School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China.
School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China; Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District, Weihai, 264400, PR China.
Eur J Med Chem. 2020 May 1;193:112241. doi: 10.1016/j.ejmech.2020.112241. Epub 2020 Mar 16.
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 IC = 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 IC 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.
c-Met 激酶与许多人类癌症的进展密切相关，临床预后较差，甚至出现耐药性，因此已成为开发小分子抗肿瘤药物的有前途的靶点。在这项研究中，设计、合成了两个含有 α-烷氧羰酰胺或 α-酰氨基酰胺支架的 6,7-二取代-4-(2-氟苯氧基)喹啉衍生物系列，并评估了它们对 c-Met 激酶和四种癌细胞系（H460、HT-29、MKN-45 和 MDA-MB-231）的体外生物活性。大多数靶化合物表现出中等至显著的活性，并对 H460 和 HT-29 癌细胞系具有选择性。初步的构效关系表明，α-烷氧羰酰胺或 α-酰氨基酰胺作为 5 原子连接体有助于抗肿瘤活性。在这些化合物中，化合物 10m（c-Met IC = 2.43 nM，一种多靶点酪氨酸激酶抑制剂）对 H460、HT-29 和 MDA-MB-231 细胞系的抑制活性最强，IC 为 0.14 ± 0.03 μM、0.20 ± 0.02 μM 和 0.42 ± 0.03 μM，分别比 foretinib 活性高 1.7 倍、1.3 倍和 1.6 倍。此外，浓度依赖性测定和时间依赖性测定表明，化合物 10m 可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，表明 10m 是一种有前途的癌症治疗候选药物，值得进一步研究。
