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

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 IC50 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 IC50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC50 = 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.

Design, synthesis and molecular modeling of phenyl dihydropyridazinone derivatives as B-Raf inhibitors with anticancer activity.

Three new series of phenyl dihydropyridazinone derivatives 4b-8i have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Nine compounds showed strong inhibitory activity, among which compound 8b exhibited potent activity against PC-3 cell line with IC50 value of 7.83 µM in comparison to sorafenib (IC50 11.53 µM). Compounds 6a, 6c, 7f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7f-h and 8a-d showed high B-Raf inhibition with ranges of IC50 values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf inhibitor with IC50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 8b showed cell cycle arrest at G2-M phase with significant apoptotic effect. Molecular modeling study was performed to understand the binding mode of the most active synthesized compounds with B-Raf enzyme.