Synthesis of oxygenated cholesterols as structural mimics of phorbol ester-type tumor promoters

Article abstract of DOI:10.1248/cpb.42.462

We designed several oxygenated steroids in which functional groups including a hydrophobic group are arranged analogously to those of phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA), with the aim of finding compounds with TPA-like activity, but having a different skeleton and a rigid conformation. The designed steroids, 1β,5α-dihydroxy-3β- hydroxymethylcholestan-6-one (4), 3β,5α-dihydroxycholestan-6-one (5), 3β- hydroxymethylcholestan-5α-ol-6-one (6) and 1β,3β,5α-trihydroxycholestan- 6-one (7), were synthesized. A related oxygenated steroid isolated from soft coral, cholestane-1β,3β,5α,6β-tetrol (8), was also synthesized. Among these analogs, compound 7 showed weak TPA-like activities in three biological tests: inhibition of [³H]TPA binding to protein kinase C and to cytosolic- nuclear tumor promoter-binding protein (CN-TPBP), and induction of differentiation of human promyelocytic leukemia cells (HL-60) to monocyte- like cells. On the other hand, compound 5 was found to be a specific ligand for CN-TPBP, but lacked the other TPA-like activities.

Full text of DOI:10.1248/cpb.42.462

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