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

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 mu M 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 pyrim-idine and the 3,4,5-trimethoxyphenyl ring may deserve consideration for cancer therapy.

Automated summary

A library of new pyrimidine analogs was synthesized and compound K10 showed the most potent activity against four cancer cell lines, inhibiting microtubule polymerization and inducing apoptosis in HepG2 cells. It also inhibited the migration and invasion of HepG2 cells. Overall, this study suggests that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5-trimethoxyphenyl ring may be a promising candidate for cancer therapy.