Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

详细信息    查看全文

• 作者：Wufu Zhu^a ; ^&dagger ; ; ^{zhuwf@jxstnu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; ^{zhuwufu-1122@163.com" class="auth_mail" title="E-mail the corresponding author} ; Wenhui Wang^a ; ^&dagger ; ; Shan Xu^a ; Qidong Tang^a ; Rong Luo^b ; Min Wang^a ; Ping Gong^c ; Pengwu Zheng^a ; ^{zhengpw@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Phenylpicolinamide ; 1H-Pyrrolo[2 ; 3-b]pyridine ; Synthesis ; Docking ; c-Met inhibitors ; Antitumor activity
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：812-819
• 全文大小：1147 K

文摘

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.