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

Abstract

<jats:sec> <jats:title>Background:</jats:title> <jats:p> 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 a great efforts to make an effective drug, no drug has been introduced which inhibit colchicine binding site.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p> 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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 thio-methylene 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).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion :</jats:title> <jats:p>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 treatment of breast cancer.</jats:p> </jats:sec>

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…Incorporation of thioether between 1,2,3‐triazole and pyrimidine moieties was tolerated as evidenced by that hybrid 50 (IC 50 : 48.6 and 30.3 µM, MTT assay) was active against MCF‐7 and T47D breast cancer cell lines, and the antiproliferative activity was superior to that of paclitaxel (IC 50 : 40.2 µM) against T47D breast cancer cells. [ 78 ] The phenyl ring on the pyrimidine moiety was not essential for the activity, and hybrid 51 (IC 50 : 5.85 µM, MTT assay) showed promising antiproliferative activity against MCF‐7 breast cancer cells. [ 79 ] In addition, these hybrids could target the histone deacetylases in MCF‐7 breast cancer cells.…”

Review: Pyrimidine Derivatives as Anticancer Agents

“…When compared to other wellestablished treatments, such as 5-fluorouracil and erlotinib, these numbers are comparable. In the same year [57], a group of investigators evaluated the cytotoxic effects of some pyrimidine derivatives against human colon adenocarcinoma HT-29, two breast cancer cell lines (MCF-7, T47D), as well as a mouse embryonic fibroblast cell line, (NIH-3T3). Compound 62 showed the best cytotoxicity against all cell lines with IC50 = 60, and 1.5, 10, 16 μM, respectively.…”

“…Journal of Pharmaceutical Sciences and Drug Manufacturing 1 (2024)[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] …”