1253-84-5Relevant academic research and scientific papers
Design and synthesis of polyhydroxy steroids as selective inhibitors against AKR1B10 and molecular docking
Chen, Wenli,Chen, Xinying,Zhou, Shujia,Zhang, Hong,Wang, Ling,Xu, Jun,Hu, Xiaopeng,Yin, Wei,Yan, Guangmei,Zhang, Jingxia
, p. 1 - 8 (2016)
AKR1B10 is a member of the human aldo-keto reductase superfamily which is highly expressed in several types of cancers, and has been regarded as a promising cancer therapeutic target. In this paper, a series of polyhydroxy steroids were designed and synthesized to selectively inhibit AKR1B10 activity. The most selective compound, novel compound 6, has an IC50 of 0.83 ± 0.07 μM and a selectivity of more than 120-fold for AKR1B10/AKR1B1. Structure-activity relation analyses indicate that hydroxyl at C-19 can significantly improve the selective inhibition of AKR1B10. The binding mode of AKR1B10 and its inhibitors were studied.
Identification and pharmacological characterization of cholesterol-5,6- epoxide hydrolase as a target for tamoxifen and AEBS ligands
De Medina, Philippe,Paillasse, Michael R.,Segala, Gregory,Poirot, Marc,Silvente-Poirot, Sandrine
, p. 13520 - 13525 (2010)
The microsomal antiestrogen binding site (AEBS) is a high-affinity target for the antitumor drug tamoxifen and its cognate ligands that mediate breast cancer cell differentiation and apoptosis. The AEBS, a hetero-oligomeric complex composed of 3β-hydroxysterol-Δ8-Δ7- isomerase (D8D7I) and 3β-hydroxysterol-Δ7-reductase (DHCR7), binds different structural classes of ligands, including ring B oxysterols. These oxysterols are inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), a microsomal epoxide hydrolase that has yet to be molecularly identified. We hypothesized that the AEBS and ChEH might be related entities. We show that the substrates of ChEH, cholestan-5α,6α-epoxy-3β-ol (α-CE) and cholestan-5β,6β-epoxy-3β-ol (β-CE), and its product, cholestane-3β,5α,6β-triol (CT), are competitive ligands of tamoxifen binding to the AEBS. Conversely, we show that each AEBS ligandis aninhibitor of ChEH activity, and that there is a positive correlation between these ligands' affinity for the AEBS and their potency to inhibit ChEH (r2 = 0.95; n = 39; P a dimer is required for ChEH activity. Similarly, the single knockdown of D8D7I or DHCR7 using siRNA partially inhibited ChEH in MCF-7 cells, whereas the knockdown of both D8D7I and DHCR7 abolished ChEH activity by 92%. Taken together, our findings strongly suggest that the AEBS carries out ChEH activity and establish that ChEH is a new target for drugs of clinical interest, polyunsaturated fatty acids and ring B oxysterols.
4,5-Epoxycholestane-3,6-diols: Templates for generating the full set of eight cholestane-3,5,6-triol stereoisomers in multigram scales, but not for a cholestane-3,4,6-triol
Zhao, Kejun,Wang, Yongfeng,Han, Li
, p. 95 - 104 (2007)
Cholestane-3β,5α,6β-triol is an extensively studied biologically important oxysterol. The full set of eight cholestane-3,5,6-triol stereoisomers was synthesised in diastereomerically pure forms by the stereoselective cleavage of eight diastereomerically pure 4,5-epoxycholestane-3,6-diols with LiAlH4, in high yields on multigram scales and without chromatography for most of them. However, applying various reportedly successful combinations of a hydride donor and a Lewis acid to the same substrates under a variety of conditions failed to generate a single unsubstituted cholestane-3,4,6-triol. The products of the eight cholestane-3,5,6-triol stereoisomers will serve as a good probe in the study of biological functions of oxysterols in a biological process.
Catalytic Oxygenation of Cholesterol with a Platinum Catalyst under Moderate Pressure of Oxygen
Sakamaki, Hiroshi,Take, Masa-aki,Akihisa, Toshihiro,Matsumoto, Taro,Ichinohe, Yoshiyuki
, p. 3023 - 3025 (1988)
The catalytic oxigenation of cholesterol 1 with a platinum black catalyst under moderate pressure (20-25 atm) of oxygen yielded eleven oxidation products, 3-13a.The reaction pathway of the catalytic oxygenation is discussed on the basis of the results for several reaction conditions.
Oxidized phytosterols increase by ageing in photoautotrophic cell cultures of Chenopodium rubrum
Meyer, Werner,Spiteller, Gerhard
, p. 297 - 302 (1997)
Young and old cell cultures of Chenopodium rubrum were investigated for their content of phytosterol derivatives by gas chromatography-mass spectrometry. The ratio of the main phytosterol constituents, sito-sterol, stigmasterol and campesterol (1,2: 2.4:1.0) remained approximately constant, but their overall content (402.5 μg g-1 dry wt) decreased from 11 days to 8 weeks old cell cultures by about 64% (260.1 μg g-1 dry wt); in contrast the content of corresponding epoxides increased from traces at day 11 to 11.1 μg g-1 (dry wt) at the 8th week. A comparable increase was observed for 3,5,6-trihydroxysteranes (2.8 μg g-1 dry wt), day 11; 27.5 μg g-1 dry wt), 8 weeks). The content of sterois oxidized in position C-7 showed also an increase from 1.9 μg g-1 dry wt) (11 days) to 51.7 μg g-1 dry wt) (8 weeks). These results show that the increase of phytosterol oxidation products correlated with age of the cell culture. Therefore, the sterol epoxide content and related oxidation products may be used as a measure for ageing.
H-Atom Abstraction vs Addition: Accounting for the Diverse Product Distribution in the Autoxidation of Cholesterol and Its Esters
Zielinski, Zosia A. M.,Pratt, Derek A.
, p. 3037 - 3051 (2019/02/19)
We recently communicated that the free-radical-mediated oxidation (autoxidation) of cholesterol yields a more complex mixture of hydroperoxide products than previously appreciated. In addition to the epimers of the major product, cholesterol 7-hydroperoxide, the epimers of each of the regioisomeric 4- and 6-hydroperoxides are formed as is the 5α-hydroperoxide in the presence of a good H-atom donor. Herein, we complete the story by reporting the products resulting from competing peroxyl radical addition to cholesterol, the stereoisomeric cholesterol-5,6-epoxides, which account for 12% of the oxidation products, as well as electrophilic dehydration products of the cholesterol hydroperoxides, 4-, 6-, and 7-ketocholesterol. Moreover, we interrogate how their distribution - and abundance relative to the H-atom abstraction products - changes in the presence of good H-atom donors, which has serious implications for how these oxysterols are used as biomarkers. The resolution and quantification of all autoxidation products by LC-MS/MS was greatly enabled by the synthesis of a new isotopically labeled cholesterol standard and corresponding selected autoxidation products. The autoxidation of cholesteryl acetate was also investigated as a model for the cholesterol esters which abound in vivo. Although esterification of cholesterol imparts measurable stereoelectronic effects, most importantly reflected in the fact that it autoxidizes at 4 times the rate of unesterified cholesterol, the product distribution is largely similar to that of cholesterol. Deuteration of the allylic positions in cholesterol suppresses autoxidation by H-atom transfer (HAT) in favor of addition, such that the epoxides are the major products. The corresponding kinetic isotope effect (kH/kD ～ 20) indicates that tunneling underlies the preference for the HAT pathway.
NANOEMULSIONS AND METHODS FOR CANCER THERAPY
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Page/Page column 25; 26, (2017/12/15)
An oxysterol or oxysterol-like compound is provided, which finds use in treating and/or targeting cancer.
Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein
Ohgane, Kenji,Karaki, Fumika,Noguchi-Yachide, Tomomi,Dodo, Kosuke,Hashimoto, Yuichi
supporting information, p. 3480 - 3485 (2014/07/22)
Niemann-Pick disease type C is a fatal neurodegenerative disease, and its major cause is mutations in NPC1 gene. This gene encodes NPC1 protein, a late endosomal polytopic membrane protein required for intracellular cholesterol trafficking. One prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization of the protein, leading to loss-of-function phenotype. We have previously demonstrated that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to NPC1I1061T mutant protein corrects the localization/maturation defect of the mutant protein. Here, we disclose detailed structure-activity relationships of oxysterol derivatives as pharmacological chaperones for NPC1I1061T mutant.
Efficient trans-diaxial hydroxylation of Δ5-steroids
Carvalho, Jo?o F.S.,Silva, M. Manuel Cruz,Sá e Melo, M. Luisa
scheme or table, p. 2455 - 2462 (2010/06/14)
A convenient, fast, and high-yielding process to synthesize 5α,6β-dihydroxysteroids directly from the correspondent Δ5-steroids is reported. The reaction protocol consists in the conjugation of a readily available and stable oxidant, magnesium bis(monoperoxyphthalate) hexahydrate, with the non-toxic bismuth(III) triflate in acetone to afford the trans-diaxial hydroxylation product in a stepwise manner and in excellent yields.
Sterols as anticancer agents: Synthesis of ring-B oxygenated steroids, cytotoxic profile, and comprehensive SAR analysis
Carvalho, Jo?o F. S.,Silva, M. Manuel Cruz,Moreira, Jo?o N.,Sim?es, Sérgio,Sá E Melo, M. Luisa
supporting information; experimental part, p. 7632 - 7638 (2011/02/21)
The cytotoxicity of oxysterols was systematically studied in tumor and normal cells. Synthetic strategies to prepare this library included oxidations at ring B and a new method to yield 6β-hemiphthalates directly from Δ5-steroids. Most oxysterols were cytotoxic and showed selectivity toward cancer cells, LAMA-84 cells (leukemia) being particularly sensitive to 4, 8, 22, and 27 (IC50 5.6 μM). The structural requirements to induce selective toxicity are discussed to shed light on the development of new anticancer drugs.
