Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors
Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors
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作为c-Met抑制剂的带有1H-吡咯并[2,3-b]吡啶部分的苯基吡啶酰胺衍生物的设计、合成和对接研究
DOI：
10.1016/j.bmc.2016.01.001
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发表时间：
2016-02-15
影响因子：
3.5
通讯作者：
Zheng, Pengwu
中科院分区：
文献类型：
--
作者：
Zhu, Wufu;Wang, Wenhui;Zheng, Pengwu
设计、合成了4个系列的含1H-吡咯并[2，3-B]吡啶结构的苯基吡啶酰胺衍生物（12 a-e、13 a-f、14 a-f和15 a-i），并测定了它们对3种肿瘤细胞株（A549、PC-3和MCF-7）和c-Met激酶的IC 50值。进一步评价了五种所选化合物（13 b、15 b、15 d、15 e和15 f）对HepG 2和Hela细胞系的活性。18种化合物显示出优异的细胞毒性活性和选择性，IC 50值在个位数μ M至纳摩尔范围内。其中7种对一种或多种细胞系的活性等于或高于阳性对照Foretinib。最有希望的化合物15 f显示出比Foretinib更好的上级活性，其对A549、PC-3和MCF-7细胞系的IC 50值为1.04 +/- 0.11 μ M、0.02 +/- 0.01 μ M和9.11 +/- 0.55 μ M，其活性是Foretinib的0.62至19.5倍（IC 50值：0.64 +/- 0.26 μ M，0.39 +/- 0.11 μ M，9.47 +/- 0.22 μ M）。构效关系（SAR）和对接研究表明，1 H-吡咯并[2，3-B]吡啶取代喹啉核后，化合物的细胞毒活性得到了保持甚至提高。结果表明，在目标化合物的氨基苯氧基部分引入氟原子或在嘧啶的C-4位引入取代的苯基有利于提高活性。(c)2016爱思唯尔有限公司版权所有。
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 mu M 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 mu M, 0.02 +/- 0.01 mu M and 9.11 +/- 0.55 mu M 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 mu M, 0.39 +/- 0.11 mu M, 9.47 +/- 0.22 mu M), 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. (c) 2016 Elsevier Ltd. All rights reserved.