Synthesis and tumor-promoting activities of 12-epi-phorbol-12, 13-dibutyrate

12-Epi-phorbol-12,13-dibutyrate (1), the C12-epimer of the most frequently used phorbol ester probe, phorbol-12,13-dibutyrate (PDBu), has been synthes ized from phorbol in 9 steps in order to investigate the structural require ments for tumor-promoting activity. Compound 1 showed about 100-fold weaker in vitro biological activities related to in vivo tumor promotion, Epstein -Barr virus early antigen (EBV-EA)-inducing ability, superoxide (O-2(-)) ge neration-inducing ability, and binding to the protein kinase C (PKC) regula tory domain surrogate peptides. The results indicated that the beta -stereo chemistry at position 12 of the phorbol skeleton is important for optimal a ctivity. Binding selectivity to each PKC C1 domain of 1 was almost equal to that of PDBu.