Hydroxamic Acids as PARP-1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

Poly(ADP-ribose)polymerase-1 (PARP-1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N-O substituted phenanthridinones form a complex interplay with PARP-1. A series of cyclic aryl hydroxamic acids, N-(benzyloxy)- and N-(hydroxy)phenanthridinones, were prepared through a ligand-free methodology from N-(benzyloxy)benzamides using dual C-H/N-H bond activation. Three of the computed hit compounds exhibited significant activity in cell-based and enzymatic assays, inhibiting PARP-1 in the low-nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA-MD-231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N-(benzyloxy)- and an N-(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target-specific design to minimize toxicity and side effects. image