A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.

中文翻译：

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基于5,10-二氢-二苯并[b，e] [1,4] diazepin-11-one的强效选择性Chk-1抑制剂的设计，合成和生物学活性。

通过基于结构的设计，已经合成了一系列新颖的5,10-二氢-二苯并[b，e] [1,4]二氮杂-11-酮作为有效和选择性的检查点激酶1（Chk1）抑制剂。在蛋白质X射线晶体学的帮助下，药物化学工作导致了对化合物46d的鉴定，该化合物对Chk1激酶具有强大的酶促活性。在保持自身低细胞毒性的同时，化合物46d表现出强大的消除G2阻滞的能力，并使喜树碱对SW620细胞的细胞毒性增加了19倍。药代动力学研究表明，它在小鼠中具有20％的中等生物利用度。X射线共晶结构揭示了化合物46b和Chk1激酶之间的两个重要结合相互作用，