Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents
Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents
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新型羟吲哚类RTK抑制剂的合成及抗癌生物学评价
DOI：
10.1016/j.bmc.2014.10.017
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发表时间：
2014-12-15
影响因子：
3.5
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Gaozhi;Weng, Qiaoyou;Liang, Guang
鉴于受体酪氨酸激酶（RTK）已成为癌症发展的所有方面（包括增殖、侵袭、血管生成和转移）的关键调节剂，RTK家族代表抗癌药物开发的重要治疗靶标。羟吲哚结构已被用于RTK抑制剂，如SU 4984和Ketamine。本研究设计并合成了两个系列的含羟吲哚骨架的新型杂环化合物，并评价了它们对9种癌细胞株的增殖抑制活性。其中，化合物9a和9 b显示出最强的抗增殖活性，IC（50）低于10 μ M。流式细胞仪分析显示化合物9a和9 b呈剂量依赖性地将细胞周期阻滞于G 0/G1期。虽然先导化合物SU 4984和SU 4984靶向FGFR 1，但激酶活性测试显示这些化合物仅对FGFR 1激酶显示出轻微的抑制活性。通过ATP结合位点的分子对接模拟辅助的进一步的酶促测试表明，9a和9 b是c-Kit激酶的有效抑制剂。这些化合物作为抗癌药物值得进一步评价。(C)2014爱思唯尔有限公司版权所有。
Given that receptor tyrosine kinases (RTKs) have emerged as key regulators of all aspects of cancer development, including proliferation, invasion, angiogenesis and metastasis, the RTK family represents an important therapeutic target for anti-cancer drug development. Oxindole structure has been used in RTK inhibitors such as SU4984 and intedanib. In this study, two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized, and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated. Among them, compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC(50)s below 10 mu M. Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/G1 phase. Although the leading compounds SU4984 and intedanib targets FGFR1, the kinase activity test revealed that these compounds only showed slight inhibitory activity on FGFR1 kinase. Further enzymatic test aided by molecular docking simulation in the ATP-binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase. These compounds are worthy of further evaluation as anticancer agents. (C) 2014 Elsevier Ltd. All rights reserved.