2. Academic Validation
  3. Design, synthesis, and bioevaluation of imidazo [1,2-a] pyrazine derivatives as tubulin polymerization inhibitors with potent anticancer activities

Design, synthesis, and bioevaluation of imidazo [1,2-a] pyrazine derivatives as tubulin polymerization inhibitors with potent anticancer activities

  • Bioorg Med Chem. 2022 Dec 15:76:117098. doi: 10.1016/j.bmc.2022.117098.
Bulian Deng 1,  Zhiqiang Sun 1,  Yuxi Wang 2,  Ruiyao Mai 1,  Zichao Yang 1,  Yichang Ren 1,  Jin Liu 1,  Junli Huang 1,  Zeli Ma 3,  Ting Chen 3,  Canjun Zeng 4,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 2 Targeted Tracer Research and Development Laboratory, Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 4 Department of Foot and Ankle Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China. Electronic address: zengcanjun@163.com.
  • 5 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China. Electronic address: jchen21@smu.edu.cn.
PMID: 36455508 DOI: 10.1016/j.bmc.2022.117098
Abstract

Through structural optimization and ring fusion strategy, we designed a series of novel imidazo[1,2-a]pyrazine derivatives as potential tubulin inhibitors. These compounds displayed potent anti-proliferative activities (micromolar to nanomolar) against a panel of Cancer cell lines (including HepG-2, HCT-116, A549 and MDA-MB-231 cells). Among them, compound TB-25 exhibited the strongest inhibitory effects against HCT-116 cells with an IC50 of 23 nM. Mechanism studies revealed that TB-25 could effectively inhibit tubulin polymerization in vitro, and destroy the dynamic equilibrium of microtubules in HCT-116 cells. In addition, TB-25 dose-dependently induced G2/M phase cell cycle arrest and Apoptosis in HCT-116 cells. Furthermore, TB-25 suppressed HCT-116 cell migration in a concentration-dependent manner. Finally, molecular docking showed that TB-25 fitted well in the colchicine binding site of tubulin and overlapped nicely with CA-4. Collectively, these results suggest that TB-25 represents a promising tubulin inhibitor deserving further investigation.

Keywords

Antiproliferative; Colchicine binding site; Imidazo[12–a]; Pyrazine; Tubulin inhibitor.

Figures