Design, Synthesis, and Preliminarily Biological Evaluations of Derivatives of the PARP-1 Inhibitor AZD2461 With...

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.