Dramatic switching of protein kinase C agonist/antagonist activity by modifying the 12-ester side chain of phorbol esters.
A dramatic switching of PKC agonist and antagonist activity was observed by modification of the hydrophilicity of the 12-ester side chain of phorbol. Thus, phorbol ester 4 that contains a glycol at the 12-ester chain demonstrated a pure and significant antagonist ability of PKC; however, 3 that contains an alkanol at the 12-ester chain demonstrated a potent PKC agonist activity. On the basis of the structural difference between 3 and 4 and results of the partition assay in the Hela cell/PBS buffer system, we propose that 4 acts as a translocation poison of the PKC-phorbol ester complex. The approach of controlling the agonist/antagonist activity of phorbol esters by the nature (i.e., hydrophilicity, charge, and rigidity, etc.) of the 12-ester chain may be very useful for developing selective PKC inhibitors and a potential pharmaceutical compound for anticancer therapies.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Reiko
R
Wada
Yutaka
Y
Suto
Motomu
M
Kanai
Masakatsu
M
Shibasaki
D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010703:Phorbol Esters / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010703:Phorbol Esters; C016658:phorbolol myristate acetate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate