PARP activity inhibitors

Chemistry. Nicotinamide (NAm), a product of PARP-1 enzymatic action on NAD and a weak inhibitor of PARP-1 activity (Curtin, 2006), was used as a model for the first PARP-1 inhibitors, including benzamide and 3-aminobenzamide (3AB) (Shall, 1975) (Fig. 7a). Benzamide and 3AB inhibit PARP-1 activity in the mM range and may also inhibit other PARP family members e.g., PARP-2 and tankyrase Smith et al, 1998 Ame et al, 1999), thus lacking the potency and specificity required for therapeutic purposes. Banasik et al developed 1,5-dihydroisoquinoline (Fig. 7c) and a variety of other inhibitors (Banasik et al, 1992), which were used in turn to develop even more inhibitors with greater specificity. 

Currently flow-cytometric methods are also under development to examine effects of various inhibitors of PARP (poly(ADP-ribose)polymerase) that are in preclinical development or clinical trials and use native or stimulated PARP activity in peripheral blood mononuclear cells. 

PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer (Calabrese et al, 2004). GR205171 has the most potent anti-emetic activity of any tachykinin NKl receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent (Gardner et al, 1996). 

PARP inhibitors have been synthesized (11) and are shown in Figs. 11.4 and 11.5. Some of them have been tested in stroke models with good results in terms of preventing infarction (12-18). Most of the inhibitors are based on the structure of nicotinamide and therefore bind to the nicotinamide site of PARP. Several inhibitors are well known, such as nicotinamide, benzamide, and 3-aminobenzamide (19,20). However, new quinazolinone, phen-anthradinone, and other inhibitors are being investigated. Nicotinamide has a of about 5 xM for PARP (19). Activity is decreased in 6-aminonicotinamide, isonicotinamide, 1-methylnicotinamide, 5-methylnicotinamide, 8-methylnicotinamide, and thionicotinamide (Table 11.1 >... 

Hinshaw et al. (1999) have shown that activation of PARP may be linked to ATP-dependent changes in microfilament architecture in cells. The PARP activation hypothesis is thus well supported although Lin et al. (1994) failed to find a link between depletion of NAD+ and cell damage in rat keratinocyte cultures. These authors used nicotinamide to prevent a fall in NAD+ levels but found that this did not prevent the decline in DNA content used as an index of cytotoxicity. This is a particularly important finding as Papirmeister et al. (1985) have also used nicotinamide and niacin to increase levels of NAD+ in cells. They noted, however, that nicotinamide was an inhibitor of PARP but that niacin was not. They argued that niacin would allow DNA repair without concomitant depletion of NAD+. They... 

As discussed above, the kidney is sensitive to different forms of oxidant-mediated injury. An early study su ested by Schnellmann and colleagues su ested that in PT cell suspensions, PARP activation did not play a role of acute renal PT cell injury and death caused by agents which cause oxidative stress. Specifically, suspensions of raH>it PT cells were exposed to antimycin A (a mitochondrial inhibitor), carbonyl cyanide p-(trifruoromethoxy)phenylhydiazone (FCCP, a protonophore) and tert-butyl hydroperoxide (t-BHP, an oxidant). No evidence of DNA fragmentation was observed with any of these agents durii cell death. ... 

Various inhibitors of PARP activity have been used in an attempt to elucidate the role(s) of PARP activation in the development and progression of I-R injury and inflammation and to reduce the organ injury associated with PARP activation during these pathophysiological processes.Over the last two decades, two major classes of inhibitors of PARP activity have been developed analogues of benzamide and the isoquinolinones. Inhibitors of both types have been used extensively in in vitro and in vivo models of I-R injury and inflammation. ... 

Table 1. Effect of PARP inhibitors and inactive analogues on PARP activation, ceilular injury and cell death caused by H2O2. The effects of a ROS scavenger (Tempo ), deferoxamine and catalase were also assessed...

Figure 2. Effect of PARP inhibitors on PARP activation in primary cultures of human PT cells caused by H2O2. Human PT cells were incubated in the absence or presence of H2O2 (1 mM for 1 h). Cultures were also pretreated with inhibitors of PARP activity or their inaaive struaural analogues 10 min prior to addition of H2O2. P<0.05 vs. H202-only, N = 2.

ISO providing beneficial actions at ten times lower concentration than 3-AB or nicotinamide. 3-Aminobenzoic acid and nicotinic acid did not inhibit PARP activation (Fig. 2) and did not provide any protection against cellular injury caused by H2O2 (Fig. 3). The beneficial actions provided by PARP inhibitors against oxidative stress were similar in magnitude to those obtained using Tempol, deferoxamine and catalase. 

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