On the way to selective PARP-2 inhibitors. Design, synthesis, and preliminary evaluation of a series of isoquinolinone derivatives.

PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. We thus demonstrated that selective inhibition of individual PARP isoforms can in fact be achieved through chemical manipulation of simple isoquinolinone derivatives bearing the 'canonical' PARP pharmacophore. Particularly intriguing is the notion that very subtle chemical modifications seem to govern PARP-1/PARP-2 selectivity. We identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60. This compound can therefore be considered a prototype tool for further in vitro and in vivo pharmacological characterizations of the involvement of PARP-2 in pathophysiological conditions.