Novel side chain modified Δ8(14)-15-ketosterols

Synthesis of five novel Δ8(14)-15-ketosterols comprising modified side chains starting from ergosterol is described. Ergosteryl acetate was converted into (22E)-3β-acetoxy-5α-ergosta-8(14),22-dien-15-one through three stages in 32% overall yield; further transformations of the product obtained led to (22E)-3β-hydroxy-5α-ergosta-8(14),22-dien-15-one, (22S,23S)-3β-hydroxy-22,23-oxido-5α-ergost-8(14)-en-15-one, (22R,23R)-3β-hydroxy-22,23-oxido-5α-ergost-8(14)-en-15-one, (22R,23R)-5α-ergost-8(14)-en-15-on-3β,22,23-triol and (22R,23R)-3β-hydroxy-22,23-isopropylidenedioxy-5α-ergost-8(14)-en-15-one. New Δ8(14)-15-ketosterols were evaluated for their cytotoxicity and effects on sterol biosynthesis in human hepatoma Hep G2 cells in comparison with known 3β-hydroxy-5α-cholest-8(14)-en-15-one. Among the compounds tested, (22R,23R)-3β-hydroxy-22,23-oxido-5α-ergost-8(14)-en-15-one was found to be the most potent inhibitor of sterol biosynthesis (IC50 = 0.6 ± 0.2 μM), whereas (22R,23R)-5α-ergost-8(14)-en-15-on-3β,22,23-triol exhibited the highest cytotoxicity (TC50 = 12 ± 3 μM at a 24 h incubation).