Design, Synthesis, and Preliminarily Biological Evaluations of Derivatives of the PARP‐1 Inhibitor AZD2461 With Mitochondria‐Protecting Activities

ABSTRACT Poly (ADP‐ribose) polymerase‐(PARP)‐1 repairs the damaged DNA to maintain genome integrity, with nicotinamide adenine dinucleotide (NAD) + being a substrate. Hyperactivation of PARP‐1 causes the depletion of NAD + pool and inhibits ATP production in mitochondria, ultimately leading to mitochondrial dysfunction, energy failure and cell death. These processes are involved in the pathological mechanisms of a range of neurodegenerative diseases. Inhibiting PARP‐1 activity may therefore be valuable in the treatment of these diseases. As NAD + is most highly distributed within mitochondria, direct inhibition of PARP‐1 activity in the organelle may be more efficacious. Therefore, three mitochondrial‐targeting compounds 4a – 4c were synthesized by coupling the triphenylphosphonium (TPP + ) moiety with the ─OH derivative of the PARP‐1 inhibitor AZD2461 through various linkers. A fourth compound 4d , was synthesized by coupling the ─OH derivative with the enol form of the antioxidant edaravon. The compounds 4a – 4d were tested for protective activity in PC12 cells injured by D‐galactose (D‐gal) at 60 mM, and the results showed that compound 4c prevented the PC12 cell impairment. Further assays indicated that 4c could restore the loss of mitochondrial membrane potential triggered by D‐gal in PC12 cells. This study demonstrated that a mitochondria‐targeting PARP‐1 inhibitor could improve mitochondrial function and prevent PC12 cell death caused by excessive oxidative stress induced by D‐gal.