Precision-Oriented Theophylline-Platinum(IV) Prodrugs: Eliciting Synthetic Lethality in BRCA1-Deficient Ovarian Cancer with Enhanced Efficacy and Reduced Toxicity In Vitro and In Vivo.

Ovarian cancer (OC) is a lethal gynecologic malignancy with limited treatments. Platinum(II) drugs are commonly used but faced severe toxicities and resistance. This study developed theophylline-platinum(IV) prodrugs (1-8) to combat BRCA1-deficient OC via synthetic lethality strategy. Representative compound 4 displayed the most potent antitumor effect by synergizing theophylline-induced PARP-1 inhibition with platinum-induced DNA damage to fully exert synthetic lethality in BRCA1-deficient cells with homologous recombination repair deficiencies. In vitro, 4 exhibited 80- and 581-fold higher antiproliferative activities than cisplatin in SKOV3 and SKOV3-BRCA1-KD cells, respectively. Subsequent tests revealed 4 enhanced DNA damage, ROS production, mitochondrial dysfunction, and S-phase arrest, along with reducing invasion and metastasis. In SKOV3-BRCA1-KD xenograft models, 4 exhibited 71.70% tumor growth inhibition, surpassing cisplatin (50.48%) and olaparib (47.63%), with mitigated nephrotoxicity. Immunohistochemistry showed PARP-1 suppression (74.68% to 9.14%), validating synthetic lethality mechanism. These findings underscore theophylline-Pt(IV) prodrugs potential in overcoming platinum(II) drugs limitations and advancing personalized oncology.