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

Eur J Med Chem. 2022 May 17;238:114463. doi: 10.1016/j.ejmech.2022.114463. Online ahead of print.ABSTRACTSix 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.PMID:35617856 | DOI:10.1016/j.ejmech.2022.114463

Source: European Journal of Medicinal Chemistry - May 26, 2022 Category: Chemistry Authors: Yan Liu Jiaqing Huang Min Wu Bi Liu Qiaofa Lin Jingjing Wu Yuhua Ouyang Xin Guo Ruyi Huang Yongmin Zhang Jianhua Xu Source Type: research