Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) has been shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase (PARG) [1]. While ADP-HPD inhibits PARG in vitro with an IC50 of approximately 0.2 KM, it is not bioavailable to intact cells due to its highly polar nature. Thus, we have synthesized a number of derivatives of ADP-HPD and evaluated their potency as PARG inhibitors in vitro and their ability to inhibit PARG in cells. Previous studies have shown that substitutions at the 2 position of the adenine ring greatly reduces the potency of ADP-HPD, thus a number of lipophilic derivatives at positions 8 and N6 of the adenine ring were synthesized for evaluation. Modifications at N6 resulted in an unacceptable loss of potency. Modifications at position 8 showed that addition of very bulk groups resulted in greatly diminished potency but a number of lipophilic groups retained good potency. For example, 8-octylamino-ADP-HPD (OA-ADP-HPD) inhibits PARG in vitro with an IC50 of approximately 1.0 KM. The ability of OA-ADP-HPD to inhibit PARG in cells was examined demonstrated by increased ADP-ribose polymer accumulation in MCF-7 cells following genotoxic stress. The effects of inhibition of PARG on ADP-ribose polymer metabolism and biological responses to genotoxic stress will be reported. Cell permeable analogs of ADP-HPD should be useful pharmacological tools to study ADP-ribose polymer metabolism and they have the potential to be useful therapeutic agents.References: 1.Slama et al: J Med Chem, 1995; 38: 389-393

Keywords: Poly(ADP-ribose) glycohydrolase, PARG, PARG inhibitors