Six positional isomers of
triptolide-
glucose conjugates (TG1α, TG1β, TG2, TG3, TG4 and TG6) were designed and synthesized. These conjugates exhibited better water solubility, and had selective cytotoxicity between
tumor cells with high expression of
glucose transport-1 (Glut-1) and non-
tumor cells with low expression of Glut-1, in which TG2 formed by
triptolide (TPL) and
d-glucose C2-OH had the strongest cytotoxicity to
tumor cells and lowest toxicity in non-
tumor cells, therefore the highest relative therapeutic index, which was 5.7 times that of
triptolide and consequent the most powerful selective antitumor activity in vitro. The cytotoxicity of TG2 was highly correlated with Glut-1 function. As a
prodrug of
triptolide, TG2 could promote
RNA Pol II degradation and induce apoptosis as TPL does. TG2 had a stronger dose-dependent antitumor effect in vivo than TPL and no adverse reaction occurred when its
tumor inhibition was higher than 90%, which was associated with its selective distribution in
tumor tissues. TG2 could be used as a promising drug candidate for the treatment of solid
tumors with high expression of Glut-1, which is worthy of further study.