C-20 epimers of 20-hydroxycholesterol

Mijares, A.; Cargill, D. Innes; Glasel, Jay A.; Lieberman, Seymour

doi:10.1021/jo01278a066

Cited by 53 publications

(35 citation statements)

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“…The loss of scalar coupling to the proton at C20 and the downfield shifts clearly indicate the hydroxylation is at C20. The characteristic proton chemical shift for the 21-methyl group suggests a 20␣-hydroxyl configuration (according to Fischer projection), consistent with many reported 20-hydroxylation metabolites (Mijares et al, 1967;Corey et al, 1991;Li et al, 2010). All other methyl protons are intact.…”

Section: Metabolism Of Ergosterol By Human Cytochrome P450sccsupporting

confidence: 87%

“…We further examined our spectra and the literature to try to define the configuration at C20, C22, and C23. The many literature reports on hydroxylation at C20 by P450scc established stereospecific 20␣-hydroxylation (Mijares et al, 1967;Nes and Varkey, 1976;Corey et al, 1991). The characteristic chemical shift for protons at C21 (␦ ϭ 1.29 ppm) in this metabolite further confirms the 20␣-hydroxyl configuration .…”

Section: Metabolism Of Ergosterol By Human Cytochrome P450sccsupporting

confidence: 57%

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Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Tuckey¹,

Nguyen²,

Chen³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D 3 precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D 2 precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k cat of 53 mol ⅐ min

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Section: Metabolism Of Ergosterol By Human Cytochrome P450sccsupporting

confidence: 87%

Section: Metabolism Of Ergosterol By Human Cytochrome P450sccsupporting

confidence: 57%

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Tuckey¹,

Nguyen²,

Chen³

et al. 2011

Drug Metab Dispos

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“…The NMR data of 2 were similar to those of compound 6, except for the presence of the ∆ 6,7 double bond and a hydroxyl attached at C-20. 14, 15 The absolute configuration at C-24 of 2 remained unresolved. Take these data together, the structure of compound 2 was elucidated as (17α,20S)-20-Hydroxy-stigmasta-4,6-dien-3-one, namely ailanthaltone A.…”

Section: Resultsmentioning

confidence: 99%

Triterpenoids and Sterones from the Stem Bark of Ailanthus altissima

Zhou¹,

Xu²,

Li³

et al. 2011

Bulletin of the Korean Chemical Society

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One new tirucallane-type triterpenoid, alianthusaltinin A (1), one new C29 sterone, alianthaltone A (2), and 12 known compounds have been isolated from the stem bark of Ailanthus altissima. The structures of new compounds were identified by means of spectroscopic methods. Compound 3 was isolated from natural sources for the first time, and compounds 4, 5, and 9 were isolated from this plant for the first time.

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“…This enantiomer was completely inactive in Hh pathway assays, suggesting that nat -20(S)-OHC activates Hh signaling by binding to a highly chiral protein binding pocket, rather than by incorporating into a dynamic lipid membrane wherein even “ordered” domains are likely rapidly assembling and disassembling, and are therefore insensitive to stereochemical changes 31 . In addition, we have also reported the improved synthesis of the C-20 epimer of nat -20(S)-OHC, nat -20(R)-OHC 44 ( 2 ). nat -20(R)-OHC did not activate Hh signaling, further exemplifying the structural discrimination associated with a specific protein interaction.…”

Section: Discussionmentioning

confidence: 99%

Oxysterols are allosteric activators of the oncoprotein Smoothened

et al. 2012

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Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which plays critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with their function through a specific protein target. We present several lines of evidence that this protein target is the 7-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing their mechanism of action.

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C-20 epimers of 20-hydroxycholesterol

Cited by 53 publications

References 0 publications

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Triterpenoids and Sterones from the Stem Bark of Ailanthus altissima

Oxysterols are allosteric activators of the oncoprotein Smoothened

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