2. Academic Validation
  3. Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors

  • Eur J Med Chem. 2023 Oct 15:262:115881. doi: 10.1016/j.ejmech.2023.115881.
Yuchen Tan 1,  Han Hu 1,  Wenjian Zhu 1,  Tao Wang 1,  Tian Gao 1,  Hongqi Wang 1,  Jian Chen 2,  Jinyi Xu 3,  Shengtao Xu 4,  Huajian Zhu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 2 Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou, Jiangsu, 215300, PR China.
  • 3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China; Shenzhen Research Institute of China Pharmaceutical University, Nanshan District, Shenzheng, 518052, PR China.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China; Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou, Jiangsu, 215300, PR China; Shenzhen Research Institute of China Pharmaceutical University, Nanshan District, Shenzheng, 518052, PR China. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 37883897 DOI: 10.1016/j.ejmech.2023.115881
Abstract

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as Anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four Cancer cell lines with IC50 values among 0.003-0.024 μM and tubulin polymerization inhibitory activity (IC50 = 3.06 μM). Further mechanism studies revealed that compound 6t could induce K562 cells Apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent Anticancer properties in vitro and in vivo.

Keywords

Anti-angiogenesis; Antiproliferative agents; Colchicine binding site inhibitors; Dihydroquinolin-4(1H)-one derivatives; Tubulin.

Figures
Products