474-63-5Relevant academic research and scientific papers
Synthesis of polyhydroxysterols (V): Efficient and stereospecific synthesis of 24-methylene-cholest-5-ene-3β,7α-diol and its C-7 epimer
Lu, Weigang,Zhang, Cuixian,Zeng, Longmei,Su, Jingyu
, p. 803 - 808 (2004)
This paper describes the efficient and stereospecific synthesis of cytotoxic dihydroxylated sterols, 24-methylene-cholest-5-ene-3β,7α- diol 1, and its C-7 epimer, 24-methylene-cholest-5-ene-3β,7β-diol 2. The crux of the synthesis is that the selective allylic oxidation of 24-methylene-cholesteryl acetate proceeds to 24-methylene-7-keto-cholesteryl acetate without extensive byproduct formation from reaction at the Δ24(28) double bond. This methodology may be useful for the preparation of other oxysterols with non-standard side chains.
Synthesis of?oxysterols and?nitrogenous sterols with antileishmanial and?trypanocidal activities
Bazin, Marc-Antoine,Loiseau, Philippe M.,Bories, Christian,Letourneux, Yves,Rault, Sylvain,El Kihel, La?la
, p. 1109 - 1116 (2006)
Two sterol families have been synthesized: the first one is nitrogenous sterols containing amino, N-hydroxyimino or cyano group and the second one is oxysterols such as ketosterol and hydroxysterols. These compounds were then evaluated in vitro against Leishmania donovani promastigotes and Trypanosoma brucei brucei trypomastigotes. The most active compounds against L.?donovani promastigotes were 7β-aminomethylcholesterol and 7α,β-aminocholesterol (IC50 in a range from 1 to 3?μM, pentamidine: 2.8?μM). These compounds were active on intramacrophage amastigotes with IC50 of 1.3?μM. Such an activity justifies further in vivo antileishmanial evaluation. Against T. b. brucei, (24R,S)-24-hydroxy-24-methylcholesterol (MEC, 12.5?μM) was the most active compound from these series.
Synthesis of polyhydroxysterols (III): synthesis and structural elucidation of 24-methylenecholest-4-en-3beta,6 alpha-diol.
Cui, Jian Guo,Lin, Cui Wu,Zeng, Long Mei,Su, Jing Yu
, p. 1015 - 1019 (2007/10/03)
Using stigmasterol as the starting material, 24-methylenecholest-4-en-3beta,6 alpha-diol (2) was synthesized in eight steps in 13% overall yield. The introduction of the sterol side-chain was carried out using (3-methyl-2-oxobutyl)-triphenylarsonium bromide (11) and K(2)CO(3) in a solid-liquid phase-transfer Wittig reaction. Construction of the steroidal nucleus was finished by oxidation of 24-methylenecholest-5-en-3beta-ol (9) with pyridinium chlorochromate (PCC) in dichloromethane at ambient temperature and by reduction of 24-methylenecholest-4-en-3,6-dione (10) with NaBH(4) in the presence of CeCl(3).7H(2)O.
Site-directed mutagenesis of the sterol methyl transferase active site from Saccharomyces cerevisiae results in formation of novel 24-ethyl sterols
Nes, W. David,McCourt, Brian S.,Marshall, Julie A.,Ma, Jianzhong,Dennis, Allen L.,Lopez, Monica,Li, Haoxia,He, Ling
, p. 1535 - 1542 (2007/10/03)
Δ(24(28))-Sterols are end products of a mono C-methylation pathway catalyzed by the native Δ(24(25))- to Δ(24(28))-sterol methyl transferase (SMT) enzyme from Saccharomyces cerevisiae. Using a Tyr81 to Phe mutant SMT enzyme of S. cerevisiae, generated by site-directed mutagenesis of a highly conserved residue in the sterol binding site, we found that several Δ(24(25))- and Δ(24(28))-sterols, which are not substrates for the native protein, were catalyzed to mono- and bis-C24-alkylated side chains. The mutant protein behaved similarly to the native protein in chromatography and in binding zymosterol, the preferred substrate. Zymosterol was converted to fecosterol by the Y81F mutant protein with similar turnover efficiency as the native protein (K(m) = 12 μM and k(cat) = 0.01 s-1); trace 24-ethyl sterols were detected from these incubations. 4α-Methyl zymosterol, which is not a normal substrate for the wild-type SMT enzyme, was converted to 4α- methy fecosterol in high yield. When fecosterol and 4α-methyl fecosterol were assayed individually at saturating concentrations only fecosterol served as an effective substrate for the second C-transfer step (K(m) = 38 μM and k(cat) = 0.002 s-1), suggesting that successive C-methylation of Δ(24(28))-substrates is limited by product release and that molecular recognition of sterol features involves hydrogen bond formation. Isomeric 24- ethyl sterol olefins generated from 24(28)-methylene cholesterol were characterized by chromatographic (GC and HPLC) and spectral methods (MS and 1H NMR), viz., fucosterol, isofucosterol, and clerosterol. Changes in rate of C-methylation and product distributions resulting from deuterium substitution at C28 were used to establish the kinetic isotope effects (KIEs) for the various deprotonations leading to C24-methylene, C24-ethylidene, and C24-ethyl sterols. An isotope effect on C28 methyl deprotonation generated during the first C1-transfer was detected with zymosterol and desmosterol paired with AdoMet and [2H3-methyl]AdoMet. A similar experiment to test for a KIE generated during the second C1-transfer reaction with AdoMet paired with 24(28)-methylenecholesterol and [28-2H2]24(28)-methylene cholesterol indicated an inverse isotope effect associated with C27 deprotonation. Alteration in the proportion of the C24 alkylated olefinic products generated by the pure Y81F mutant resulted from the suppression of the formation of Δ(24(28))-ethylidene sterols (C28 deprotonation) by a primary deuterium isotope effect with a compensating stimulation of the formation of 24-ethyl sterols (C27 deprotonation). Kinetic study on the rate of product formation indicated a normal KIE of k(H)/k(D) = 2.62 for the first C1-transfer. Alternatively, an inverse KIE was established with k(H)/k(D) = 0.9 for the second C1-transfer resulting from conversion of the 24(28)-double bond (sp2 hybridization) to a 24β-ethyl group (sp3 hybridization). From the structures and stereochemical assignments of the C-ethyl olefin products, the stereochemistry of the attack of AdoMet in the second C1-transfer was found to operate a Si-face (backside) attack at C24, analogous to the first C1- transfer reaction.
APPLICATION OF SELENOSULFONATION TO MARINE STEROL SYNTHESIS. PREPARATION OF 24,28-DEHYDROAPLYSTEROL, XESTOSTEROL AND OSTREASTEROL FROM A COMMON ACETYLENIC INTERMADIATE
Back, Thomas G.,Proudfoot, John R.,Djerassi, Carl
, p. 2187 - 2190 (2007/10/02)
The title compounds were synthesized from a readily available steroidal acetylene by a protocol employing selenosulfonation, introduction of the appropriate side chain at C-24 via an alkyl selenocuprate, and reductive desulfonylation.
