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

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

  • Eur J Med Chem. 2022 Aug 5:238:114463. doi: 10.1016/j.ejmech.2022.114463.
Yan Liu 1,  Jiaqing Huang 2,  Min Wu 2,  Bi Liu 2,  Qiaofa Lin 2,  Jingjing Wu 2,  Yuhua Ouyang 2,  Xin Guo 2,  Ruyi Huang 2,  Yongmin Zhang 3,  Jianhua Xu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, 350122, China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 Place Jussieu, 75005, Paris, France.
  • 2 Department of Pharmacology, School of Pharmacy, Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, 350122, China.
  • 3 Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), UMR 8232, 4 Place Jussieu, 75005, Paris, France. Electronic address: yongmin.zhang@upmc.fr.
  • 4 Department of Pharmacology, School of Pharmacy, Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, 350122, China. Electronic address: xjh@fjmu.edu.cn.
PMID: 35617856 DOI: 10.1016/j.ejmech.2022.114463
Abstract

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.

Keywords

Antitumor; Glucose transporter; Triptolide; Triptolide-glucose conjugate.

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