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

ABSTRACT

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(1 H )‐ones ( 7–14 ) and 4‐(4‐substituted phenylamino)‐1‐(β‐ d ‐ribofuranosyl)‐5‐methylpyrimidine‐2(1 H )‐ones ( 21–24 )—compound 8 exhibited the most potent cytotoxic activity. It significantly reduced cell viability in OVCAR‐3 (IC ₅₀  = 27.1 ± 4.56 µM) and KURAMOCHI (IC ₅₀  = 46.2 ± 4.87 µM) cells, outperforming the reference PARP inhibitor olaparib (IC ₅₀  = 75.8 ± 6.1 µM for OVCAR‐3, IC ₅₀  = 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.