Design, synthesis of novel triptolide-glucose conjugates targeting glucose Transporter-1 and their selective antitumor effect.

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. [Display omitted] TG2 conjugated by triptolide and d -glucose C2–OH has a stronger selective antitumor activity than triptolide due to selective transport of TG2 into tumor cells via glucose transporters. • ●Triptolide-Glucose Conjugate TG2 formed by triptolide C14–OH and d -glucose C2–OH. • ●The cytotoxicity of TG2 is highly dependent on Glut-1 function. • ●TG2 distributes in tumor selectively and has a highly selective antitumor activity. [ABSTRACT FROM AUTHOR]