Smaill Jeff B, Baker Edward N, Booth R John, Bridges Alexander J, Dickson James M, Dobrusin Ellen M, Ivanovic Ivan, Kraker Alan J, Lee Ho H, Lunney Elizabeth A, Ortwine Daniel F, Palmer Brian D, Quin John, Squire Christopher J, Thompson Andrew M, Denny William A
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand.
Eur J Med Chem. 2008 Jun;43(6):1276-96. doi: 10.1016/j.ejmech.2007.07.016. Epub 2007 Aug 6.
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 IC(50) 0.057 microM) 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.
由N-取代的(5-甲氧基苯基)乙烯基吲哚制备了一系列N-6取代的9-羟基-4-苯基吡咯并[3,4-c]咔唑-1,3(2H,6H)-二酮。测试了目标化合物抑制G2/M细胞周期检查点激酶Wee1和Chk1的能力。具有中性或阳离子N-6侧链的类似物是有效的双重抑制剂。酸性侧链提供了有效的（平均IC(50) 0.057 microM）和选择性的（平均比值223倍）Wee1抑制作用。与Wee1结合的抑制剂的共晶体结构表明，吡咯并[3,4-c]咔唑支架结合在ATP结合位点，N-6取代基参与与保守水分子的氢键形成。用阿霉素处理后再用目标化合物处理的HT-29细胞表现出活性的Cdc2/细胞周期蛋白B复合物，抑制了阿霉素诱导的Cdc2酪氨酸15位点的磷酸化，并消除了G2检查点。
