毛叶假鹰爪素C衍生物的合成、构效关系分析及其抗肿瘤活性研究

向卓,郭宏举,梁海,钱奇芳,史宁,李明春,吴久鸿

中国药学杂志 ›› 2017, Vol. 52 ›› Issue (16) : 1387-1392.

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中国药学杂志 ›› 2017, Vol. 52 ›› Issue (16) : 1387-1392. DOI: 10.11669/cpj.2017.16.003
论著

毛叶假鹰爪素C衍生物的合成、构效关系分析及其抗肿瘤活性研究

  • 向卓1,3,郭宏举3,梁海2,3,钱奇芳3,史宁3,李明春1*,吴久鸿3*
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Synthesis, QSAR Study and Antitumor Activity of Desmosdumotin-C Analogues

  • XIANG Zhuo1,3, GUO Hong-ju3, LIANG Hai2,3, QIAN Qi-fang3, SHI Ning3, LI Ming-chun1*, WU Jiu-hong3*
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文章历史 +

摘要

目的 毛叶假鹰爪素C(Des-C)衍生物的进一步优化设计合成,及其抗肿瘤作用机制的初步探讨。方法 结合已报道的毛叶假鹰爪素C衍生物,进行比较分子场法(CoMFA)分析,构建模型,指导设计新结构衍生物,对合成衍生物进行体外抗肿瘤细胞活性评价,验证模型有效性,运用流式细胞技术考察衍生物对细胞凋亡的影响。结果 构建的模型可有效指导衍生物的设计合成并预测毛叶假鹰爪素C衍生物的活性,通过优化合成路线,得到10个新衍生物,对A549和HL60的抗肿瘤活性明显提高,并且可通过诱导细胞凋亡来发挥抗肿瘤作用。结论 通过对先导物毛叶假鹰爪素C进行结构修饰和改造可有效提高化合物的抗肿瘤活性,初步明确了衍生物可通过诱导肿瘤细胞凋亡发挥抗肿瘤作用,为后续衍生物的研究提供方向和数据支持。

Abstract

OBJECTIVE To further design and synthesize Desmosdumotin-C(Des-C) derivatives and investigate their antitumor activities. METHODS QSAR study using the CoMFA method was performed on a set of reported Des-C derivatives to facilitate the elucidation of their SAR and discovery of new potent Des-C derivatives. Flow cytometry was used to investigate antitumor activity. RESULTS The established model showed good predictive ability and aid in the design of potent Des-C derivatives. An efficient three-step synthetic strategy toward Des-C derivatives was developed and applied to synthesize 10 new derivatives which showed superior antitumor activities against A549 and HL60 cells in vitro. CONCLUSION The structural modification of Des-C would significantly increase the antitumor activity. It is preliminarily confirmed that the derivatives are potent antitumor agents with apoptosis-inducing ability, which provides the basis for the further study.

关键词

毛叶假鹰爪素C衍生物 / 比较分子场法分析 / 构效关系研究 / 合成 / 抗肿瘤 / 凋亡

Key words

Des-C derivatives / CoMFA study / structure-activity relationship / synthesis / antitumor / apoptosis

引用本文

导出引用
向卓,郭宏举,梁海,钱奇芳,史宁,李明春,吴久鸿. 毛叶假鹰爪素C衍生物的合成、构效关系分析及其抗肿瘤活性研究[J]. 中国药学杂志, 2017, 52(16): 1387-1392 https://doi.org/10.11669/cpj.2017.16.003
XIANG Zhuo, GUO Hong-ju, LIANG Hai, QIAN Qi-fang, SHI Ning, LI Ming-chun, WU Jiu-hong. Synthesis, QSAR Study and Antitumor Activity of Desmosdumotin-C Analogues[J]. Chinese Pharmaceutical Journal, 2017, 52(16): 1387-1392 https://doi.org/10.11669/cpj.2017.16.003
中图分类号: R97   

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基金

国家自然科学基金资助项目(81470156);山东省医药卫生科技发展计划项目资助(2016WS0734)
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