Misharin Alexander Yu, Ivanov Vitali S, Mehtiev Arif R, Morozevich Galina E, Tkachev Yaroslav V, Timofeev Vladimir P
V.N. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia.
Steroids. 2007 Mar;72(3):305-12. doi: 10.1016/j.steroids.2006.12.002. Epub 2007 Feb 6.
Synthesis of five novel Delta8(14)-15-ketosterols comprising modified side chains starting from ergosterol is described. Ergosteryl acetate was converted into (22E)-3beta-acetoxy-5alpha-ergosta-8(14),22-dien-15-one through three stages in 32% overall yield; further transformations of the product obtained led to (22E)-3beta-hydroxy-5alpha-ergosta-8(14),22-dien-15-one, (22S,23S)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-one, (22R,23R)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-one, (22R,23R)-5alpha-ergost-8(14)-en-15-on-3beta,22,23-triol and (22R,23R)-3beta-hydroxy-22,23-isopropylidenedioxy-5alpha-ergost-8(14)-en-15-one. New Delta8(14)-15-ketosterols were evaluated for their cytotoxicity and effects on sterol biosynthesis in human hepatoma Hep G2 cells in comparison with known 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Among the compounds tested, (22R,23R)-3beta-hydroxy-22,23-oxido-5alpha-ergost-8(14)-en-15-one was found to be the most potent inhibitor of sterol biosynthesis (IC(50)=0.6+/-0.2microM), whereas (22R,23R)-5alpha-ergost-8(14)-en-15-on-3beta,22,23-triol exhibited the highest cytotoxicity (TC(50)=12+/-3microM at a 24h incubation).
描述了从麦角甾醇出发合成五种具有修饰侧链的新型Δ8(14)-15-酮甾醇。醋酸麦角甾醇经三个阶段转化为(22E)-3β-乙酰氧基-5α-麦角甾-8(14),22-二烯-15-酮，总产率为32%；所得产物的进一步转化得到(22E)-3β-羟基-5α-麦角甾-8(14),22-二烯-15-酮、(22S,23S)-3β-羟基-22,23-环氧-5α-麦角甾-8(14)-烯-15-酮、(22R,23R)-3β-羟基-22,23-环氧-5α-麦角甾-8(14)-烯-15-酮、(22R,23R)-5α-麦角甾-8(14)-烯-15-酮-3β,22,23-三醇和(22R,23R)-3β-羟基-22,23-异丙叉二氧基-5α-麦角甾-8(14)-烯-15-酮。与已知的3β-羟基-5α-胆甾-8(14)-烯-15-酮相比，对新的Δ8(14)-15-酮甾醇进行了细胞毒性及其对人肝癌Hep G2细胞中甾醇生物合成影响的评估。在所测试的化合物中，发现(22R,23R)-3β-羟基-22,23-环氧-5α-麦角甾-8(14)-烯-15-酮是甾醇生物合成的最有效抑制剂(IC(50)=0.6±0.2μM)，而(22R,23R)-5α-麦角甾-8(14)-烯-15-酮-3β,22,23-三醇表现出最高的细胞毒性(在24小时孵育时TC(50)=12±3μM)。
