小檗碱衍生物的合成及其抗血管生成活性研究  

Synthesis and antiangiogenic activity of berberine derivatives

作　　者：黄雪梅 张宏桂[1] 田学浩 贾晓慧[1] 曹寅秋 周菲[1] 张文曦 郭文博[1] 蔡德生 杨玉琴[1] 张昊 王鹏龙[1] 雷海民[1] HUANG Xue-mei;ZHANG Hong-gui;TIAN Xue-hao;JIA Xiao-hui;CAO Yin-qiu;ZHOU Fei;ZHANG Wen-xi;GUO Wen-bo;CAI De-sheng;YANG Yu-qin;ZHANG Hao;WANG Peng-long;LEI Hai-min(School of Chinese Pharmacy,Beijing University of Chinese Medicine,Beijing 102488,China)

机构地区：[1]北京中医药大学中药学院

出　　处：《现代药物与临床》2019年第10期2881-2886,共6页Drugs & Clinic

基　　金：国家自然科学基金资助项目（81603256）;中华中医药学会青年人才托举工程项目（CACM-2018-QNRC2-B08）;中央高校基金科研业务项目（杰出青年BUCM-2019-JCRC002、BUCM-2018-2020和岐黄团队2019-JYB-TD005）;中央高校基金科研业务项目（2019-JYB-XS-078）

摘　　要：目的结构拼合是获得先导化合物的有效途径,以此为指导合成一系列新型小檗碱衍生物,并用Ⅳ型胶原酶和鸡胚尿囊膜(CAM)模型评价其活性和安全性。方法以小檗碱为母核,结合中药常见活性成分,运用"拼合原理",设计、合成小檗碱系列衍生物,并采用课题组前期建立的Ⅳ型胶原酶和CAM模型,快速评价小檗碱衍生物对Ⅳ型胶原酶的抑制作用和对新生胚胎血管生成的影响。结果设计并合成了4个新化合物,结构经1H-NMR、13C-NMR和HRMS确认,其中化合物CYQ-44、CYQ-48、CYQ-50对Ⅳ型胶原酶有剂量相关性抑制作用,且均高于阳性药盐酸四环素;与此同时,化合物CYQ-48、CYQ-对新生胚胎血管生成有一定抑制作用。结论成功合成了4个新型小檗碱衍生物,它们不仅对Ⅳ型胶原酶和新生血管具有抑制作用,而且安全指数高,进一步表明以结构拼合为指导可高效、简便获得具有中医药特点的先导化合物。Objective Structural combination is an effective way to obtain leading compounds. Under the guidance of this, a series of new berberine derivatives were synthesized, and their activity and safety were evaluated by type IV collagenase and chick chorioallantoic membrane(CAM) model. Methods Using berberine as the mother nucleus, combined with the common active components of traditional Chinese medicine, a series of berberine derivatives were designed and synthesized by using "combination principle", and the models of type IV collagenase and CAM established by preliminary research were used. The inhibitory effect of berberine derivatives on type IV collagenase and the effect of berberine derivatives on angiogenesis of newborn embryos were evaluated rapidly. Results Four compounds were synthesized in the article, and their chemical structures were confirmed by 1 H-NMR, 13 C-NMR, and HRMS, in which compounds CYQ-44, CYQ-48, and CYQ-50 had a dose-dependent inhibitory effect on type IV collagenase, which was higher than that of tetracycline hydrochloride. Meanwhile, compounds CYQ-48 and CYQ-50 had certain inhibitory effects on neovascularization of newborn embryos. Conclusion Four new berberine derivatives have been successfully synthesized, which not only inhibit type IV collagenase and neovascularization, but also have high safety index. It is further shown that the lead compounds with the characteristics of traditional Chinese medicine can be obtained efficiently and easily under the guidance of structural combination.

关 键 词：小檗碱衍生物 拼合原理 Ⅳ型胶原酶 鸡胚尿囊膜 

分 类 号：R914[医药卫生—药物化学] R965[医药卫生—药学]