新型蓝萼甲素-1,2,3-三氮唑类衍生物的合成与抗增殖活性研究

Synthesis and Antiproliferative Activity Evaluation of Novel Glaucocalyxin A-1,2,3-Triazole Derivatives

设计并合成了一系列新型的天然产物蓝萼甲素(GlaucocalyxinA,GLA)-1,2,3-三氮唑类衍生物,并评估该系列衍生物对Hep G2、NCI-H460、JEG-3、K562、HL-60和Hela等六种人肿瘤细胞株的抗增殖活性.结果表明大多数化合物具有很强的抗增殖作用,其中一些化合物的活性明显优于GLA.其中(3S,3a R,3a1R,6a R,11a R)-5-(1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)-8,8,11a-三甲基-13-亚甲基十氢-1H-3,3a1-乙吩并[1,10-de][1,3]二噁-9,12(2H)-二酮(16)对HL-60细胞株表现出最强的抑制作用(IC50=0.25μmol·L^(-1)),其活性比阳性药阿霉素强6.9倍,比蓝萼甲素强25.8倍.这些结果表明在保留D环上α,β-不饱和酮药效基团的前提下,间羟基或对羟基苯基取代的1,2,3-三氮唑缩醛结构片段的引入是提高蓝萼甲素抗肿瘤活性的有效途径.细胞凋亡形态学和流式细胞仪测定表明蓝萼甲素-1,2,3-三氮唑类衍生物具有诱导肿瘤细胞凋亡的作用.

A series of novel 1,2,3-triazole derivatives based on natural product glaucocalyxin A(GLA)were designed and prepared.Their antiproliferative activity was evaluated against six human tumor cell lines(HepG2,NCI-H460,JEG-3,K562,HL-60,Hela).Most compounds exhibited potent antiproliferative effects with low micromolar IC50 values.The activity of some of the compounds is significantly superior to GLA.In particular,(3S,3a R,3a1R,6a R,11a R)-5-(1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)-8,8,11a-trimethyl-13-methylenedecahy-dro-1H-3,3a1-ethanophenanthro[1,10-de][1,3]dioxine-9,12(2H)-dione(16)displayed the highest inhibition efficacy(IC50=0.25μmol·L^(-1)),which was 6.9 times higher than that of the positive control adriamycin and 25.8 times higher than that of GLA against HL-60 cells.The results also demonstrated that the introduction of triazole acetal with meta-and para-hydroxyl substitution on phenyl without change of methylene cyclopentanone on the D-ring could improve the antitumor activity of GLA significantly.The apoptosis morphology and flow cytometry studies indicated that the triazole-fused GLA derivatives could induce apoptosis of tumor cells.