Synergy trap for guardian angels of DNA: Unraveling the anticancer potential of phthalazinone-thiosemicarbazone hybrids through dual PARP-1 and TOPO-I inhibition.

Targeting DNA repair, like PARP-1 and TOPO-I, shows promise in cancer therapy. However, resistance to single agents requires complex and costly combination strategies with significant side effects. Thus, there's an urgent need for single agents with dual inhibition. Current dual inhibitors focusing on the C-4 position of the phthalazinone core for PARP inhibition often have high molecular weights. Clinical use of PARP inhibitors is limited by hematological and other toxicities from concurrent PARP-2 inhibition. They're mainly effective in gynecological cancers, despite high PARP-1 and TOPO-I expression in various cancers. Moreover, their efficacy is limited to BRCA1-expressing breast cancer. In this study, we synthesized 27 dual inhibitors for PARP-1 and TOPO-I with molecular weights below 500 g/mol through hybridizing a phthalazinone core with a thiosemicarbazone linker. Among these, 6c demonstrated exceptional broad spectrum and potency against the NCI 60 cancer cell lines, with GI₅₀ values from 1.65 to 5.63 µM. Notably, 6c exposed the highest PARP-1 inhibition (IC₅₀ = 32.2 ± 3.26 nM) and a selectivity over PARP-2 (IC₅₀ = 2844 ± 111 nM). Furthermore, 6c's inhibition of TOPO-I (IC₅₀ = 46.2 ± 3.3 nM) surpassed the control camptothecin by eleven-fold. Mechanistically, 6c disrupted the cell cycle at the S phase, induced apoptosis, and displayed a favorable safety profile against normal cells. Compound 6c induced PARP trapping and synthetic lethality and showed high efficacy on BRCA1-expressing cell lines. So, decreasing the likelihood of cancer cell resistance to chemotherapy. Drug-likeness predictions and molecular modeling were also performed.