Targeting Ovarian Cancer With Pyrimidine Nucleobase and Nucleoside Analogs: Synthesis, In Vitro Cytotoxic Activity, and Molecular Docking

Ovarian cancer remains one of the most lethal gynecological malignancies, underscoring the need for novel therapeutic strategies. In this study, a series of pyrimidine-based nucleobase (7-14) and nucleoside (21-24) analogs were synthesized and evaluated for their potential anticancer activity through poly(ADP-ribose) polymerase (PARP) inhibition. These compounds were tested for in vitro cytotoxicity on ovarian cancer cell lines OVCAR-3 and KURAMOCHI. Among the synthesized derivatives-namely, 4-(4-substituted phenylamino)-1-cyclopentyl-5-(H/methyl)pyrimidine-2(1H)-ones (7-14) and 4-(4-substituted phenylamino)-1-(β-d-ribofuranosyl)-5-methylpyrimidine-2(1H)-ones (21-24)-compound 8 exhibited the most potent cytotoxic activity. It significantly reduced cell viability in OVCAR-3 (IC₅₀ = 27.1 ± 4.56 µM) and KURAMOCHI (IC₅₀ = 46.2 ± 4.87 µM) cells, outperforming the reference PARP inhibitor olaparib (IC₅₀ = 75.8 ± 6.1 µM for OVCAR-3, IC₅₀ = 84.5 ± 11.4 µM for KURAMOCHI). These results suggest that compound 8 is a promising lead candidate for further development as an anticancer agent targeting PARP in ovarian cancer.