潜在Procaspase-3激活剂的设计、合成及活性评价研究  

Design,Synthesis and Activity Evaluation of Potential Procaspase-3 Activators

作　　者：王润 郭中原[1,2] 曹雨婷 刘晓谦 杨红[3] 孟辰笑凝[2] 李玉贤 王智民[1,2] WANG Run;GUO Zhongyuan;CAO Yuting;LIU Xiaoqian;YANG Hong;MENG Chenxiaoning;LI Yuxian;WANG Zhimin(College of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046,China;National Engineering Laboratory for Quality Control Technology of Chinese Herbal Medicine,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China;Yanjing Medical College,Capital Medical University,Beijing 100300,China)

机构地区：[1]河南中医药大学药学院,郑州450046 [2]中国中医科学院中药研究所,中药质量控制技术国家工程实验室,北京100700 [3]首都医科大学燕京医学院,北京100300

出　　处：《中国药学杂志》2023年第22期2033-2047,共15页Chinese Pharmaceutical Journal

基　　金：中国中医科学院科技创新工程项目资助(CI2023E001TS03)。

摘　　要：目的本研究设计并合成一系列新的半胱天冬酶-3(procaspase-3)激活剂,同时进行分子模拟研究和抗肿瘤活性评价。方法以具有苯丙-2-烯酸结构的反式阿魏酸为原料,设计并合成了系列苯丙烯类化合物。采用分子模拟技术构建procaspase-3激活剂的药效团模型,选择最优药效团模型预测目标化合物的活性。利用CCK-8法研究目标化合物对肺癌细胞系A549半胱天冬酶-3(caspase-3高表达)和乳腺癌细胞系MCF-7(caspase-3不表达)的体外抗增殖活性。结果共设计并合成了29个目标化合物,其中包含26个新化合物。药效团模型预测结果显示有23个目标化合物活性优于阳性对照PAC-1。肺癌细胞系A549的体外抗增殖活性结果表明有20个目标化合物优于阳性对照PAC-1,其中活性最优的化合物AWS-XAPI-06的半抑制浓度(IC_(50))值为8.99μmol·L^(-1)。乳腺癌细胞系MCF-7的体外抗增殖活性结果表明在30μmol·L^(-1)给药浓度下目标化合物和阳性对照PAC-1的抑制率均较差。结论该系列化合物对Procaspase-3高表达的A549细胞有良好的抗增殖活性,且酰肼结构的保留有利于procaspase-3的直接激活,因此可进行深入研究。OBJECTIVE To design and synthesize a series of new Procaspase-3 activators and evaluate them by carrying out computer simulation and antitumor activity tests.METHODS A series of phenylpropene compounds were designed and synthesized using trans ferulic-acid with phenylpropan-2-enoic acid structure as raw material.The Procaspase-3 activating pharmacophore models were established using molecular simulation technology,and the activities of target compounds were predicted by the best performing pharmacophore model.The anti-proliferation activity of compounds against tumor cell line A549(caspase-3 high expression)and MCF-7(caspase-3 no expression)were evaluated using CCK-8 assay.RESULTS Twenty-nine target compounds in total were designed and synthesized,of which 26 were novel.Twenty of the 29 compounds showed better anti-proliferation activity on lung cancer cell line A549 in vitro than the positive control PAC-1.Compound AWS-XAPI-06 displayed the most significant antitumor activity with the IC_(50) value of 8.99μmol·L^(-1).The anti-proliferation activity analysis on breast cancer cell line MCF-7 in vitro showed that the target compounds and positive control PAC-1 had low inhibition rates at 30μmol·L^(-1) concentration.CONCLUSION The study shows that the series of compounds have good anti-proliferative activity against A549 cell line with Procaspase-3 high expression.Furthermore,the retention of hydrazide structure contributes to the direct activation of Procaspase-3,which makes the target compounds worthy of further study.

关 键 词：半胱天冬酶-3 抗肿瘤活性 药效团 苯丙烯 酰肼 

分 类 号：R914[医药卫生—药物化学]