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目的:通过对穿心莲内酯引入亲水性基团,探索衍生物的抗肿瘤活性和构效关系。方法:碱性条件下,穿心莲内酯1与硝基甲烷进行Michael加成反应,重排生成12-硝基甲基-14-去氧穿心莲内酯,再以锌粉盐酸还原硝基生成12-氨基亚甲基-14-去氧穿心莲内酯2,最后与异氰酸酯反应成脲3a～3n,所有化合物考察了抗肿瘤和抑制NA活性。结果:经结构改造后,两个化合物(3f和3m)显示了中等的抗肿瘤活性,并且都是单取代芳环,提示芳环的引入优于脂肪链(环)和杂环;所有衍生物都无抑制NA活性。结论:穿心莲内酯对流感病毒神经氨酸酶无抑制活性;12位引入芳环有意义,但芳环所处的支链不能过长;水溶性基团的引入对活性提高没有帮助,具体有待进一步研究。
OBJECTIVE: To explore the antitumor activity and structure-activity relationship of derivatives by introducing hydrophilic groups into andrographolide. METHODS: Under alkaline conditions, andrographolide 1 was subjected to Michael addition reaction with nitromethane, rearranged to form 12-nitromethyl-14-deoxyandrographolide, and the nitro group was reduced with zinc chloride to produce 12- Aminomethylene-14-deoxy-andrographolide 2, and finally reacted with isocyanates to urea 3a ~ 3n. All the compounds investigated the anti-tumor activity and inhibit NA activity. Results: The two compounds (3f and 3m) showed moderate anti-tumor activity after structural modification and were all monosubstituted aromatic rings, suggesting the introduction of aromatic rings was better than that of aliphatic chains (rings) and heterocycles. All the derivatives No inhibition of NA activity. CONCLUSION: Andrographolide has no inhibitory activity on the influenza virus neuraminidase. The introduction of aryl ring at position 12 is of significance, but the branch of aromatic ring can not be too long. The introduction of water-soluble group is not helpful to improve the activity. further research.