Design, synthesis, and biological activity evaluation of novel tubulin polymerization inhibitors based on pyrimidine ring skeletons

  • Bioorg Med Chem Lett. 2023 Mar 15:84:129195. doi: 10.1016/j.bmcl.2023.129195.
Yingying Kang  1 ,  Yuanyuan Pei  1 ,  Jinling Qin  1 ,  Yixin Zhang  1 ,  Yongtao Duan  2 ,  Hua Yang  1 ,  Yongfang Yao  3 ,  Moran Sun  4
Affiliations
  • 1. School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
  • 2. Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • 3. School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: [email protected].
  • 4. School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: [email protected].
PMID: 36828299 DOI: 10.1016/j.bmcl.2023.129195
Abstract

A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC50 values of 0.07-0.80 μM against four Cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced Apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5‑trimethoxyphenyl ring may deserve consideration for Cancer therapy.

Keywords
Antitumor; Colchicine site; Pyrimidine; Tubulin; Tubulin inhibitors.