Synthesis and structure–activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases

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• 作者：Jeff B. Smaill ; Edward N. Baker ; R. John Booth ; Alex ; er J. Bridges ; James M. Dickson ; Ellen M. Dobrusin ; Ivan Ivanovic ; Alan J. Kraker ; Ho H. Lee ; Elizabeth A. Lunney ; Daniel F. Ortwine ; Brian D. Palmer ; John Quin III ; Christopher J. Squire ; Andrew M. Thompson ; William A. Denny
• 关键词：Phenylpyrrolocarbazole ; Wee1 ; Chk1 ; G2/M checkpoint abrogation
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 2008
• 年：2008
• 卷：43
• 期：6
• 页码：1276-1296
• 全文大小：986 K

文摘

A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC₅₀ 0.057 μM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.