Synthesis and Biological Evaluation of 3,16,20-Polyoxygenated Steroids of Marine Origin and Their Analogs

Abstract

The natural polyoxygenated steroids (20S)-20-hydroxycholestane-3,16-dione (1), (16S, 20S)-16,20-dihydroxycholestan-3-one (2), (20S)-20-hydroxycholest-1-ene-3,16-dione (3) and (20S)-20-hydroxycholest-4-ene-3,16-dione (4), isolated from the gorgonian, Leptogorgia sarmentosa and unnatural analogs (5) (6), (12) and (13) were synthesized from tigogenin. Antitumor activity against three tumor cell lines (breast cancer, MCF 7, lung cancer NCI and oral cancer KB) was evaluated. Two compounds (3 and 4) containing α,β-unsaturated ketone at ring A showed strong activity against NCI-H 187 (IC₅₀ 2.55, 4.35 μg/ml) and moderate activity against MCF 7 and KB, the IC50 being in the range 12.69–19.55 μg/ml whereas the analog quinone steroid 5 showed moderate activity against all tested cells. Compound 1 containing a keto group at C-3 and a hydroxyl group at C-16 showed moderate activity against NCI (IC50 17.84 μg/ml), but was inactive against MCF 7 and KB, whereas compound 2 showed no activity against all tested cells. Cholestane (6) with dihydroxyl groups at C-3 and C-16 showed moderate activity against NCI-H 187 and KB the IC50 being in the range 10.22-11.04 μg/ml, but was weakly active against MCF 7 (IC₅₀ 50.0 μg/ml). The aromatic cholestane 13, the analog of 6 was strongly active against KB (IC₅₀ 4.69 μg/ml), weakly active against MCF 7 (IC₅₀ 38.2 μg/ml) and inactive against NCI-H 187 cell lines. Surprisingly compound 12 containing on unsaturated side chain was inactive with all tested cells.