Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors
Synthesis, and docking studies of phenylpyrimidine-carboxamide 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]吡啶部分的苯基嘧啶-甲酰胺衍生物的合成和对接研究
DOI：
10.1016/j.bmc.2016.02.046
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发表时间：
2016-04-15
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]吡啶结构的苯基嘧啶甲酰胺衍生物（14 a-e、15 a-g、16 a-e和17 a-g），并测定了它们对3种肿瘤细胞（A549、PC-3和MCF-7）的IC_（50）值。进一步评价了四种选择的化合物（15 e、16 a-b和17 a）对c-Met激酶、HepG 2和Hela细胞系的活性。大多数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11个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 e显示出比Foretinib更好的抗A549、PC-3和MCF-7细胞系的上级活性，其IC 50值为0.14 +/- 0.08 μ M、0.24 +/- 0.07 μ M和0.02 +/- 0.01 μ M，分别为4.6，活性分别是Foretinib的1.6和473.5倍（0.64 +/- 0.26 μ M，0.39 +/- 0.11 μ M，9.47 +/- 0.22 μ M）。构效关系（SAR）和分子对接研究表明，目标化合物的苯基嘧啶片段取代苯基吡啶酰胺骨架有利于活性的提高。氨基苯氧基部分引入氟原子对活性影响不大，芳基上的取代基对活性不利。(C)2016爱思唯尔有限公司版权所有。
Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a-e, 15a-g, 16a-e and 17a-g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a-b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit mu M to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14 +/- 0.08 mu M, 0.24 +/- 0.07 mu M and 0.02 +/- 0.01 mu M, which were 4.6, 1.6 and 473.5 times more active than Foretinib (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 the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What's more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity. (C) 2016 Elsevier Ltd. All rights reserved.