Developing new anticancer agents: Design, synthesis, biological evaluation and in silico study of several functionalized pyrimidine-5-carbonitriles as small molecules modulators targeting breast cancer.

Committed to our growing effort addressed toward the development of potent anti-breast cancer candidates, new 4-hydrazinylpyrimidine-5-carbonitriles featuring a morpholinyl or piperidinyl moiety at the position-2 and derivatized with various functionalities at the hydrazinyl group were designed through structure optimization, and their antiproliferative potency against two human breast cancer (BC) cell lines, relative to the reference drug 5-FU, was evaluated. Compounds showing remarkable cytotoxic activity versus the hormone dependent MCF-7 cell line (IC ₅₀  = 1.62 ± 0.06 µM- 9.88 ± 0.38 µM) and the non-hormone dependent MDA-MB-231 cell line (IC ₅₀  = 3.26 ± 0.14 µM-12.93 ± 0.55 µM) were further tested by multiple assays for clarification of their potential activity. Promising derivatives revealing low damage to healthy cells were subject to enzymatic inhibitory assessment against ARO and EGFR and their activities compared to letrozole and erlotinib respectively. Compounds 3c, 6a as well as compounds 4c, 4d proved to be good inhibitors of the ARO and EGFR enzymes respectively. Active compounds were also evaluated for their underlying mode of action by further investigation for CDK, Hsp90, PI3K inhibition and compared to normal MCF-10A cells and assessed for their enhancement of the caspase 9 levels. Additionally, cell cycle analysis and apoptotic induction were performed. They demonstrated remarkable activities in the previous assays and emanated as leads as anti-breast cancer candidates. Eventually, molecular docking analysis revealed that hit compounds 3c, 4c, 4d, and 6a could bind favorably to the proposed in silico models of various protein-ligand interactions. Therefore, our promising top candidates, by demonstrating appreciable anti-breast cancer activities, present valuable prospects for optimization, potency enhancement and future application.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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