灵芝酸A-靛红拼合物的合成、抗肿瘤活性及靶点预测研究  

Synthesis, antitumor activity and target prediction of ganoderic acid A-isatin conjugate

作　　者：贾怡 李艳 王晓琳 尚海[1] 田瑜[1] JIA Yi;LI Yan;WANG Xiao-lin;SHANG Hai;TIAN Yu(Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100193,China)

机构地区：[1]中国医学科学院北京协和医学院药用植物研究所,北京100193

出　　处：《中草药》2023年第7期2044-2055,共12页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学基金资助项目(82173710);中国医学科学院医学与健康科技创新工程项目(2021-I2M-1-028,2022-I2M-2-002);科技部国家重点研发计划项目(2019YFC1710504);北京市自然科学基金资助项目(7192129)。

摘　　要：目的 将灵芝三萜中的主要成分灵芝酸A与具有抗肿瘤作用的靛红片段进行拼合,对所得的拼合物进行体外抗肿瘤活性评价,分析构效关系,并对灵芝酸A及其拼合物的靶点进行预测。方法 将灵芝酸A与1个单元或3个单元长度的聚乙二醇连接,再通过点击化学反应与靛红片段进行拼合,采用噻唑蓝(MTT)法考察合成拼合物对乳腺癌MCF-7细胞、肝癌HepG2细胞、骨肉瘤SJSA-1细胞和正常细胞系HK-2细胞的抗增殖活性。结果 共合成16个不同长度及不同取代的灵芝酸A-靛红拼合物,确定结构,为结构全新的化合物。部分拼合物表现出良好的抗肿瘤活性,且靛红片段上的取代基对抗肿瘤效果影响较大,其中6位取代活性最优。反向找靶及分子对接结果表明,灵芝酸A及拼合物可能通过调控鼠双微体2/X蛋白(mouse double minute 2/X,MDM2/X)发挥抗肿瘤作用。结论 该系列化合物对MCF-7细胞的选择性较强,化合物A11和A16具有进一步研究的价值,具有开发为双靶点或多靶点抗肿瘤化合物的潜力。Objective To combine the main component of triterpenoid in Chinese traditional and precious nourishing medicine Ganoderma lucidum,ganoderic acid A(GAA),with anti-tumor compound isatin,evaluate the anti-tumor activity of the obtained conjugate in vitro,analyze the structure-activity relationship,and predict the targets of GAA and these conjugate.Methods GAA was connected with polyethylene glycol with one or three unit lengths,and then combined with isatin by click reaction.The anti-proliferation activity of the synthesized compounds on MCF-7,HepG2,SJSA-1 and normal cell line HK-2 was investigated by MTT assay.Results A total of 16 new GAA-isatin conjugates with different lengths and different substitutions were synthesized and their structures were determined.Some of the compounds showed good anti-tumor activity,and the substitution of the isatin fragment had a great impact on the anti-tumor effect,especially in the 6-position.Target fishing and molecular docking results showed that GAA and its conjugate may exert anti-tumor effect through regulating mouse double minute 2/X(MDM2/X).Conclusion The series of the compounds have strong selectivity for MCF-7.Compounds A11 and A16 have the value of further research and have the potential to develop a dual-target or multi-target anti-tumor compound.

关 键 词：灵芝酸A 靛红 拼合物 抗肿瘤 构效关系 靶点预测 

分 类 号：R284.1[医药卫生—中药学]