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
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Key words
Des-C derivatives /
CoMFA study /
structure-activity relationship /
synthesis /
antitumor /
apoptosis
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中图分类号：
R97
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参考文献
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脚注
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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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