2. Academic Validation
  3. Design, synthesis and biological evaluation of colchicine glycoconjugates as tubulin polymerization inhibitors

Design, synthesis and biological evaluation of colchicine glycoconjugates as tubulin polymerization inhibitors

  • Bioorg Med Chem. 2022 Mar 15:58:116671. doi: 10.1016/j.bmc.2022.116671.
Zhan Wang 1,  Runlai Liu 2,  Xin Zhang 2,  Xing Chang 3,  Minghuan Gao 3,  Shuai Zhang 2,  Qi Guan 4,  Jun Sun 5,  Daiying Zuo 6,  Weige Zhang 7
Affiliations

Affiliations

  • 1 Pharmaceutical Department, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Road, Erqi District, Zhengzhou 450052, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 3 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: guanqi@syphu.edu.cn.
  • 5 Clinical Pharmacology Laboratory, Henan Province People's Hospital, Zhengzhou University People's Hospital, 7 Weiwu Road, Jinshui District, Zhengzhou 450003, China. Electronic address: Jun_84@163.com.
  • 6 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zuodaiying@163.com.
  • 7 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zhangweige2000@sina.com.
PMID: 35193066 DOI: 10.1016/j.bmc.2022.116671
Abstract

A series of new colchicine glycoconjugates as tubulin polymerization inhibitors were designed by targeting strategy based on Warburg effect. All of the colchicine glycoconjugates were synthesized and then evaluated for their antiproliferative activities against three human Cancer lines HT-29, MCF-7 and Hep-3B. Among them, 1e exhibited greater than 10 times selectivity between GLUT1 highly expressed cells (HT-29 and MCF-7) and GLUT1 lowly expressed cells (Hep-3B), and also showed lower cytotoxicity against HUVECs compared with colchicine. Moreover, 1e significantly inhibited tubulin polymerization and disrupted microtubule networks. GLUT1 inhibitor-dependent cytotoxicity assay demonstrated that the uptake of 1e was regulated via GLUT1. Molecular docking studies showed that 1e could be a substrate of GLUT1 and bind to the colchicine site of tubulin.

Keywords

Colchicine glycoconjugates; Glucose transporter; Molecular docking; Tubulin; Warburg effect.

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