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 ¹H-NMR, ¹³C-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.

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）