Novel side chain modified Delta8(14)-15-ketosterols.
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).
Misharin
Alexander Yu
AY
V.N. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia.
Ivanov
Vitali S
VS
Mehtiev
Arif R
AR
Morozevich
Galina E
GE
Tkachev
Yaroslav V
YV
Timofeev
Vladimir P
VP
D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002782:Cholestenes / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007653:Ketocholesterols / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D013261:Sterols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D002782:Cholestenes; D007653:Ketocholesterols; D013261:Sterols; D002784:Cholesterol