芬戈莫德类似物的设计合成及抗肿瘤活性研究.pdfVIP

·1282 · 中草药 Chinese Traditional and Herbal Drugs 第 47 卷 第 8 期 2016 年 4 月 芬戈莫德类似物的设计合成及抗肿瘤活性研究 陈 锴，马 宣，严 宁，解晓霞，姚 雷* 烟台大学 分子药理和药物评价教育部重点实验室，新型制剂与生物技术药物研究山东省高校协同创新中心，山东 烟台 264005 摘 要：目的 对基于由冬虫夏草提取物多球壳菌素 ISP-1 结构改造而得到的药物芬戈莫德进行结构修饰，并初步考察其类 似物的抗肿瘤活性。方法 以不同的取代苯为原料，按照本课题组开发的芬戈莫德合成路线，经过傅克酰基化、亚硝基SN2 取代反应、羰基还原、双亨利反应和硝基还原反应制得目标化合物。通过 MTT 方法，检测化合物对 3 种人类肿瘤细胞 Siha、 PC-3 和 MKN-45 的抗肿瘤活性。结果 制得芬戈莫德（1）及其 18 个类似物（2～19），化合物 10、11、12 具有与芬戈莫德 相当的抗肿瘤活性。结论 化合物 2～10 及 12～19 为未见文献报道的新化合物，为基于 1-磷酸鞘氨醇（S1P）受体拮抗作 用的抗肿瘤药物的发现提供依据。 关键词：冬虫夏草；多球壳菌素；芬戈莫德；结构修饰；抗肿瘤；1-磷酸鞘氨醇受体 中图分类号：R284.3 文献标志码：A 文章编号：0253 - 2670(2016)08 - 1282 - 07 DOI: 10.7501/j.issn.0253-2670.2016.08.006 Design and synthesis of fingolimod analogues as well as evaluation on their antitumor activity CHEN Kai, MA Xuan, YAN Ning, XIE Xiao-xia, YAO Lei Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, and Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China Abstract: Objective To modify the structure of fingolimod which was derived from the extract of medicinal plant Cordyceps ISP-1 and evaluate the antitumor activity of the derivatives. Methods According to the synthesis way developed before, target compounds were synthesized by using suitable substitued benzenes, through chemical reactions such as Friedel-Crafts reaction, Nitros-substitution reaction, Carbonyl reduction, Henry reaction, and Nitro-reduction. The cytotoxicities to three cell lines, Siha, PC-3, and MKN-45, were evaluated through MTT method. Results Fingolinod and 18 fingolimod analogues were synthesized, and compounds 10—12 had the equal antitumor activities like fingolimod. Conclusion The compounds 2—10, 12—19 are new compounds not reported before. This study provides the foundation for finding antitumor compounds with S1PRs inhibiting effect. Key words: