Synthesis of Oxygenated Cholesterols as Structural Mimics of Phorbol Ester-Type Tumor Promoters

Abstract

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, TP A), with the aim of finding compounds with TPA-like activity, but having a different skeleton and a rigid conformation. The designed steroids, l/f,5a-dihydroxy-3/Miydroxymethylcholestan-6-one (4), 3/f,5a-dihydroxycholestan-6-one (5), 3/Miydroxymethyl-cholestan-5a-ol-6-one (6) and l/?,3/?,5a-trihydroxycholestan-6-one (7), were synthesized. A related oxygenated steroid isolated from soft coral, cholestane-l/l,3/l,5a,6/J-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. © 1994, The Pharmaceutical Society of Japan. All rights reserved.