水飞蓟宾C-3位衍生物的设计、合成及抗肿瘤活性研究  

Design,Synthesis and Antitumor Activity of C-3 Derivatives of Silybin

作　　者：刘家越 李学城 赵风菊 霍荣迪 孟艳秋[1] LIU Jia-yue;LI Xue-cheng;ZHAO Feng-ju;HUO Rong-di;MENG Yan-qiu(Department of Pharmaceutical Engineering,Shenyang University of Chemical Technology,Shenyang 110142,China)

机构地区：[1]沈阳化工大学制药工程学院,辽宁沈阳110142

出　　处：《化学试剂》2023年第7期144-151,共8页Chemical Reagents

基　　金：国家自然科学基金项目(21372156);辽宁省重点研发计划项目(2019JH2/10300034);辽宁省教育厅重点项目(LJKZ0427);辽宁省教育厅面上项目(LJKZ0427);沈阳市重大科技成果转化项目(20-203-5-45);沈阳化工大学重点攻关和服务地方项目(LDB2019001)。

摘　　要：设计并合成一系列新型水飞蓟宾衍生物,研究其抗肿瘤活性。以水飞蓟宾为起始原料,经过酰化、选择性氨解、烷基化、氧化脱氢等手段,合成目标化合物。通过MTT法测定了化合物对乳腺癌MCF-7和胃癌SGC7901两株细胞的体外抗肿瘤活性。利用分子对接技术,将目标化合物与MEK受体模拟偶联,分析其与MEK的作用方式。设计并合成12个新型水飞蓟宾衍生物,通过^(1)HNMR、^(13)CNMR及MS对化合物进行结构表征。细胞试验表明7-O-苄基-3-O-氯乙酰-5,20,23-三-O-乙酰-2,3-脱氢水飞蓟宾(I_(2))和7-O-苄基-3-O-苯磺酰-5,20,23-三-O-乙酰-2,3-脱氢水飞蓟宾(I_(12))明显高于母体水飞蓟宾,与阳性对照药物拉帕替尼表现相当。分子对接结果显示化合物可以与MEK的氨基酸残基通过氢键等作用稳定结合。合成的水飞蓟宾衍生物对乳腺癌MCF-7和胃癌SGC7901细胞有明显的抑制作用,C-3位羟基的选择性酰化是增强抗肿瘤活性的关键。A series of novel silybin derivatives were designed and synthesized and their antitumor activities were evaluated.The target compounds were synthesized from silybin by acylation,selective ammonolysis,alkylation,and oxidative dehydrogenation.The antitumor activities of the compounds against breast cancer MCF-7 and gastric cancer SGC7901 cells in vitro were determined by the MTT assay.Using molecular docking technology,the target compounds were simulated to couple with MEK receptor,and their interaction mode with MEK was analyzed.Twelve new silybin derivatives were designed,synthesized,and characterized by ^(1)HNMR,^(13)CNMR and MS analysis.Cell tests showed that the antitumor activities of compounds 7-O-benzyl-3-O-chloroacetyl-5,20,23-tri-O-acetyl-2,3-dehydrosilybin(I_(2))and 7-O-benzyl-3-O-benzenesulfonyl-5,20,23-tri-O-acetyl-2,3-dehydrosilybin(I_(12))were significantly higher than those of silybin,and were equivalent to those of positive control drug rapatinib.The results of molecular docking showed that the compounds can stably bind with amino acid residues of MEK through hydrogen bonding and other effects.The synthesized silybin derivatives have obvious inhibitory effects on breast cancer MCF-7 and gastric cancer SGC7901 cells,and the selective acylation of C-3 hydroxyl group plays a key role to enhance the anti-tumor activity.

关 键 词：水飞蓟宾 结构修饰 MEK 分子对接 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]