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

Zivali H., Akdag A., Demirkan B., Durmaz Sahin I., TUNÇBİLEK M.

ARCHIV DER PHARMAZIE, cilt.358, sa.10, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 358 Sayı: 10
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1002/ardp.70117
  • Dergi Adı: ARCHIV DER PHARMAZIE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, Index Chemicus (IC)
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

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-(beta-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 mu M) and KURAMOCHI (IC50 = 46.2 +/- 4.87 mu M) cells, outperforming the reference PARP inhibitor olaparib (IC50 = 75.8 +/- 6.1 mu M for OVCAR-3, IC50 = 84.5 +/- 11.4 mu M 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.