Blocking c-Met kinase activity by small-molecule inhibitors has been identified as a promising approach for the treatment of cancers. Herein, we described the design, synthesis, and biological evaluation of a series of 4-phenoxypyridine-based 3-oxo-3,4-dihydroquinoxaline derivatives as c-Met kinase inhibitors. Inhibitory activitives against c-Met kinase evaluation indicated that most of compounds showed excellent c-Met kinase activity in vitro, and IC₅₀ values of ten compounds (23a, 23e, 23f, 23l, 23r, 23s, 23v, 23w, 23x and 23y) were less than 10.00 nM. Notably, three of them (23v, 23w and 23y) showed remarkable potency with IC₅₀ values of 2.31 nM, 1.91 nM and 2.44 nM, respectively, and thus they were more potent than positive control drug foretinib (c-Met, IC₅₀ = 2.53 nM). Cytotoxic evaluation indicated the most promising compound 23w showed remarkable cytotoxicity against A549, H460 and HT-29 cell lines with IC₅₀ values of 1.57 μM, 0.94 μM and 0.65 μM, respectively. Furthermore, the acridine orange/ethidium bromide (AO/EB) staining, cell apoptosis assays by flow cytometry, wound-healing assays and transwell migration assays on HT-29 and/or A549 cells of 23w were performed. Especially compound 23w, which displayed potent antitumor, apoptosis induction and antimetastatic activity, could be used as a promising lead for further development. Meanwhile, their preliminary structure-activity relationships (SARs) were also discussed.

通过小分子抑制剂阻断c-Met激酶活性已被认为是治疗癌症的有前途的方法。在这里，我们描述了一系列基于4-苯氧吡啶的3-氧代-3,4-二氢喹喔啉衍生物作为c-Met激酶抑制剂的设计，合成和生物学评估。对c-Met激酶的抑制活性评估表明，大多数化合物在体外均表现出出色的c-Met激酶活性，十种化合物（23a，23e，23f，23l，23r，23s，23v，23w，23x和23y）的IC ₅₀值）小于10.00 nM。值得注意的是，它们中的三个（23v，23w和23y）显示出显着的效价，IC ₅₀值分别为2.31 nM，1.91 nM和2.44 nM，因此它们比阳性对照药物foretinib（c-Met，IC ₅₀  = 2.53 nM）。细胞毒性评估表明，最有希望的化合物23w对A549，H460和HT-29细胞系表现出显着的细胞毒性，IC ₅₀值分别为1.57μM，0.94μM和0.65μM。此外，对23w的HT-29和/或A549细胞进行the啶橙/溴化乙锭（AO / EB）染色，流式细胞术细胞凋亡测定，伤口愈合测定和透孔迁移测定被执行。尤其是显示出有效抗肿瘤，凋亡诱导和抗转移活性的化合物23w，可以用作进一步开发的有前途的线索。同时，还讨论了它们的初步构效关系。