CA4偶氮化衍生物的合成及其性能研究  

Synthesis of Azo Derivatives of CA4 and Evaluation of Their Properties

作　　者：全梦香 金佳澄 邓双 李思仪 黄蓓 张珊 王尊元 

机构地区：[1]杭州医学院药学院,浙江 杭州

出　　处：《药物化学》2025年第1期95-106,共12页Hans Journal of Medicinal Chemistry

基　　金：浙江省大学生科技创新活动计划(新苗人才计划) (编号:2024R424A009)、浙江省大学生创新创业训练计划项目(编号:S202213023047,S202413023055)资助。

摘　　要：目的:将微管蛋白抑制剂康普瑞汀(Combretastatin A4, CA4)的顺式二苯乙烯结构改造为偶氮苯类化合物,以其体内分布的特异性活化性能来增强其靶向性。方法:以3,4,5-三甲氧基苯胺为起始原料,经过重氮化反应后,与邻炔丙氧基苯酚进行偶合,得到关键中间体AzO-OH;关键中间体进一步与碘甲烷、溴丙烷或溴代正丁烷在K2CO3存在下进行酚羟基的取代反应,得到产物AzO-Me,AzO-Pr,AzO-Bu。结果:设计并合成得到CA4的偶氮化衍生物,其结构经NMR、MS确证;分子对接表明,该类化合物与微管蛋白具有较强的结合性,其结合模式与顺式CA4相近,因而可能具有类似或更强的微管蛋白抑制作用;光学性能研究发现,该类偶氮化合物在不同波长光照下会发生顺-反或反-顺的构型变化;初步的药理实验的结果显示,细胞增殖抑制活性在光照后大大提高。结论:将CA4改造为偶氮苯类化合物后,通常情况下以无生物活性但性质更稳定的反式结构存在,而在体内靶部位给予特定波段的光,就可以转化为具有活性的顺式结构发挥作用,从而可以实现“全身给药,局部激活”的靶向性能,加强了CA4的靶向性,初步的药理实验证实了上述设想。Objective: To transform the cis-stilbene structure of the tubulin inhibitor Combretastatin A4 (CA4) into an azobenzene compound, so as to enhance its targeting ability in vivo. Method: The starting material 3,4,5-trimethoxyaniline was diazotized, then coupling with o-propargyloxyphenol to obtain the key intermediate AzO-OH;the key intermediate was further substituted with the reaction of the phenolic hydroxyl group to obtain the product AzO-Me, AzO-Pr, AzO-Bu, by combining with methyl iodide, bromopropane or bromo-n-butane in the presence of K2CO3. Results: The azo derivatives of CA4 were synthesized. Their structures were confirmed by NMR and MS. Molecular docking showed that these compounds had strong binding activities to tubulin, and the binding

关 键 词：微管蛋白抑制剂 CA4 偶氮 光致异构性 合成 

分 类 号：O62[理学—有机化学]