Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

Abstract

We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis., and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC 50 values of 8. 36, 7.81, 6.40, and 7.35 (pK i 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC 50 values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC 50 values for inhibition of poly(ADPribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H 2 O 2 were highly significantly correlated with those at cell-free PARP-1 (r 2 ϭ 0.89 -0.96, P Ͻ 0.001) but less with those at PARP-2 (r 2 ϭ 0.78 -0.84, P Ͻ 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P Ͻ 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.Poly(ADP-ribose) polymerases (PARP) 1 and 2 are abundant nuclear enzymes in eukaryotic cells that have been implicated in the cellular response to DNA damage (Schreiber et al., 2006). PARPs catalyze an energy-consuming reaction by transferring ADP-ribose moieties from the substrate NAD ϩ to nuclear acceptor proteins, including PARP itself, and to existing ADP-ribose adducts on protein, thus forming chains of poly(ADP-ribose) (PAR), to render damaged DNA accessible to the repair system and to maintain cell survival, genomic stability, and mammalian longevity (D'Amours et al., 1999). This beneficial, cytoprotective effect of PARP activity is apparent under conditions of low to modArticle, publication date, and citation information can be found at

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…This process leads to the depletion of intracellular nicotinamide adenine dinucleotide (NAD + ) and ATP pools leading to cellular mitochondrial dysfunction and cell death, via the necrotic route (Gilad et al, 1997;Zingarelli et al, 1997;Zingarelli et al, 1998). Follow-on studies extended these findings, both using pharmacological PARP inhibitors of various classes (Thiemermann et al, 1997;Bowes et al, 1998;Docherty et al, 1999;Liaudet et al, 2001;Zingarelli et al, 2003;Zingarelli et al, 2004;Kaplan et al, 2005;Eltze et al, 2008;Oh et al, 2009;Roesner et al, 2010;Gerö et al, 2014), as well as genetically modified mice deficient in PARP1 (Zingarelli et al, 1998;Grupp et al, 1999;Pieper et al, 2000;Yang et al, 2000). The cardiac protective effect of PARP inhibitors was subsequently extended into various models of heart transplantation.…”

Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription

“…To inhibit transcription, cells were treated with α-amanitin (25 μg/ml) for 12 h or with DRB (75 μM) for 1 h. To inhibit methylation, cells were treated with AdOX (adenosine dialdehyde) (20 μM or 100 μM) for 12 h. For poly(ADP-ribose) polymerase (PARP) inhibition experiments, cells were treated with olaparib (AZD2281, 10 μM) or PJ34 (10 μM) for 1 h (29,33). Efficient PARP inhibition by both inhibitors (Supplementary Figure S4B) was demonstrated by immunofluorescence (IF) using monoclonal PAR antibody 10H (Alexis Biochemicals) following 5-min 50-mM H 2 O 2 treatment, which induces granular nuclear polyADP ribose (PAR) staining (19,34). To inhibit deacetylation, cells were treated with histone deacetylase (HDAC) inhibitors, TSA (trichostatin A, 45 nM) for 20 h or NaBu (sodium butyrate, 10 mM) for 2 h.…”

Poly(ADP-ribose) polymerase-1 (PARP-1) gene deficiency alleviates diabetic kidney disease

“… Initial and final blood glucose concentrations were measured after confirmation of diabetes (after 7–8 daily consecutive streptozotocin injections [33]) and at the 12-wk time point, respectively. Data are expressed as Means SEM.…”