新型c-Met抑制剂的设计合成及生物活性研究

Design,synthesis and pharmacological activities of c-Met inhibitors derivatives

目的设计合成一系列新型c-Met抑制剂,并评价其对c-Met激酶的抑制活性,探讨构效关系,为后续设计合成高活性化合物提供参考。方法以上市药物卡博替尼(cabozantinib)为基础,通过骨架跃迁和生物电子等排设计、合成具有新母核结构的c-Met抑制剂,采用均相时间分辨荧光法测定化合物对激酶c-Met的抑制活性。结果与结论合成了9个未见文献报道的新型c-Met抑制剂(包含不同母核结构),目标化合物结构均经MS、~1H-NMR谱确证。活性结果表明化合物7c、7f具有较强的c-Met激酶抑制活性,IC50值分别为4.01、0.137μmol·L^(-1)。

c-Met protein tyrosine kinase（PTK） plays an important role in the promotion of malignant tumor cell development, survival and metastasis, c-Met has been suggested as one of the most attractive target for new anticancer drug development. In this paper, a series of c-Met kinase inhibitors were designed and synthe- sized. The target compounds were prepared through different methods with mild conditions and high yields, The structures of the target compounds were identified by Mass and 1H-NMR spectra. The results of biological evaluation indicated that compounds 7c and 7f showed potent inhibitory activities against PTK with inhi- bition rates of 84. 34% and 94.44% at 5 μmol · L-1 , and with IC50 values of 4.01 μmol · L-1 and 0. 137 μmol· L -1 , respectively,