title: Potent selective inhibition of 7-O-methyl UCN-01 against protein kinase C.
abstract: UCN-01 is a staurosporine-related compound that was isolated from the culture broth of Streptomyces sp. and shows potent and selective inhibitory activity against protein kinase C. Cellular inhibitory activity of UCN-01 against protein kinase C and cytotoxicity of UCN-01 were compared with those of staurosporine. When the mechanism of inhibitory activity was investigated in vitro, UCN-01 as well as staurosporine inhibited the activity of the catalytic domain of protein kinase C. In spite of direct inhibition against the catalytic domain of protein kinase C, cytotoxicity of UCN-01 was much lower than that of staurosporine. In addition, UCN-01 showed more selective inhibitory activity against protein kinase C than did staurosporine because of the sole structural difference at C-7. Therefore, a series of 7-O-alkyl derivatives of UCN-01 was synthesized and investigated. Interestingly, one of the compounds, the beta-methoxy derivative, showed 3-fold greater potency and 17-fold more selective inhibitory activity against protein kinase C than did UCN-01.
authors: Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd, Tokyo, Japan.
authors: I
authors: I
authors: Takahashi
authors: E
authors: E
authors: Kobayashi
authors: H
authors: H
authors: Nakano
authors: C
authors: C
authors: Murakata
authors: H
authors: H
authors: Saitoh
authors: K
authors: K
authors: Suzuki
authors: T
authors: T
authors: Tamaoki
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C066683:7-O-methyl-UCN 01; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate