The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC₅₀ = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC₅₀ of 0.14 ± 0.03 μM, 0.20 ± 0.02 μM and 0.42 ± 0.03 μM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.

由于c-Met激酶与许多人类癌症的进展，不良的临床结果甚至耐药性密切相关，因此它已成为小分子抗肿瘤药开发的有希望的目标。在这项研究中，设计，合成和评估了两个新颖的系列的6,7-取代的4-（2-氟苯氧基）喹啉衍生物，它们包含α-酰氧基羧酰胺或α-酰氨基酰胺支架。针对c-Met激酶和四种癌细胞系（H460，HT-29，MKN-45和MDA-MB-231）的生物学活性。大多数目标化合物显示出中等至显着的效力，并具有对H460和HT-29癌细胞系的选择性。初步的结构活性关系表明，α-酰氧基羧酰胺或α-酰氨基酰胺作为5-原子连接体有助于抗肿瘤效力。在这些化合物中，化合物10m（c-Met IC ₅₀  = 2.43 nM，多靶酪氨酸激酶抑制剂）对具有IC _50的H460，HT-29和MDA-MB-231细胞系表现出最强的抑制活性0.14±0.03μM，0.20±0.02μM和0.42±0.03μM的活性分别是福瑞替尼的1.7倍，1.3倍和1.6倍。另外，浓度依赖性测定和时间依赖性测定表明化合物10m可以以时间和浓度依赖性方式抑制H460细胞的增殖。此外，对接研究揭示了与c-Met结合位点相互作用的常见模式，这表明10m是潜在的癌症治疗候选药物，值得进一步研究。