Synthesis, Evaluation of Biological Activity, Docking and Molecular Dynamic Studies of Pyrimidine Derivatives

The microtubule is composed of αβ-tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite great efforts to make an effective drug, no drug has been introduced which inhibit colchicine binding site. In the current work, a series of pyrimidine derivatives were designed and synthesized. Furthermore, their cytotoxic activities were evaluated and molecular docking studies were performed. Twenty compounds of pyrimidine were synthesized in 2 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thiomethylene spacer. In the second group, this linker was substituted by S-CH2-triazole moiety. The cytotoxic activity of these compounds was evaluated against 4 different cell lines (HT-29, MCF-7, T47D, NIH3T3). Compounds 6d, 6m, 6p showed potent cytotoxic activity against MCF7 cancerous cell lines. Between these compounds, compound 6p did not show cytotoxic activity against NIH- 3T3 (normal cell) cell line. Docking studies show that these compounds occupy colchicine binding site in tubulin protein and probably their anticancer mechanism is inhibition of tubulin polymerization. Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents. Attention to the selectivity index of 6p on MCF7 cell line could be valuable in design new chemical agents for the treatment of breast cancer.