Sobel,Kaye,Spoerri

, p. 471,472 (1942)

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.

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Pirrone,Vannucchi

, p. 470,477 (1939)

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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.

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.

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.