Discovery of novel thiosemicarbazone dimers as effective inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) for use in cancer therapy.

For the development of anticancer drugs, poly(ADP-ribose) polymerase-1 (PARP-1) has become an attractive target. With superior binding affinity and cytotoxic effects, dimeric molecules exhibit greater anti-tumor efficacy than monomers, positioning them as promising candidates for next-generation anticancer drugs. In this investigation, the pharmacological skeleton of active molecules as PARP-1 inhibitors served as the basis for the design and synthesis of a series of thiosemicarbazone dimers, and their anticancer properties were assessed. Compound 13, one of the dimers, exhibited nanomolar activity against PARP-1 (IC50 = 64.98 ± 2.46 nM) and inhibited the growth of BRCA mutant cells, especially the BRCA1 mutant breast cancer HCC-1937 cell line (IC50 = 0.88 ± 0.21 μM). The mechanism study demonstrated that compound 13 inhibited PAR formation, induced PARP-1-DNA trapping, and DSBs on HCC-1937 cells. The flow cytometry analysis's findings showed that compound 13 caused HCC-1937 cells to enter a G2/M phase arrest. It has also been shown that compound 13 triggers apoptosis via the mitochondrial apoptotic pathway. In vivo studies showed a reduction in the growth of HCC-1937 xenografts following treatment with compound 13, with an acceptable safety profile. In conclusion, compound 13 demonstrated favorable preliminary activity, especially those that have BRCA mutations.