Design, synthesis and antitumor activity study of PARP-1/HDAC dual targeting inhibitors

Both poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) are important antitumor targets and have attracted extensive attention. In this work, a total of fourteen PARP-1/HDAC dual targeting inhibitors were designed and synthesized using either benzopyrazole or benzimidazole as core structures. Two leading compounds 1-8-6 and 1-8-7 were proven to be dual targeting inhibitors of PARP-1 and HDAC6, and showed high antiproliferative activities against six human cancer cell lines with IC₅₀ values in micromole range. Moreover, compounds 1-8-6 and 1-8-7 could impair tumor cell proliferation in 48 h and 72 h with much higher potency than co-treatment of Olaparib and Tubastatin A. 1-8-6 displayed remarkable anti-migration and anti-angiogenesis activities. Meanwhile, western blot experiment result showed that 1-8-6 was able to heighten expression level of acetylated α-tubulin with marginal effects to acetylated histones H3 and H4. Finally, docking simulation work showed that 1-8-6 could fit into the active sites of PARP-1 and HDAC6. All results indicated that 1-8-6 is a promising candidate for further preclinical studies.