基于肿瘤细胞响应性释药的安吖啶缀合物的设计合成及抗肿瘤活性研究  

Rational design of amsacrine conjugates for tumor responsive drug release and the antitumor activity in vivo

作　　者：杜灵芝 陈冰[2] 高凡[2] 张树峰[2] 张亚宏[2] 王建红[2] DU Ling-zhi;CHEN Bing;GAO Fan;ZHANG Shu-feng;ZHANG Ya-hong;WANG Jian-hong(Jiaozuo Second People's Hospital,Affiliated Hospital of He'nan Polytechnic University,Jiaozuo 454001,China;Key Laboratory of Natural Medicine and Immuno-Engineering of He'nan Province,He'nan University,Kaifeng 475004,China)

机构地区：[1]河南理工大学附属医院焦作市第二人民医院,河南焦作454001 [2]河南大学天然药物与免疫工程重点实验室,河南开封475004

出　　处：《中国药物化学杂志》2020年第7期389-398,共10页Chinese Journal of Medicinal Chemistry

基　　金：National Natural Science Foundation of China(21272056,U1404814);HASTIT(16HASTIT029)funded by Education Department of He’nan Province

摘　　要：目的改善抗肿瘤药物安吖啶的药效学性质以期增强其靶向抗肿瘤作用。方法基于拼合设计原理,以安吖啶为原料,经与吡啶-2-过硫乙醇偶联、与巯基多胺硫交换反应合成安吖啶-二硫键-胺基缀合物;采用MTT法测试目标化合物8a(m=1,R=H)对人肝癌细胞(HepG2)的体外生长抑制活性;在H22肝癌细胞移植的荷瘤小鼠模型上测试化合物8a的体内抗肿瘤作用。结果与结论合成了5个未见文献报道的安吖啶缀合物,目标化合物的结构经核磁共振氢谱、核磁共振碳谱及高分辨质谱确证。体外试验结果表明,化合物8a在谷胱甘肽作用下发生二硫键降解并释放出安吖啶原药;高谷胱甘肽水平能够增强化合物8a对人肝癌细胞HepG2的生长抑制作用;体内活性试验表明,在1.25 mg·kg-1剂量下化合物8a对荷瘤小鼠的肿瘤(hepatoma H22)生长抑制率达到51.3%,荷瘤小鼠的生存时间明显延长。In this study,a series of amsacrine-disulfide-amine conjugates were designed and synthesized as biothiol-responsive anticancer prodrug for improving the chemotherapeutic efficacy of amsacrine.Upon exposure in the elevated GSH levels,the disulfide bond was disassembled,leading to release of free amsacrine in its active form.The in vitro cell-growth inhibition experiments indicated that conjugate 8 a(m=1,R=H)possessed the reduced cytotoxicity compared with parent drug amsacrine.The in vivo biological evaluation revealed that conjugate 8 a could suppress tumor-growth by 51.3%at the dose of 1.25 mg·kg-1,and the effects on survival time in hepatoma H22-bearing mice were superior to that of the reference compound.Therefore,the present amsacrine-disulfide-amine conjugate could combine the additive features of their subunits and thus provide a smart approach for ameliorating chemotherapeutic efficacy of anticancer drugs.

关 键 词：安吖啶缀合物 二硫键 肿瘤响应性 肿瘤生长抑制 

分 类 号：R914[医药卫生—药物化学]