European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2017-09-14 , DOI: 10.1016/j.ejmech.2017.08.060 Daowei Huang , Lei Huang , Qingwei Zhang , Jianqi Li
Over expression of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein a series of novel 6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepine derivatives were designed, synthesised and evaluated for their c-Met kinase inhibition. Compounds 17e, 17f, 18a, and 18b were further examined for their anti-proliferative activities against four typical cancer cell lines (PC-3, Panc-1, HepG2, and Caki-1). The promising compound 17f was identified as a multi-target receptor tyrosine kinase inhibitor, which also displayed favourable pharmacokinetic properties in rats, had an acceptable safety profile in preclinical studies, and significant anti-tumour activity in the Caki-1 tumour xenograft model.
中文翻译:
新型6,11-二氢-5 H-苯并[e]嘧啶-[5,4- b ] [1,4]二氮杂衍生物作为潜在的c-Met抑制剂的合成及生物学评价
已知c-Met酪氨酸激酶的过表达促进肿瘤发生和转移,并引起治疗抗性。本文设计,合成并评价了一系列新颖的6,11-二氢-5 H-苯并[e]嘧啶[5,4- b ] [1,4]二氮杂卓衍生物,并对其c-Met激酶抑制作用进行了评估。进一步检查了化合物17e,17f,18a和18b对四种典型癌细胞系(PC-3,Panc-1,HepG2和Caki-1)的抗增殖活性。有前途的化合物17f 被鉴定为多靶受体酪氨酸激酶抑制剂,在大鼠中也显示出良好的药代动力学特性,在临床前研究中具有可接受的安全性,并且在Caki-1肿瘤异种移植模型中具有显着的抗肿瘤活性。