Synthesis and Biological Evaluation of 2,4,5-Substituted Pyrimidines as a New Class of Tubulin Polymerization Inhibitors

Members of a series of 2,4,5-substituted pyrimidine derivatives were synthesized, and their interactions with tubulin and their antiproliferative activities against the human hepatocellular carcinoma cells of liver (BEL-7402) were evaluated. One member of this family, the indole-pyrimidine 4k, having an indole-aryl-substituted aminopyrimidine structure, was observed to be an excellent inhibitor of tubulin polymerization (IC50 = 0.79 mu M) and to display significantly high antiproliferative activities against several cancer cell lines with IC50 values ranging from 16 to 62 nM. This substance displayed a high propensity to arrests cells at the G(2)/M phase of the cell cycle (EC50 = 20 nM). In addition, 4k was found to competitively inhibit colchicine binding to tubulin, indicating that it binds to the colchicine-binding site of tubulin. The observations made in this investigation demonstrate that 2,4,5-substituted pyrimidines represent a new class of tubulin polymerization inhibitors with significant antiproliferative activity.