Poly(ADP-ribose) polymerase (PARP) plays a key role in
repairing
DNA damage, and several PARP inhibitors have been approved as treatments
in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also
supports their application as neuroprotective agents since PARP overactivation
compromises the mitochondrial homeostasis by consumption of NAD+reserves, leading to an increase in reactive oxygen and nitrogen
species and a spike in intracellular Ca2+levels. Herein,
we present the synthesis and preliminary evaluation of new mitochondria-targeting
PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance
potential neuroprotective properties without impairing the repair
of damaged DNA in the nucleus.