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

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, 1 beta,5 alpha-dihydroxy-3 beta-hydroxymethylcholestan-6-one (4), 3 beta,5 alpha-dihydroxycholestan-6-one (5), 3 beta-hydroxymethylcholestan-5 alpha-ol-6-one (6) and 1 beta,3 beta,5 alpha-trihydroxycholestan-6-one (7), were synthesized. A related oxygenated steroid isolated from soft coral, cholestane-1 beta,3 beta-5 alpha,6 beta-tetrol (8), was also synthesized. Among these analogs, compound 7 showed weak TPA-like activities in three biological tests: inhibition 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.