Synthesis and Tumor-promoting Activities of 12-Epi-phorbol-12,13-dibutyrate
2000
Irie, Kazuhiro | NAKAHARA, Akifumi | IKAWA, Yasuyuki | Tanaka, Minoru | NAKAGAWA, Yu | NAKAMURA, Yoshimasa | OHIGASHI, Hajime | Wender, Paul A.
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 synthesized from phorbol in 9 steps in order to investigate the structural requirements 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 (O₂ ⁻) generation-inducing ability, and binding to the protein kinase C (PKC) regulatory domain surrogate peptides. The results indicated that the β-stereochemistry at position 12 of the phorbol skeleton is important for optimal activity. Binding selectivity to each PKC C1 domain of 1 was almost equal to that of PDBu.
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