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

Zivali H., Akdağ A., Demirkan B., Durmaz Şahin İ., TUNÇBİLEK M.

Archiv der Pharmazie, cilt.358, sa.10, 2025 (SCI-Expanded) 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, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Anahtar Kelimeler: molecular docking, nucleobase, nucleoside, ovarian cancer, pyrimidine
  • Ankara 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-(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.