2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition

  • Eur J Med Chem. 2024 Apr 16:271:116425. doi: 10.1016/j.ejmech.2024.116425.
Si-Si Li 1,  Jun-Jie Chen 1,  Miao-Miao Zhang 1,  Wei-Xu Wang 1,  Wei-Yi Zhang 2,  Cheng Ma 3
Affiliations

Affiliations

  • 1 Department of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China.
  • 2 Department of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China; Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Xinjiang Medical University, Urumqi, 830011, China; Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology, Xinjiang Medical University, Urumqi, 830011, China; Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Xinjiang Medical University, Urumqi, 830011, China. Electronic address: zwy@xjmu.edu.cn.
  • 3 Department of Medicinal and Organic Chemistry, College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China; Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Xinjiang Medical University, Urumqi, 830011, China; Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology, Xinjiang Medical University, Urumqi, 830011, China; Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Xinjiang Medical University, Urumqi, 830011, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, 830011, China. Electronic address: mac2008hk@126.com.
PMID: 38636129 DOI: 10.1016/j.ejmech.2024.116425
Abstract

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical Cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical Cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical Cancer cell lines HeLa, SiHa and CA Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 μM and 23.96 μM respectively). Its IC50 value was at 3.38 μM to the SiHa cells. Further mechanistic studies revealed that 4r induced Apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical Cancer treatment.

Keywords

Anti-Cervical cancer; Benzimidazole derivatives; PI3Kα tubulin dual inhibitors; Synergistic antiproliferation.

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