Synthesis, bioevaluation and molecular dynamics of pyrrolo-pyridine benzamide derivatives as potential antitumor agents in vitro and in vivo
Synthesis, bioevaluation and molecular dynamics of pyrrolo-pyridine benzamide derivatives as potential antitumor agents in vitro and in vivo
复制标题
吡咯并吡啶苯甲酰胺衍生物作为体内外潜在抗肿瘤药物的合成、生物评价和分子动力学
DOI：
10.1016/j.ejmech.2022.114215
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发表时间：
2022
影响因子：
6.7
通讯作者：
Qidong Tang
中科院分区：
文献类型：
--
作者：
Jianqing Zhang;Jintian Dai;Xin Lan;Ying Zhao;Feiyi Yang;Han Zhang;Sheng Tang;Guang Liang;Xu Wang;Qidong Tang
设计、合成了27个新型吡咯并吡啶苯甲酰胺衍生物，并对其进行了生物活性评价。其中14个化合物的细胞毒活性上级优于卡博替尼，其中化合物21的体外和体内抗肿瘤活性最好。化合物21对A549细胞具有凋亡活性，尤其是晚期凋亡明显增强（8.13%vs4.49%），上级卡博替尼（6.89%）。同样，21可使A549细胞阻滞于G 0/G1期和G2/M期，并呈剂量依赖性。此外，与相同浓度（10 μM）的卡博替尼相比，化合物21可以抑制c-Met表达。分子对接和动力学研究结果表明，化合物21与c-Met激酶形成了4个关键氢键。其中，Met 1160、Phe 1134和Phe 1223三个关键氨基酸对结合自由能起着关键作用。此外，21在肿瘤生长抑制率方面表现出较高的抗肿瘤效果，其上级优于卡博替尼（64.5% vs47.9%）。化合物21具有良好的抗肿瘤活性。
A total of 27 novel pyrrolo-pyridine benzamide derivatives were designed, synthesized and biologically evaluated. 14 of these derivatives were superior to Cabozantinib in cytotoxic assay, and compound21exhibited the best antitumor effectin vitroandvivo. Apoptosis activity was implemented by compound21on A549 cells, especially for the greatly enhanced late apoptosis compared with the control group (8.13%vs4.49%), which was superior to that of Cabozantinib (6.89%). Similarly,21stagnated the A549 cells arrest in the two cell distribution phases (G0/G1and G2/M) in dose-dependence manner. In addition, compound21could inhibit c-Met expression compared with Cabozantinib at the same concentration (10 μM). The results of molecular docking and dynamics study demonstrated that compound21formed four key hydrogen bonds with c-Met kinase. And key amino acids Met1160, Phe1134 and Phe1223 played a key functional role in the binding free energy. Furthermore,21exhibited high antitumor efficacy in tumor growth inhibition rate, which was superior to Cabozantinib (64.5%vs47.9%). Overall, compound21could be considered as a promising antitumor agent.