Insights into modulating the monastrol scaffold: Development of new pyrimidinones as Eg5 inhibitors with anticancer activity

Abstract

Based on modulation of the monastrol scaffold, two series of pyrimidinone derivatives, 3a-e and 5a-k, were designed, synthesized, and investigated for their in vitro anticancer activity. Compound 5j exhibited the most potent cytotoxic activity against four cancer cell lines, including HCT-116, HeLa, HEPG-2, and MCF-7, with IC 50 values of 3.75-5.13 µM, while proving to be safe in the normal human cell line WI-38, with a selectivity index value of 13.7 on HCT-116 cells. Compounds 3d, 3e, and 5h-j were further assessed for their Eg5 inhibitory activity, where 3d and 5h-j showed high Eg5 inhibition with IC 50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC 50 = 14.89 µM). Cell cycle distribution of HCT-116 cells monitored with compound 5j illustrated that the cell cycle was arrested at the G2/M phase, with considerable apoptotic effect.A molecular docking study was performed to investigate the mode of action of the synthesized anticancer agents as Eg5 inhibitors.

Review: Pyrimidine Derivatives as Anticancer Agents

“…Modulation of the Monastrol scaffold was conducted by Thabit et al [63] to produce compounds with potent cytotoxic activity. Compound 68 exhibited a notably high level of cytotoxicity against two specific cancer cell lines: colorectal carcinoma (HCT-116) and breast cancer cells (MCF-7), with IC50 values of 3.75-5.13 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] …”