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

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,3aR,3a1R,6aR,11aR)-5-(1-(4-hydroxyphenyl)-1H1,2,3-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=0.25 mu mol(.)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.