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

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2000-11, Vol.64 (11), p.2429-2436
• Main Authors: Irie, K. (Kyoto Univ. (Japan)), Nakahara, A, Ikawa, Y, Tanaka, M, Nakagawa, Y, Nakamura, Y, Ohigashi, H, Wender, P.A
• Format: Article
• Language: English
• Subjects: 12-epi-phorbol-12,13-dibutyrate; Antigens, Viral - drug effects; Antigens, Viral - metabolism; Biological and medical sciences; BUTYRATES (ESTERS); Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - chemical synthesis; Carcinogens - chemistry; Carcinogens - pharmacology; Chemical agents; CHEMICAL STRUCTURE; CHEMICAL SYNTHESIS; Epstein-Barr virus; EUPHORBIA; Medical sciences; NEOPLASMS; Phorbol 12,13-Dibutyrate - chemical synthesis; Phorbol 12,13-Dibutyrate - chemistry; Phorbol 12,13-Dibutyrate - pharmacology; phorbol ester; protein kinase C; Protein Kinase C - drug effects; Protein Kinase C - metabolism; Structure-Activity Relationship; Superoxides - metabolism; tumor promoter; Tumors
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1271/bbb.64.2429

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 (O 2 - ) 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.