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 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 beta-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.
Irie
K
K
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan. irie@kais.kyoto-u.ac.jp
Nakahara
A
A
Ikawa
Y
Y
Tanaka
M
M
Nakagawa
Y
Y
Nakamura
Y
Y
Ohigashi
H
H
Wender
P A
PA
D000956:Antigens, Viral / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
D000956:Antigens, Viral; D002273:Carcinogens; C033305:Epstein-Barr virus early antigen; D013481:Superoxides; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C