Synthesis and Cytotoxicity Studies of Polyhydroxysterols and Their Sulfate Analogs

Abstract

The six new polyhydroxy steroids, 3β, 20(S)-dihydroxy-5α-cholest-24-ene (19), 3β, 20(S)-dihydroxy-5α-cholestane (20), 3β, 20(S), 24-trihydroxy-5α-cholestane (23), 2β, 3α, 20(S)-trihydroxy-5α-cholestane (29), 2β, 3α, 20(S)-trihydroxy-5α-cholest-24-ene (31), 2β, 3α, 20(S), 24-tetrahydroxycholestane
(37) and the sulfate derivative 21 were synthesized from tigogenin. Antitumor activity against two tumor cell lines (lung cancer NCI-H187 and oral cancer KB) was evaluated. Compound 23 containing trihydroxy groups at the C-3, C-20 and C-24 positions showed strong activity against both NCI-H187 and KB cells (IC₅₀ 2.11 and 5.39 μg/mL). The 3, 20-dihydroxy steroid 19 showed strong activity against NCI-H187 (IC₅₀ 4.24 μg/mL) but was weakly active against KB (IC₅₀ 39.12 μg/mL) whereas the analog 20 which has a saturated side chain showed moderate activity against KB (IC₅₀ 20.51 μg/mL) and was inactive against the NCI-H187 cell line. Surprisingly, the sulfate derivative of 20, compound 21, was inactive to both tested cells. Compounds 29 and 31, having vicinal dihydroxy groups in ring A at C-2, C-3 as well as a hydroxyl group at the C-20 position, showed similar activity against NCI-H187 (IC₅₀ 9.08 and 9.59 μg/mL) but for the KB cell, only 31 showed strong activity (IC₅₀ 10.14 μg/mL) whereas 29 was inactive. The analogue compound 37, which has an extra hydroxyl group at C-24, was inactive against both tested cell lines.