Discovery of novel 2,3,4,5-tetrahydrospiro[benzo[c]azepine-1,1'-cyclohexan]-5-ol derivatives as PARP-1 inhibitors

As an essential marker of cancer treatment, PARP-1 inhibitors could effectively kill tumor cells through a mechanism known as synthetic lethality and are used to treat a variety of cancers. In order to explore novel PARP-1 inhibitors, a series of 22 novel erythrina derivatives were reported and preliminarily explored their mechanism of action. The antitumor activities against four human cancer cell lines including A549, OVCAR-3, HCT-116, and MCF-7 were evaluated, and the preliminary SARs were summarized. Among them, compound 11b exhibited better anti-proliferative effects against A549 cells (IC50 = 1.95 mu M). The SI results showed that compound 11b had low toxicity. Moreover, compound 11b displayed excellent PARP-1 inhibitory activities with IC50 values of 19.24 nM. In addition, molecular docking studies provided the rational binding modes of compound 11b in complexes with PARP-1. The flow cytometry assays revealed that compound 11b could induce apoptosis of A549 cells (P < 0.001). Simultaneously, compound 11b could effectively reduce the formation of PAR (P < 0.001). The ADMET prediction results indicated compound 11b had similar properties to rucaparib. Collectively, compound 11b has potential research value for further investigation.

Automated summary

This study reported 22 novel erythrina derivatives as PARP-1 inhibitors with antitumor activities and explored their mechanism of action. Compound 11b exhibited better anti-proliferative effects against A549 cells and had low toxicity. Flow cytometry assays and molecular docking studies revealed that compound 11b induced apoptosis and effectively reduced the formation of PAR.