cell death and accelerated senescence also explain antroquinonol-mediated anticancer effect.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymtrvO&md5=e9ba90526a809ea91ebec180ea3d1871
(g) Yang, S. M.; Ka, S. M.; Hua, K. F.; Wu, T. H.; Chuang, Y. P.; Lin, Y. W.; Yang, F. L.; Wu, S. H.; Yang, S. S.; Lin, S. H.; Chang, J. M.; Chen, A. Free Radical Biol. Med. 2013, 61, 285 DOI: 10.1016/j.freeradbiomed.2013.03.024
Google Scholar
2g
Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome
Yang, Shun-Min; Ka, Shuk-Man; Hua, Kuo-Feng; Wu, Tzu-Hua; Chuang, Yi-Ping; Lin, Ya-Wen; Yang, Feng-Ling; Wu, Shih-Hsiung; Yang, Sung-Sen; Lin, Shih-Hua; Chang, Jia-Ming; Chen, Ann
Free Radical Biology & Medicine (2013), 61 (), 285-297CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compd. from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been detd. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic anal. in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathol. in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addn., Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS prodn. in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptV2gurs%253D&md5=f32e6ab26398fafacef219e9863c6643
(h) Chen, C. K.; Kang, J. J.; Wen, W. C.; Chiang, H. F.; Lee, S. S. J. Nat. Prod. 2014, 77, 1061 DOI: 10.1021/np400670a
Google Scholar
There is no corresponding record for this reference.
(i) Ho, C. L.; Wang, J. L.; Lee, C. C.; Cheng, H. Y.; Wen, W. C.; Cheng, H. H.; Chen, M. C. Biomed. Pharmacother. 2014, 68, 1007 DOI: 10.1016/j.biopha.2014.09.008
Google Scholar
2i
Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells
Ho, Ching-Liang; Wang, Jui-Ling; Lee, Cheng-Chung; Cheng, Hsiu-Yi; Wen, Wu-Che; Cheng, Howard Hao-Yu; Chen, Miles Chih-Ming
Biomedicine & Pharmacotherapy (2014), 68 (8), 1007-1014CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
Antroquinonol is the smallest anticancer mol. isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a mol. docking anal. illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The mol. docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogs. We also found that the levels of LC3B-II and the autophagosome-assocd. LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and assocd. mode of cell death in cancer cells.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1agsLnI&md5=f507267a297f883d3e1a6ce9f2093e4a
(j) Hsu, C. Y.; Sulake, R. S.; Huang, P. K.; Shih, H. Y.; Sie, H. W.; Lai, Y. K.; Chen, C.; Weng, C. F. Br. J. Pharmacol. 2015, 172, 38 DOI: 10.1111/bph.12828
Google Scholar
2j
Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities
Hsu, C. Y.; Sulake, R. S.; Huang, P.-K.; Shih, H.-Y.; Sie, H.-W.; Lai, Y.-K.; Chen, C.; Weng, C. F.
British Journal of Pharmacology (2015), 172 (1), 38-49CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
Background and Purpose : The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chem. synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity. Exptl. Approach : Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycemic control in vivo. Key Results : The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clin. used inhibitor, sitagliptin. The phosphorylation of AMPK Thr172 in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. Conclusions and Implications : Chem. synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFWlsLvE&md5=9e1efa8476f5d04f4ef7732a5223ba59
(k) Lee, W. T.; Lee, T. H.; Cheng, C. H.; Chen, K. C.; Chen, Y. C.; Lin, C. W. Food Chem. Toxicol. 2015, 78, 33 DOI: 10.1016/j.fct.2015.01.012
Google Scholar
2k
Antroquinonol from Antrodia Camphorata suppresses breast tumor migration/invasion through inhibiting ERK-AP-1- and AKT-NF-κB-dependent MMP-9 and epithelial-mesenchymal transition expressions
Lee, Wai-Theng; Lee, Tzong-Huei; Cheng, Chia-Hsiung; Chen, Ku-Chung; Chen, Yen-Chou; Lin, Cheng-Wei
Food and Chemical Toxicology (2015), 78 (), 33-41CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
Antroquinonol (ANQ) is an ubiquinon deriv. isolated from the mycelium of Antrodia camphorata. However, the effect of ANQ on breast cancer treatment is unknown. We found that ANQ significantly suppressed the migration and invasion of breast cancer MDA-MB-231 cells, and inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced invasiveness by MCF7 cells. ANQ inhibiting MMP-9 gene expression and enzymic activity occurred at transcriptional regulation. Mechanistically, activation of ERK and AKT is crucial for MMP-9 gene expression, and the addn. of ANQ suppressed phosphorylation of ERK and AKT. The induction of the AP-1 and NF-κB pathway participated in MMP-9 gene expression. Suppression of ERK inhibited AP-1, whereas blocking AKT diminished NF-κB activity, and treatment with ANQ suppressed both AP-1 and NF-κB signaling. Moreover, ANQ suppressed EMT protein expression, and inhibited TPA-induced EMT through downregulating the ERK-AP-1 and AKT-NF-κB signaling cascades. Together, our data showed for the first time that ANQ inhibited breast cancer invasiveness by suppressing ERK-AP-1- and AKT-NF-κB-dependent MMP-9 and EMT expressions.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisVSis74%253D&md5=bbd88fa98bb732bace62dfd0ff4dbcb6
3
ClinicalTrials.gov Identifier: NCT02047344.
There is no corresponding record for this reference.
4
GoldenBiotech’s new cancer drug Hocena has been awarded the “Research and Development Innovation Award” in Taipei Biotech Awards 2014. http://www.goldenbiotech.com.tw/en/newslist.html, accessed on July 18, 2015.
Google Scholar
There is no corresponding record for this reference.
5
Michaudel, Q.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2015, 48, 712 DOI: 10.1021/ar500424a
Google Scholar
There is no corresponding record for this reference.
6
Three total syntheses of 1 were reported while this manuscript was in preparation:
(a) Hsu, C. S.; Chou, H. H.; Fang, J. M. Org. Biomol. Chem. 2015, 13, 5510 DOI: 10.1039/C5OB00411J
Google Scholar
There is no corresponding record for this reference.
(b) Sulake, R. S.; Chen, C. Org. Lett. 2015, 17, 1138 DOI: 10.1021/acs.orglett.5b00046
Google Scholar
There is no corresponding record for this reference.
(c) Sulake, R. S.; Lin, H. H.; Hsu, C. Y.; Weng, C. F.; Chen, C. J. Org. Chem. 2015, 80, 6044 DOI: 10.1021/acs.joc.5b00345
Google Scholar
There is no corresponding record for this reference.
7
(a) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc. 2004, 126, 1624 DOI: 10.1021/ja0399066
Google Scholar
7a
Remarkably facile hexatriene electrocyclizations as a route to functionalized cyclohexenones via ring expansion of cyclobutenones
Magomedov, Nabi A.; Ruggiero, Piero L.; Tang, Yuchen
Journal of the American Chemical Society (2004), 126 (6), 1624-1625CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A cascade reaction sequence that led to highly functionalized cyclohexenones, e.g., I, by reacting cyclobutenones with α-lithio-α,β-unsatd. sulfones, is described. This reaction sequence is believed to involve the hexatriene-cyclohexadiene cyclization.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXosFOhsQ%253D%253D&md5=06dcb6c65c5494abdd7382b08cb70783
(b) Matsumoto, T.; Hamura, T.; Miyamoto, M.; Suzuki, K. Tetrahedron Lett. 1998, 39, 4853 DOI: 10.1016/S0040-4039(98)00920-4
Google Scholar
There is no corresponding record for this reference.
8
Beckwith, A. L. J.; Chai, C. L. L. Tetrahedron 1993, 49, 7871 DOI: 10.1016/S0040-4020(01)88012-1
Google Scholar
There is no corresponding record for this reference.
9
Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett. 2009, 11, 5330 DOI: 10.1021/ol902173g
Google Scholar
There is no corresponding record for this reference.
10
Kündig, E. P.; Enriquez-Garcia, A. Beilstein J. Org. Chem. 2008, 4, 37 DOI: 10.3762/bjoc.4.37
Google Scholar
There is no corresponding record for this reference.
11
Mantilli, L.; Gerard, D.; Torche, S.; Besnard, C.; Mazet, C. Angew. Chem., Int. Ed. 2009, 48, 5143 DOI: 10.1002/anie.200901863
Google Scholar
11
Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols
Mantilli, Luca; Gerard, David; Torche, Sonya; Besnard, Celine; Mazet, Clement
Angewandte Chemie, International Edition (2009), 48 (28), 5143-5147, S5143/1-S5143/19CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Under appropriate reaction conditions, iridium hydride catalysts formed in situ promote the isomerization of primary allylic alcs. The best precatalysts, e.g., I (Ad = 1-adamantyl; cod = 1,5-cyclooctadiene), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotVensL4%253D&md5=27be175b3203cecd08d4249d8c6e9f97
12
Solomon, M.; Jamison, C. L.; McCormick, M.; Liotta, D. J. Am. Chem. Soc. 1988, 110, 3702 DOI: 10.1021/ja00219a079
Google Scholar
There is no corresponding record for this reference.
13
Koreeda, M.; Koo, S. Tetrahedron Lett. 1990, 31, 831 DOI: 10.1016/S0040-4039(00)94639-2
Google Scholar
There is no corresponding record for this reference.
14
Meister, A. C.; Sauter, P. F.; Brase, S. Eur. J. Org. Chem. 2013, 2013, 7110 DOI: 10.1002/ejoc.201300752
Google Scholar
There is no corresponding record for this reference.
15
Pirrung, M. C.; Nunn, D. S. Tetrahedron Lett. 1992, 33, 6591 DOI: 10.1016/S0040-4039(00)60993-0
Google Scholar
There is no corresponding record for this reference.
16
Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1, 623 DOI: 10.1021/ol990707u
Google Scholar
There is no corresponding record for this reference.
17
The IC₅₀ values for the natural product against the Hep3B and HepG2 carcinoma cell lines are reported as 0.13 ± 0.02 μM and 4.3 ± 0.03 μM respectively in ref 1, as indicated in Table 1. The GI_50′ values for 1 against the same cell lines are listed as >30 μM and 0.22 μM respectively in ref 2a. The cytotoxicity assay protocol used in this paper and ref 1 employs 10% FBS and a 72 h incubation time with compound (antroquinonol) using MTS or MTT stain. The protocol outlined in ref 2a employs 5% FBS, 48 h incubation time, and an SRB stain. It is clear from the discussion (vide supra) that the protocol employed in this paper to determine cytotoxicity closely mirrors the conditions used in ref 1.
There is no corresponding record for this reference.
18
ClinicalTrials.gov Identifier: NCT01134016.
There is no corresponding record for this reference.
19
For discussion regarding the in vivo activity see ref 2a, page 170, left column, third paragraph. See supplementary material of ref 2a for in vivo data. Initial tumor sizes were not identical: 50–70 mm³ (lit.) (2a) vs 75–100 mm³ (BMS).
There is no corresponding record for this reference.
20
Data shown for mouse liver microsomes.
There is no corresponding record for this reference.
21
De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974 DOI: 10.1021/jo971046m
Google Scholar
21
A Versatile and Highly Selective Hypervalent Iodine(III)/2,2,6,6-Tetramethyl-1-piperidinyloxyl-Mediated Oxidation of Alcohols to Carbonyl Compounds
De Mico, Antonella; Margarita, Roberto; Parlanti, Luca; Vescovi, Andrea; Piancatelli, Giovanni
Journal of Organic Chemistry (1997), 62 (20), 6974-6977CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Catalytic amts. of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) are used in combination with [bis(acetoxy)iodo]benzene (BAIB) as a stoichiometric oxidant in the conversion of primary and secondary alcs. to carbonyl compds. This procedure works efficiently at room temp. in almost all common solvents and neat in some cases. This process exhibits a very high degree of selectivity for the oxidn. of primary alcs. to aldehydes, without any noticeable overoxidn. to carboxyl compds., and a high chemoselectivity in the presence of either secondary alcs. or of other oxidizable moieties. This procedure allows an easy, convenient, high-yielding method for the oxidn. of alcs. starting from com. available compds.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtVenur8%253D&md5=df6a370727f2bcb72fdd520371150d0d
22
The Caco-2 value for 15 (Pc A → B, 62 nm/s, and B → A, 63 nm/s) suggests that cell permeability may not be an issue with 15.
There is no corresponding record for this reference.
23
(a)
Met2 (Figure S2; structure based on MS–MS data) is a reported metabolite of antroquinonol
.
Google Scholar
There is no corresponding record for this reference.
(b)
Met2 is inactive in the H838 tumor cell line (IC₅₀ > 100 μM vs antroquinonol IC₅₀ of ∼ 3 μM).
Ho, C.-L.; Wang, J.-L.; Lee, C.-C.; Cheng, H.-Y.; Wen, W.-C.; Cheng, H. H-Y.; Chen, M. C-M. Biomed. Pharmacother. 2014, 68, 1007 DOI: 10.1016/j.biopha.2014.09.008
Google Scholar
23b
Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells
Ho, Ching-Liang; Wang, Jui-Ling; Lee, Cheng-Chung; Cheng, Hsiu-Yi; Wen, Wu-Che; Cheng, Howard Hao-Yu; Chen, Miles Chih-Ming
Biomedicine & Pharmacotherapy (2014), 68 (8), 1007-1014CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
Antroquinonol is the smallest anticancer mol. isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a mol. docking anal. illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The mol. docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogs. We also found that the levels of LC3B-II and the autophagosome-assocd. LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and assocd. mode of cell death in cancer cells.
>> More from SciFinder ^®
https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1agsLnI&md5=f507267a297f883d3e1a6ce9f2093e4a
(c)
Synthetic antroquinonol appears to have a relatively better in vitro metabolic stability in human hepatocytes compared to human liver microsomes.
.
Google Scholar
There is no corresponding record for this reference.
24
A thorough investigation of the antiproliferative activity against a large panel of human tumor cell lines was not performed.
There is no corresponding record for this reference.
25
Antroquinonol is being administered to patients at 200 mg tid in the ongoing phase II clinical trial (ref 3).
There is no corresponding record for this reference.

Cited By

Click to copy section linkSection link copied!

This article is cited by 34 publications.

David S. Peters, Cody Ross Pitts, Kyle S. McClymont, Thomas P. Stratton, Cheng Bi, Phil S. Baran. Ideality in Context: Motivations for Total Synthesis. Accounts of Chemical Research 2021, 54 (3) , 605-617. https://doi.org/10.1021/acs.accounts.0c00821
Marianne Piochon, Pauline M. L. Coulon, Armand Caulet, Marie-Christine Groleau, Eric Déziel, Charles Gauthier. Synthesis and Antimicrobial Activity of Burkholderia-Related 4-Hydroxy-3-methyl-2-alkenylquinolines (HMAQs) and Their N-Oxide Counterparts. Journal of Natural Products 2020, 83 (7) , 2145-2154. https://doi.org/10.1021/acs.jnatprod.0c00171
Jacob C. Timmerman, John L. Wood. Synthesis and Biological Evaluation of Hippolachnin A Analogues. Organic Letters 2018, 20 (13) , 3788-3792. https://doi.org/10.1021/acs.orglett.8b01381
Jordan T. Koehn, Estela S. Magallanes, Benjamin J. Peters, Cheryle N. Beuning, Allison A. Haase, Michelle J. Zhu, Christopher D. Rithner, Dean C. Crick, Debbie C. Crans. A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface. The Journal of Organic Chemistry 2018, 83 (1) , 275-288. https://doi.org/10.1021/acs.joc.7b02649
Bo-Bo Zhang, Peng-Fei Hu, Jing Huang, Yong-Dan Hu, Lei Chen, and Gan-Rong Xu . Current Advances on the Structure, Bioactivity, Synthesis, and Metabolic Regulation of Novel Ubiquinone Derivatives in the Edible and Medicinal Mushroom Antrodia cinnamomea. Journal of Agricultural and Food Chemistry 2017, 65 (48) , 10395-10405. https://doi.org/10.1021/acs.jafc.7b04206
Mei-Chuan Chen, Ting-Yu Cho, Yueh-Hsiung Kuo, and Tzong-Huei Lee . Meroterpenoids from a Medicinal Fungus Antrodia cinnamomea. Journal of Natural Products 2017, 80 (9) , 2439-2446. https://doi.org/10.1021/acs.jnatprod.7b00223
Maoqun Tian, Ming Yan, and Phil S. Baran . 11-Step Total Synthesis of Araiosamines. Journal of the American Chemical Society 2016, 138 (43) , 14234-14237. https://doi.org/10.1021/jacs.6b09701
Artiom Cernijenko, Rune Risgaard, and Phil S. Baran . 11-Step Total Synthesis of (−)-Maoecrystal V. Journal of the American Chemical Society 2016, 138 (30) , 9425-9428. https://doi.org/10.1021/jacs.6b06623
Xiang Li. Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms. American Journal of Cancer Research 2024, 14 (6) , 2695-2713. https://doi.org/10.62347/XLZX8935
Ardalan Pasdaran, Bahareh Hassani, Ali Tavakoli, Ekaterina Kozuharova, Azadeh Hamedi. A Review of the Potential Benefits of Herbal Medicines, Small Molecules of Natural Sources, and Supplements for Health Promotion in Lupus Conditions. Life 2023, 13 (7) , 1589. https://doi.org/10.3390/life13071589
Thomas A. K. Prescott, Rowena Hill, Eduard Mas-Claret, Ester Gaya, Edie Burns. Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches. Biomolecules 2023, 13 (6) , 986. https://doi.org/10.3390/biom13060986
Feng-Wei Guo, Tian-Yi Zhou, Yong Qu, Mei-Yan Wei, Guang-Ying Chen, Yu-Cheng Gu, Chang-Yun Wang, Chang-Lun Shao. Highly efficient and scalable total syntheses and stereochemical assignment of potent anti-inflammatory pesimquinolones I and J. Organic Chemistry Frontiers 2023, 10 (4) , 852-858. https://doi.org/10.1039/D2QO01788A
Susan Miller, Walter Moos, Barbara Munk, Stephen Munk, Charles Hart, David Spellmeyer. Drug discovery: Chaos can be your friend or your enemy. 2023, 417-511. https://doi.org/10.1016/B978-0-12-824304-6.00012-2
Fernandez Francesca, Aust Caitlin, Lye Sarah, Griffiths Lyn Robyn. Antroquinonol administration in animal preclinical studies for Alzheimer's disease (AD): A new avenue for modifying progression of AD pathophysiology. Brain, Behavior, & Immunity - Health 2022, 21 , 100435. https://doi.org/10.1016/j.bbih.2022.100435
Minghua Jiang, Zhenger Wu, Lan Liu, Senhua Chen. The chemistry and biology of fungal meroterpenoids (2009–2019). Organic & Biomolecular Chemistry 2021, 19 (8) , 1644-1704. https://doi.org/10.1039/D0OB02162H
Yi Kuang, Bin Li, Zilong Wang, Xue Qiao, Min Ye. Terpenoids from the medicinal mushroom Antrodia camphorata : chemistry and medicinal potential. Natural Product Reports 2021, 38 (1) , 83-102. https://doi.org/10.1039/D0NP00023J
Jing‐Kai Huang, Kak‐Shan Shia. Development of a Cross‐Conjugated Vinylogous [4+2] Anionic Annulation and Application to the Total Synthesis of Natural Antibiotic (±)‐ABX. Angewandte Chemie 2020, 132 (16) , 6602-6607. https://doi.org/10.1002/ange.201914657
Jing‐Kai Huang, Kak‐Shan Shia. Development of a Cross‐Conjugated Vinylogous [4+2] Anionic Annulation and Application to the Total Synthesis of Natural Antibiotic (±)‐ABX. Angewandte Chemie International Edition 2020, 59 (16) , 6540-6545. https://doi.org/10.1002/anie.201914657
Xiao-Feng Liu, Yong-Jun Xia, Phoency F-H Lai, Yao Zhang, Zhen-Wei Yi, Chun-Liang Xie, Yi-Qiu Hong, Lian-Zhong Ai. An increase in cell membrane permeability in the in situ extractive fermentation improves the production of antroquinonol from Antrodia camphorata S-29. Journal of Industrial Microbiology and Biotechnology 2020, 47 (2) , 197-207. https://doi.org/10.1007/s10295-020-02258-8
Keita Sakamoto, Haruhiko Fuwa. Total Synthesis of a Marine Macrolide Natural Product, Iriomoteolide-2a: The Fundamental Role of Total Synthesis in Natural Product Chemistry. Journal of Synthetic Organic Chemistry, Japan 2019, 77 (8) , 831-840. https://doi.org/10.5059/yukigoseikyokaishi.77.831
Keita Sakamoto, Akihiro Hakamata, Arihiro Iwasaki, Kiyotake Suenaga, Masashi Tsuda, Haruhiko Fuwa. Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide‐2a. Chemistry – A European Journal 2019, 25 (36) , 8528-8542. https://doi.org/10.1002/chem.201900813
Bo-Bo Zhang, Yu-Yan Guan, Peng-Fei Hu, Lei Chen, Gan-Rong Xu, Liming Liu, Peter C. K. Cheung. Production of bioactive metabolites by submerged fermentation of the medicinal mushroom Antrodia cinnamomea : recent advances and future development. Critical Reviews in Biotechnology 2019, 39 (4) , 541-554. https://doi.org/10.1080/07388551.2019.1577798
Alexander A. Braddock, Emmanuel A. Theodorakis. Marine Spirotetronates: Biosynthetic Edifices That Inspire Drug Discovery. Marine Drugs 2019, 17 (4) , 232. https://doi.org/10.3390/md17040232
Hairui Yang, Xu Bai, Henan Zhang, Jingsong Zhang, Yingying Wu, Chuanhong Tang, Yanfang Liu, Yan Yang, Zhendong Liu, Wei Jia, Wenhan Wang. Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway. Molecules 2019, 24 (5) , 993. https://doi.org/10.3390/molecules24050993
Xiaoming Wang, Chao Du, Benke Hong, Xiaoguang Lei. Total synthesis of (±)-antroquinonol. Organic & Biomolecular Chemistry 2019, 17 (7) , 1754-1757. https://doi.org/10.1039/C8OB02494D
Venkatachalam Angamuthu, M. Shanmugavadivu, G. Nagarajan, Bharath Kumar Velmurugan. Pharmacological activities of antroquinonol- Mini review. Chemico-Biological Interactions 2019, 297 , 8-15. https://doi.org/10.1016/j.cbi.2018.10.009
Mairi M. Littleson, Christopher M. Baker, Anne J. Dalençon, Elizabeth C. Frye, Craig Jamieson, Alan R. Kennedy, Kenneth B. Ling, Matthew M. McLachlan, Mark G. Montgomery, Claire J. Russell, Allan J. B. Watson. Scalable total synthesis and comprehensive structure–activity relationship studies of the phytotoxin coronatine. Nature Communications 2018, 9 (1) https://doi.org/10.1038/s41467-018-03443-1
Lizhi Zhu, Wenjing Ma, Mengxun Zhang, Magnolia Muk-Lan Lee, Wing-Yan Wong, Brandon Dow Chan, Qianqian Yang, Wing-Tak Wong, William Chi-Shing Tai, Chi-Sing Lee. Scalable synthesis enabling multilevel bio-evaluations of natural products for discovery of lead compounds. Nature Communications 2018, 9 (1) https://doi.org/10.1038/s41467-018-03546-9
Chin-Sheng Hung, Sheng-Chao Wang, Yi-Ting Yen, Tzong-Huei Lee, Wu-Che Wen, Ruo-Kai Lin. Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target. International Journal of Molecular Sciences 2018, 19 (10) , 3096. https://doi.org/10.3390/ijms19103096
Hiromu Hattori, Joel Roesslein, Patrick Caspers, Katja Zerbe, Hideki Miyatake‐Ondozabal, Daniel Ritz, Georg Rueedi, Karl Gademann. Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A. Angewandte Chemie 2018, 130 (34) , 11186-11190. https://doi.org/10.1002/ange.201805770
Hiromu Hattori, Joel Roesslein, Patrick Caspers, Katja Zerbe, Hideki Miyatake‐Ondozabal, Daniel Ritz, Georg Rueedi, Karl Gademann. Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A. Angewandte Chemie International Edition 2018, 57 (34) , 11020-11024. https://doi.org/10.1002/anie.201805770
Anja Schüffler. Secondary Metabolites of Basidiomycetes. 2018, 231-275. https://doi.org/10.1007/978-3-319-71740-1_8
Susan M. Miller, Walter H. Moos, Barbara H. Munk, Stephen A. Munk. Drug discovery. 2017, 183-279. https://doi.org/10.1016/B978-0-08-100625-2.00010-6
Che‐Sheng Hsu, Jim‐Min Fang. Synthesis of (+)‐Antroquinonol and Analogues by Using Enantioselective Michael Reactions of Benzoquinone Monoketals. European Journal of Organic Chemistry 2016, 2016 (22) , 3809-3816. https://doi.org/10.1002/ejoc.201600542

Download PDF

Open PDF

Get e-Alerts

ACS Central Science

Cite this: ACS Cent. Sci. 2016, 2, 1, 27–31

Click to copy citationCitation copied!

https://doi.org/10.1021/acscentsci.5b00345

Published December 23, 2015

Request reuse permissions

Article Views

Altmetric

Citations

Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

Abstract
High Resolution Image
Download MS PowerPoint Slide
Figure 1
Figure 1. Graphical summary of retrosynthetic analyses explored for the synthesis of antroquinonol A (1).
High Resolution Image
Download MS PowerPoint Slide
Scheme 1
Scheme 1. Total Synthesis of (+)-Antroquinonol A (1)^a
High Resolution Image
Download MS PowerPoint Slide
Scheme aReagents and conditions: (a) H₂O₂ (1.0 equiv), H₂SO₄ (0.1 equiv), MeOH, 0 °C, 2 h (98%); (b) PIDA (2.0 equiv), MeOH, 23 °C, (89%); (c) 2,2-dimethyl-1,3-propanediol (2.5 equiv), PPTS (0.15 equiv), toluene, 60 °C, 1 h (75%); (d) Cu(OTf)₂ (0.05 equiv), phosphoramidite ligand SI2 (0.1 equiv), Me₂Zn (2.5 equiv), toluene, −30 °C, 18 h; LiHMDS (1.5 equiv), HMPA (2.5 equiv), farnesyl bromide (2.0 equiv), 0 °C, 3 h; (e) L-Selectride (2.5 equiv), toluene, −78 °C to −20 °C, 6 h; (f) Montmorillonite K10 Clay (30 wt %), DCM, 23 °C, 2 h. PIDA = (diacetoxyiodo)benzene, PPTS = pyridinium p-toluenesulfonate, LiHMDS = lithium bis(trimethylsilyl)amide, HMPA = hexamethylphosphoramide, L-Selectride = lithium tri-sec-butylborohydride solution, DCM = dichloromethane.
Figure 2
Figure 2. A. Antroquinonol A metabolite (15) profile in MsLM. X = sample matrix peaks, not parent related. B. Reagents and conditions: (a) LiHMDS (1.5 equiv), HMPA (2.5 equiv), allyl bromide (2.5 equiv), THF, 0 °C, 6 h (44%); (b) L-Selectride (2.0 equiv), toluene, −78 °C to −20 °C, 6 h (74%); (c) Montmorillonite K10 clay (30 wt %), DCM, 23 °C, 2 h (49%); (d) TBAF (2.0 equiv), THF, 23 °C, 2 h (99%); (e) PIDA (1.1 equiv), TEMPO (0.2 equiv), THF, 23 °C, 4 h; (f) NaClO₂ (7 equiv), NaH₂PO₄ (7 equiv), 2-methyl-2-butene (20 equiv), t-BuOH, H₂O, 23 °C, 12 h (58%). MsLM = mouse liver microsomes.
High Resolution Image
Download MS PowerPoint Slide
Figure 3
Figure 3. In vivo antitumor activity of synthetic antroquinonol in the Hep 3B HCC xenograft model. Last measurement in the control group includes only one animal, since all other mice in this group had to be euthanized due to severe tumor necrosis. Standard error of the mean (SE) is calculated using the average deviation built-in formula in Quantrix spreadsheets as part of IDBS’s EWorkBook Suite.
High Resolution Image
Download MS PowerPoint Slide
References
This article references 25 other publications.
1. 1
  Isolation and structural determination of antroquinonol A (1):
  Lee, T.; Lee, C.; Tsou, W.; Liu, S.; Kuo, M.; Wen, W. Planta Med. 2007, 73, 1412 DOI: 10.1055/s-2007-990232
  There is no corresponding record for this reference.
2. 2
  Biological activity studies of 1:
  (a) Chiang, P. C.; Lin, S. C.; Pan, S. L.; Kuo, C. H.; Tsai, I. L.; Kuo, M. T.; Wen, W. C.; Chen, P.; Guh, J. H. Biochem. Pharmacol. 2010, 79, 162 DOI: 10.1016/j.bcp.2009.08.022
  There is no corresponding record for this reference.
  (b) Kumar, K. J.; Chu, F. H.; Hsieh, H. W.; Liao, J. W.; Li, W. H.; Lin, J. C.; Shaw, J. F.; Wang, S. Y. J. Ethnopharmacol. 2011, 136, 168 DOI: 10.1016/j.jep.2011.04.030
  There is no corresponding record for this reference.
  (c) Kumar, V. B.; Yuan, T. C.; Liou, J. W.; Yang, C. J.; Sung, P. J.; Weng, C. F. Mutat. Res., Fundam. Mol. Mech. Mutagen. 2011, 707, 42 DOI: 10.1016/j.mrfmmm.2010.12.009
  2c
  Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles
  Kumar, V. Bharath; Yuan, Ta-Chun; Liou, Je-Wen; Yang, Chih-Jen; Sung, Ping-Jyun; Weng, Ching-Feng
  Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis (2011), 707 (1-2), 42-52CODEN: MUREAV; ISSN:0027-5107. (Elsevier B.V.)
  Antroquinonol a deriv. of Antrodia camphorata has been reported to have antitumor effects against various cancer cells. However, the effect of antroquinonol on cell signalling and survival pathways in non-small cell lung cancer (NSCLC) cells has not been fully demarcated. Here we report that antroquinonol treatment significantly reduced the proliferation of three NSCLC cells. Treatment of A549 cells with antroquinonol increased cell shrinkage, apoptotic vacuoles, pore formation, TUNEL pos. cells and increased Sub-G1 cell population with respect to time and dose dependent manner. Antroquinonol treatment not only increased the Sub-G1 accumulation but also reduced the protein levels of cdc2 without altering the expression of cyclin B1, cdc25C, pcdc2, and pcdc25C. Antroquinonol induced apoptosis was assocd. with disrupted mitochondrial membrane potential and activation of Caspase 3 and PARP cleavage in A549 cells. Moreover, antroquinonol treatment down regulated the expression of Bcl2 proteins, which was correlated with the decreased PI3K and mTOR protein levels without altering pro apoptotic and anti apoptotic proteins. Results from the microarray anal. demonstrated that antroquinonol altered the expression level of miRNAs compared with untreated control in A549 cells. The data collectively suggested the antiproliferative effect of antroquinonol on NSCLC A549 cells, which provides useful information for understanding the anticancer mechanism influenced by antroquinonol and is the first report to suggest that antroquinonol may be a promising chemotherapeutic agent for lung cancer.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlGrsbk%253D&md5=7163125bbb7a4d4317fec7ec570e26b1
  (d) Tsai, P. Y.; Ka, S. M.; Chao, T. K.; Chang, J. M.; Lin, S. H.; Li, C. Y.; Kuo, M. T.; Chen, P.; Chen, A. Free Radical Biol. Med. 2011, 50, 1503 DOI: 10.1016/j.freeradbiomed.2011.02.029
  2d
  Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice
  Tsai, Pei-Yi; Ka, Shuk-Man; Chao, Tai-Kuang; Chang, Jia-Ming; Lin, Shih-Hua; Li, Chen-Yun; Kuo, Mao-Tien; Chen, Peini; Chen, Ann
  Free Radical Biology & Medicine (2011), 50 (11), 1503-1516CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
  Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compd., is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide prodn. and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-β1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-β1-mediated fibrosis pathways in the kidney.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVWhtL8%253D&md5=2c0557160cdee2f39134cac332274dbb
  (e) Tsai, P. Y.; Ka, S. M.; Chang, J. M.; Lai, J. H.; Dai, M. S.; Jheng, H. L.; Kuo, M. T.; Chen, P.; Chen, A. Arthritis Rheum. 2012, 64, 232 DOI: 10.1002/art.33328
  2e
  Antroquinonol differentially modulates T cell activity and reduces interleukin-18 production, but enhances Nrf2 activation, in murine accelerated severe lupus nephritis
  Tsai, Pei-Yi; Ka, Shuk-Man; Chang, Jia-Ming; Lai, Jenn-Haung; Dai, Ming-Shen; Jheng, Huei-Lin; Kuo, Mao-Tien; Chen, Peini; Chen, Ann
  Arthritis & Rheumatism (2012), 64 (1), 232-242CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)
  Objective: Accelerated severe lupus nephritis (ASLN), with an acute onset of severe clin. manifestations and histopathol. renal lesions, may represent transformation of mild LN to a severe form of glomerulonephritis. Abnormal activation of T and B cells and/or oxidative stress may play a major role in the pathogenesis of ASLN. This study tested the hypothesis that antroquinonol, a purified compd. and major effective component of Antrodia camphorata with antiinflammatory and antioxidant activities, might prevent the transformation of mild LN into higher-grade (severe) nephritis in a murine lupus model. Methods: Exptl. ASLN was induced in (NZB × NZW)F1 mice by twice weekly i.p. injections of Salmonella-type lipopolysaccharide (LPS). Starting 2 days after the first dose of LPS, mice were treated daily with antroquinonol, administered by gavage, for different durations up to 5 wk. Results: Antroquinonol administration significantly ameliorated the proteinuria, hematuria, impairment of renal function, and development of severe renal lesions, esp. cellular crescent formation, neutrophil infiltration, fibrinoid necrosis, and T cell proliferation in the glomerulus, as well as periglomerular interstitial inflammation. Mechanistic analyses revealed that antroquinonol 1) inhibited T cell activation/proliferation, but enhanced Treg cell suppression and reduced renal prodn. of interleukin-18 (IL-18); 2) inhibited prodn. of reactive oxygen species and nitric oxide, but increased activation of Nrf2 in the kidney; and 3) suppressed renal inflammation via blocking of NF-κB activation. Conclusion : Antroquinonol may have therapeutic potential for the early treatment of ASLN via its differential regulation of T cell function and lowering of IL-18 prodn., but also via the promotion of Nrf2 activation.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs12mtbrK&md5=c14a194282503280afebacd6af5acd2e
  (f) Yu, C. C.; Chiang, P. C.; Lu, P. H.; Kuo, M. T.; Wen, W. C.; Chen, P.; Guh, J. H. J. Nutr. Biochem. 2012, 23, 900 DOI: 10.1016/j.jnutbio.2011.04.015
  2f
  Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells
  Yu, Chia-Chun; Chiang, Po-Cheng; Lu, Pin-Hsuan; Kuo, Mao-Tien; Wen, Wu-Che; Chen, Peini; Guh, Jih-Hwa
  Journal of Nutritional Biochemistry (2012), 23 (8), 900-907CODEN: JNBIEL; ISSN:0955-2863. (Elsevier)
  Pancreatic cancer is a malignant neoplasm of the pancreas. A mutation and constitutive activation of K-ras occurs in more than 90% of pancreatic adenocarcinomas. A successful approach for the treatment of pancreatic cancers is urgent. Antroquinonol, a ubiquinone deriv. isolated from a camphor tree mushroom, Antrodia camphorata, induced a concn.-dependent inhibition of cell proliferation in pancreatic cancer PANC-1 and AsPC-1 cells. Flow cytometric anal. of DNA content by propidium iodide staining showed that antroquinonol induced G1 arrest of the cell cycle and a subsequent apoptosis. Antroquinonol inhibited Akt phosphorylation at Ser473, the phosphorylation site crit. for Akt kinase activity, and blocked the mammalian target of rapamycin (mTOR) phosphorylation at Ser2448, a site dependent on mTOR activity. Several signals responsible for mTOR/p70S6K/4E-BP1 signaling cascades have also been examd. to validate the pathway. Moreover, antroquinonol induced the down-regulation of several cell cycle regulators and mitochondrial antiapoptotic proteins. In contrast, the expressions of K-ras and its phosphorylation were significantly increased. The coimmunopptn. assay showed that the assocn. of K-ras and Bcl-xL was dramatically augmented, which was indicative of apoptotic cell death. Antroquinonol also induced the cross talk between apoptosis, autophagic cell death and accelerated senescence, which was, at least partly, explained by the up-regulation of p21Waf1/Cip1 and K-ras. In summary, the data suggest that antroquinonol induces anticancer activity in human pancreatic cancers through an inhibitory effect on PI3-kinase/Akt/mTOR pathways that in turn down-regulates cell cycle regulators. The translational inhibition causes G1 arrest of the cell cycle and an ultimate mitochondria-dependent apoptosis. Moreover, autophagic cell death and accelerated senescence also explain antroquinonol-mediated anticancer effect.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymtrvO&md5=e9ba90526a809ea91ebec180ea3d1871
  (g) Yang, S. M.; Ka, S. M.; Hua, K. F.; Wu, T. H.; Chuang, Y. P.; Lin, Y. W.; Yang, F. L.; Wu, S. H.; Yang, S. S.; Lin, S. H.; Chang, J. M.; Chen, A. Free Radical Biol. Med. 2013, 61, 285 DOI: 10.1016/j.freeradbiomed.2013.03.024
  2g
  Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome
  Yang, Shun-Min; Ka, Shuk-Man; Hua, Kuo-Feng; Wu, Tzu-Hua; Chuang, Yi-Ping; Lin, Ya-Wen; Yang, Feng-Ling; Wu, Shih-Hsiung; Yang, Sung-Sen; Lin, Shih-Hua; Chang, Jia-Ming; Chen, Ann
  Free Radical Biology & Medicine (2013), 61 (), 285-297CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
  High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compd. from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been detd. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic anal. in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathol. in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addn., Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS prodn. in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptV2gurs%253D&md5=f32e6ab26398fafacef219e9863c6643
  (h) Chen, C. K.; Kang, J. J.; Wen, W. C.; Chiang, H. F.; Lee, S. S. J. Nat. Prod. 2014, 77, 1061 DOI: 10.1021/np400670a
  There is no corresponding record for this reference.
  (i) Ho, C. L.; Wang, J. L.; Lee, C. C.; Cheng, H. Y.; Wen, W. C.; Cheng, H. H.; Chen, M. C. Biomed. Pharmacother. 2014, 68, 1007 DOI: 10.1016/j.biopha.2014.09.008
  2i
  Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells
  Ho, Ching-Liang; Wang, Jui-Ling; Lee, Cheng-Chung; Cheng, Hsiu-Yi; Wen, Wu-Che; Cheng, Howard Hao-Yu; Chen, Miles Chih-Ming
  Biomedicine & Pharmacotherapy (2014), 68 (8), 1007-1014CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  Antroquinonol is the smallest anticancer mol. isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a mol. docking anal. illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The mol. docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogs. We also found that the levels of LC3B-II and the autophagosome-assocd. LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and assocd. mode of cell death in cancer cells.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1agsLnI&md5=f507267a297f883d3e1a6ce9f2093e4a
  (j) Hsu, C. Y.; Sulake, R. S.; Huang, P. K.; Shih, H. Y.; Sie, H. W.; Lai, Y. K.; Chen, C.; Weng, C. F. Br. J. Pharmacol. 2015, 172, 38 DOI: 10.1111/bph.12828
  2j
  Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities
  Hsu, C. Y.; Sulake, R. S.; Huang, P.-K.; Shih, H.-Y.; Sie, H.-W.; Lai, Y.-K.; Chen, C.; Weng, C. F.
  British Journal of Pharmacology (2015), 172 (1), 38-49CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)
  Background and Purpose : The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chem. synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity. Exptl. Approach : Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycemic control in vivo. Key Results : The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clin. used inhibitor, sitagliptin. The phosphorylation of AMPK Thr172 in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. Conclusions and Implications : Chem. synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFWlsLvE&md5=9e1efa8476f5d04f4ef7732a5223ba59
  (k) Lee, W. T.; Lee, T. H.; Cheng, C. H.; Chen, K. C.; Chen, Y. C.; Lin, C. W. Food Chem. Toxicol. 2015, 78, 33 DOI: 10.1016/j.fct.2015.01.012
  2k
  Antroquinonol from Antrodia Camphorata suppresses breast tumor migration/invasion through inhibiting ERK-AP-1- and AKT-NF-κB-dependent MMP-9 and epithelial-mesenchymal transition expressions
  Lee, Wai-Theng; Lee, Tzong-Huei; Cheng, Chia-Hsiung; Chen, Ku-Chung; Chen, Yen-Chou; Lin, Cheng-Wei
  Food and Chemical Toxicology (2015), 78 (), 33-41CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
  Antroquinonol (ANQ) is an ubiquinon deriv. isolated from the mycelium of Antrodia camphorata. However, the effect of ANQ on breast cancer treatment is unknown. We found that ANQ significantly suppressed the migration and invasion of breast cancer MDA-MB-231 cells, and inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced invasiveness by MCF7 cells. ANQ inhibiting MMP-9 gene expression and enzymic activity occurred at transcriptional regulation. Mechanistically, activation of ERK and AKT is crucial for MMP-9 gene expression, and the addn. of ANQ suppressed phosphorylation of ERK and AKT. The induction of the AP-1 and NF-κB pathway participated in MMP-9 gene expression. Suppression of ERK inhibited AP-1, whereas blocking AKT diminished NF-κB activity, and treatment with ANQ suppressed both AP-1 and NF-κB signaling. Moreover, ANQ suppressed EMT protein expression, and inhibited TPA-induced EMT through downregulating the ERK-AP-1 and AKT-NF-κB signaling cascades. Together, our data showed for the first time that ANQ inhibited breast cancer invasiveness by suppressing ERK-AP-1- and AKT-NF-κB-dependent MMP-9 and EMT expressions.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisVSis74%253D&md5=bbd88fa98bb732bace62dfd0ff4dbcb6
3. 3
  ClinicalTrials.gov Identifier: NCT02047344.
  There is no corresponding record for this reference.
4. 4
  GoldenBiotech’s new cancer drug Hocena has been awarded the “Research and Development Innovation Award” in Taipei Biotech Awards 2014. http://www.goldenbiotech.com.tw/en/newslist.html, accessed on July 18, 2015.
  There is no corresponding record for this reference.
5. 5
  Michaudel, Q.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2015, 48, 712 DOI: 10.1021/ar500424a
  There is no corresponding record for this reference.
6. 6
  Three total syntheses of 1 were reported while this manuscript was in preparation:
  (a) Hsu, C. S.; Chou, H. H.; Fang, J. M. Org. Biomol. Chem. 2015, 13, 5510 DOI: 10.1039/C5OB00411J
  There is no corresponding record for this reference.
  (b) Sulake, R. S.; Chen, C. Org. Lett. 2015, 17, 1138 DOI: 10.1021/acs.orglett.5b00046
  There is no corresponding record for this reference.
  (c) Sulake, R. S.; Lin, H. H.; Hsu, C. Y.; Weng, C. F.; Chen, C. J. Org. Chem. 2015, 80, 6044 DOI: 10.1021/acs.joc.5b00345
  There is no corresponding record for this reference.
7. 7
  (a) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc. 2004, 126, 1624 DOI: 10.1021/ja0399066
  7a
  Remarkably facile hexatriene electrocyclizations as a route to functionalized cyclohexenones via ring expansion of cyclobutenones
  Magomedov, Nabi A.; Ruggiero, Piero L.; Tang, Yuchen
  Journal of the American Chemical Society (2004), 126 (6), 1624-1625CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A cascade reaction sequence that led to highly functionalized cyclohexenones, e.g., I, by reacting cyclobutenones with α-lithio-α,β-unsatd. sulfones, is described. This reaction sequence is believed to involve the hexatriene-cyclohexadiene cyclization.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXosFOhsQ%253D%253D&md5=06dcb6c65c5494abdd7382b08cb70783
  (b) Matsumoto, T.; Hamura, T.; Miyamoto, M.; Suzuki, K. Tetrahedron Lett. 1998, 39, 4853 DOI: 10.1016/S0040-4039(98)00920-4
  There is no corresponding record for this reference.
8. 8
  Beckwith, A. L. J.; Chai, C. L. L. Tetrahedron 1993, 49, 7871 DOI: 10.1016/S0040-4020(01)88012-1
  There is no corresponding record for this reference.
9. 9
  Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett. 2009, 11, 5330 DOI: 10.1021/ol902173g
  There is no corresponding record for this reference.
10. 10
  Kündig, E. P.; Enriquez-Garcia, A. Beilstein J. Org. Chem. 2008, 4, 37 DOI: 10.3762/bjoc.4.37
  There is no corresponding record for this reference.
11. 11
  Mantilli, L.; Gerard, D.; Torche, S.; Besnard, C.; Mazet, C. Angew. Chem., Int. Ed. 2009, 48, 5143 DOI: 10.1002/anie.200901863
  11
  Iridium-Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols
  Mantilli, Luca; Gerard, David; Torche, Sonya; Besnard, Celine; Mazet, Clement
  Angewandte Chemie, International Edition (2009), 48 (28), 5143-5147, S5143/1-S5143/19CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Under appropriate reaction conditions, iridium hydride catalysts formed in situ promote the isomerization of primary allylic alcs. The best precatalysts, e.g., I (Ad = 1-adamantyl; cod = 1,5-cyclooctadiene), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotVensL4%253D&md5=27be175b3203cecd08d4249d8c6e9f97
12. 12
  Solomon, M.; Jamison, C. L.; McCormick, M.; Liotta, D. J. Am. Chem. Soc. 1988, 110, 3702 DOI: 10.1021/ja00219a079
  There is no corresponding record for this reference.
13. 13
  Koreeda, M.; Koo, S. Tetrahedron Lett. 1990, 31, 831 DOI: 10.1016/S0040-4039(00)94639-2
  There is no corresponding record for this reference.
14. 14
  Meister, A. C.; Sauter, P. F.; Brase, S. Eur. J. Org. Chem. 2013, 2013, 7110 DOI: 10.1002/ejoc.201300752
  There is no corresponding record for this reference.
15. 15
  Pirrung, M. C.; Nunn, D. S. Tetrahedron Lett. 1992, 33, 6591 DOI: 10.1016/S0040-4039(00)60993-0
  There is no corresponding record for this reference.
16. 16
  Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1, 623 DOI: 10.1021/ol990707u
  There is no corresponding record for this reference.
17. 17
  The IC₅₀ values for the natural product against the Hep3B and HepG2 carcinoma cell lines are reported as 0.13 ± 0.02 μM and 4.3 ± 0.03 μM respectively in ref 1, as indicated in Table 1. The GI_50′ values for 1 against the same cell lines are listed as >30 μM and 0.22 μM respectively in ref 2a. The cytotoxicity assay protocol used in this paper and ref 1 employs 10% FBS and a 72 h incubation time with compound (antroquinonol) using MTS or MTT stain. The protocol outlined in ref 2a employs 5% FBS, 48 h incubation time, and an SRB stain. It is clear from the discussion (vide supra) that the protocol employed in this paper to determine cytotoxicity closely mirrors the conditions used in ref 1.
  There is no corresponding record for this reference.
18. 18
  ClinicalTrials.gov Identifier: NCT01134016.
  There is no corresponding record for this reference.
19. 19
  For discussion regarding the in vivo activity see ref 2a, page 170, left column, third paragraph. See supplementary material of ref 2a for in vivo data. Initial tumor sizes were not identical: 50–70 mm³ (lit.) (2a) vs 75–100 mm³ (BMS).
  There is no corresponding record for this reference.
20. 20
  Data shown for mouse liver microsomes.
  There is no corresponding record for this reference.
21. 21
  De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974 DOI: 10.1021/jo971046m
  21
  A Versatile and Highly Selective Hypervalent Iodine(III)/2,2,6,6-Tetramethyl-1-piperidinyloxyl-Mediated Oxidation of Alcohols to Carbonyl Compounds
  De Mico, Antonella; Margarita, Roberto; Parlanti, Luca; Vescovi, Andrea; Piancatelli, Giovanni
  Journal of Organic Chemistry (1997), 62 (20), 6974-6977CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Catalytic amts. of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) are used in combination with [bis(acetoxy)iodo]benzene (BAIB) as a stoichiometric oxidant in the conversion of primary and secondary alcs. to carbonyl compds. This procedure works efficiently at room temp. in almost all common solvents and neat in some cases. This process exhibits a very high degree of selectivity for the oxidn. of primary alcs. to aldehydes, without any noticeable overoxidn. to carboxyl compds., and a high chemoselectivity in the presence of either secondary alcs. or of other oxidizable moieties. This procedure allows an easy, convenient, high-yielding method for the oxidn. of alcs. starting from com. available compds.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtVenur8%253D&md5=df6a370727f2bcb72fdd520371150d0d
22. 22
  The Caco-2 value for 15 (Pc A → B, 62 nm/s, and B → A, 63 nm/s) suggests that cell permeability may not be an issue with 15.
  There is no corresponding record for this reference.
23. 23
  (a)
  Met2 (Figure S2; structure based on MS–MS data) is a reported metabolite of antroquinonol
  .
  There is no corresponding record for this reference.
  (b)
  Met2 is inactive in the H838 tumor cell line (IC₅₀ > 100 μM vs antroquinonol IC₅₀ of ∼ 3 μM).
  Ho, C.-L.; Wang, J.-L.; Lee, C.-C.; Cheng, H.-Y.; Wen, W.-C.; Cheng, H. H-Y.; Chen, M. C-M. Biomed. Pharmacother. 2014, 68, 1007 DOI: 10.1016/j.biopha.2014.09.008
  23b
  Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells
  Ho, Ching-Liang; Wang, Jui-Ling; Lee, Cheng-Chung; Cheng, Hsiu-Yi; Wen, Wu-Che; Cheng, Howard Hao-Yu; Chen, Miles Chih-Ming
  Biomedicine & Pharmacotherapy (2014), 68 (8), 1007-1014CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)
  Antroquinonol is the smallest anticancer mol. isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a mol. docking anal. illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The mol. docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogs. We also found that the levels of LC3B-II and the autophagosome-assocd. LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and assocd. mode of cell death in cancer cells.
  >> More from SciFinder ^®
  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1agsLnI&md5=f507267a297f883d3e1a6ce9f2093e4a
  (c)
  Synthetic antroquinonol appears to have a relatively better in vitro metabolic stability in human hepatocytes compared to human liver microsomes.
  .
  There is no corresponding record for this reference.
24. 24
  A thorough investigation of the antiproliferative activity against a large panel of human tumor cell lines was not performed.
  There is no corresponding record for this reference.
25. 25
  Antroquinonol is being administered to patients at 200 mg tid in the ongoing phase II clinical trial (ref 3).
  There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.5b00345.
- Crystallographic data (CIF)
- Experimental procedures and analytical data (PDF)
- NMR spectra (PDF)
Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

STEP 1:

STEP 2:

You have not visited any articles yet, Please visit some articles to see contents here.

All Types

Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
Click to copy article linkArticle link copied!

ACS Central Science

Publication History

Abstract

Subjects

Figure 1

Scheme 1

Figure 2

Figure 3

Supporting Information

Terms & Conditions

Author Information

Acknowledgment

References

Cited By

ACS Central Science

Publication History

Article Views

Altmetric

Citations

Recommended Articles

Abstract

Figure 1

Scheme 1

Figure 2

Figure 3

References

Supporting Information

Supporting Information

Terms & Conditions

STEP 1:

STEP 2:

Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug CandidateClick to copy article linkArticle link copied!

ACS Central Science

Abstract

Figure 1

Scheme 1

Figure 2

Figure 3

Supporting Information

Terms & Conditions

Author Information

Acknowledgment

References

Cited By

ACS Central Science

Article Views

Altmetric

Citations

Recommended Articles

Abstract

Figure 1

Scheme 1

Figure 2

Figure 3

References

Supporting Information

Supporting Information

Terms & Conditions

Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate
Click to copy article linkArticle link copied!