三嗪环类和厚朴酚衍生物的合成及体外抗炎、抗肿瘤活性评价  

Design,synthesis,in vitro anti⁃inflammatory and anti⁃tumor activity evaluation of triazine derivatives of honokiol

作　　者：谭有珍 吴霞 冯毅凡 TAN You-zhen;WU Xia;FENG Yi-fan(Foshan Hospital of Traditional Chinese Medicine,Foshan 528000,China;Central Laboratory of Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]佛山市中医院,广东佛山528000 [2]广东药科大学中心实验室,广东广州510006

出　　处：《中国药物化学杂志》2023年第7期508-515,共8页Chinese Journal of Medicinal Chemistry

摘　　要：目的合成并筛选具有优良抗肿瘤、抗炎活性且毒性相对较低的三嗪环类和厚朴酚衍生物。方法以和厚朴酚和二甲双胍为原料,经Reimer-Tiemann反应、置换反应、环化反应得到目标衍生物,并结合本课题组前期合成的4个类似物,采用Griess法、酶联免疫吸附试验(ELISA)测定了7个三嗪环类和厚朴酚衍生物的体外抗炎活性。以癌细胞株MCF-7、HepG2、A549、HT29、B16和Bel7402为载体,探讨了系列化合物的体外抗肿瘤活性,并分析总结了其构效关系。结果与结论合成了3个全新的三嗪环类和厚朴酚衍生物,目标化合物的结构经HR-ESI-MS、1H-NMR及13C-NMR谱确证。系列三嗪环类和厚朴酚的构效关系表明,三嗪环的引入显著地提高了和厚朴酚抗肿瘤活性。其中,化合物Ⅱb对B16、Bel7402细胞的IC50值分别为9.17μmol·L^(-1)和7.13μmol·L^(-1),抗肿瘤活性明显优于阳性药顺铂。化合物Ⅰb和Ⅱc具有良好的炎症抑制活性,能使NO和炎症因子1L^(-1)β、TNF-α显著降低,效果与阳性药布洛芬相当,并且对细胞的毒性相比前药和厚朴酚显著降低。该研究结果为抗肿瘤和抗炎小分子药物的设计和开发提供了有价值的思路。Honokiol is one of the most valuable active ingredients with great anti⁃tumor and anti⁃inflammatory activities in Magnolia officinalis.However,it was limited by its high toxicity in clinical application.In this study,three new honokiol derivatives were designed and synthesized,their structures were characterized by 1H⁃NMR,13 C⁃NMR and HR⁃ESI⁃MS.Combined with four analogities synthesized by our group,in vitro anti⁃inflammatory,in vitro anti⁃tumor activities and structure⁃activity relationships of seven triazine derivatives of honokiol were discussed.The results are very encouraging.After the introduction of triazine ring,the anti⁃tumor activity of derivatives was greatly improved.The IC50 of compoundⅡb against B16 cells and Bel7402 cells was 9.17μmol·L^(-1) and 7.13μmol·L^(-1),respectively.The anti⁃tumor activity of compoundⅡb was significantly better than that of cisplatin.CompoundsⅠb andⅡc have great inflammatory inhibitory activity,which can significantly reduce NO and inflammatory factors 1L⁃1βand TNF⁃α,which is comparable to ibuprofen.The results of this study provide valuable ideas for the design and development of anti⁃tumor and anti⁃inflammatory small molecule drugs.

关 键 词：和厚朴酚 衍生物 三嗪环 抗炎 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]