Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. part 4: Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries

Ferraris, Dana; Ficco, Rica Pargas; Dain, David; Ginski, Mark; Lautar, Susan; Lee-Wisdom, Kathy; Shi, Liang; Lin, Qian; Lu, May; Morgan, Lisa; Thomas, Bert E.; Williams, Lawrence R.; Zhang, Jie; Zhou, Yanguang; Kalish, Vincent J.

doi:10.1016/s0968-0896(03)00333-x

Cited by 57 publications

(31 citation statements)

References 36 publications

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“…However, although evidence has been presented to indicate that PARP-1 is present in mitochondria (43), H 2 O 2 and MNNG have also both been suggested to have direct effects on mitochondria (38,45), such that the interpretation of their capacity to induce TRPM2 gating as dependent solely on their capacity to induce DNA damage and activate PARP-1 may not be justified. In addition, PARP-1 inhibitors are known to be promiscuous within the PARP family because of their structural mimicry of nicotinamide (24,33,46), and the concentrations required to inhibit oxidant-mediated TRPM2 gating are well above those required to inhibit PARP-1 in vitro, precluding an unambiguous interpretation of the in cellulo or in vivo targets of these compounds. Finally, it is not obvious, at least to these authors, why PARP-1 activation should be connected to activation of a plasma membrane cation channel.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, any mechanism involved in producing ADP-ribose likely involves a protein that interacts with and hydrolyzes NAD. A search for potential pharmacological reagents capable of acting as structural analogues of NAD revealed several classes of compounds that inhibit the poly(ADP-ribose)-polymerase family of enzymes through their structural mimicry of the nicotinamide head group of NAD (32,33), and which have been shown to prevent MNNG-induced NAD hydrolysis and resulting NAD depletion (25). We tested the effect of two such compounds, 5[H]-phenanthridin-6-one and 2-(4-methylpiperazin-1-yl)-5H-benzo[c](1,5)naphthyridin-6-one (24) (henceforth designated GPI16539), on H 2 O 2 and MNNG-mediated gating of TRPM2 (Fig.…”

Section: Fig 2 Homology Model Of the Nudt9-hmentioning

confidence: 99%

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Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels

Perraud

Takanishi

Shen

et al. 2005

Journal of Biological Chemistry

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314

358

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TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the Cterminal nudix domain. We also show that oxidative/ nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.Eukaryotic cells have been shown to react and adapt to conditions of oxidative stress produced by disulfide-inducing chemicals, reactive oxygen species (ROS), 1 or reactive nitrogen species (RNS) through a variety of redox-sensitive signaling pathways (variously reviewed in Refs. 1-12). Recently, the TRPM2 cation channel has been shown to undergo gating in response to oxidative or nitrosative stress occurring upon ROS or RNS exposure (13,14). As TRPM2 is a novel dual function protein that possesses both ion channel and ADP-ribose hydrolase functions (15, 16), there has been great interest in understanding the molecular mechanisms through which oxidative and nitrosative stress activate TRPM2 channels, as well as the physiological role(s) of TRPM2-mediated ion fluxes and enzymatic activity in the context of cellular exposure to ROS and RNS.TRPM2 is classified as a member of the transient receptor potential melastatin-related (TRPM) ion channel family based on the homology of its Ϸ600 amino acid N-terminal domain and Ϸ300 amino acid channel-forming domain to corresponding regions of other TRPM family members. The enzymatic function of TRPM is encoded by a C-terminal domain, designated the NUDT9-homology (NUDT9-H) domain, which is homologous to the NUDT9 ADP-ribose hydrolase (15,17). In vitro studies of TRPM2 channel function using patch clamp techniques have suggested that ADP-ribose and NAD are both able to directly induce gating of full-length TRPM2 channels (14,15,18), and in vitro studies of the NUDT9-H domain demonstrate that it has a low level of ADP-ribose hydrolase activity and the apparent capacity to interact with NAD through its nudix hydrolase enzymatic motif (14, 15). However, there is a significant gap in understanding how the in vitro data on TRPM2 function relate to oxidative/nitrosative stress-induced TRPM2 gating in intact c...

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Section: Discussionmentioning

confidence: 99%

Section: Fig 2 Homology Model Of the Nudt9-hmentioning

confidence: 99%

Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels

Perraud

Takanishi

Shen

et al. 2005

Journal of Biological Chemistry

Self Cite

314

358

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“…During ischemia and reperfusion injury, in the case of massive and irreparable DNA damage, overactivation of Poly(ADP-ribose) Polymerase-1 (PARP-1) can lead to necrotic cell death caused by the depletion of NAD+ and ATP, as well as enhance AIF release from mitochondria [59] . A series of PARP-1 antagonists have been developed, some of which have become promising drug candidates [60,61] . However, the characterization of natural compounds regulating PARP-1 remains to be elucidated.…”

Section: Natural Compounds With Anti-apoptotic Effectsmentioning

confidence: 99%

Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury

et al. 2010

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More and more attention in the field of drug discovery has been focused on the neuroprotection of natural compounds from traditional medicinal herbs. Cerebral ischemia is a complex pathological process involving a series of mechanisms, and a framework for the development of neuroprotectants from traditional herb medicine is a promising treatment for cerebral ischemia. Natural compounds with the effects of anti-oxidation, anti-inflammation, calcium antagonization, anti-apoptosis, and neurofunctional regulation exhibit preventive or therapeutic effects on experimental ischemic brain injury. According to the pharmacological mechanisms underlying neuroprotection, we evaluated natural products from traditional medicinal herbs that exhibit protective effects on ischemic brain injury and characterized the promising targets.

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“…An important issue is that the concentrations of the PARP inhibitor compounds required for blockade of oxidant-induced TRPM2 gating are significantly higher than those required for in-vitro inhibition of PARP-1. A second issue is that all the PARP-1 inhibitors tested in the above studies act as structural mimics of nicotinamide [12][13][14], and block PARP-1 activity by inhibiting its capacity to bind NAD. As whatever enzyme is involved in oxidant-induced ADP-ribose accumulation would also need to bind NAD (as ADP-ribose is solely produced through NAD hydrolysis in eukaryotic cells [15][16][17]), there is a real potential for these compounds to exhibit inhibitory activity against alternative NAD-binding targets at the concentrations used.…”

Section: Regulation Of Trpm2 Adpribase Activitymentioning

confidence: 99%

TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors

Scharenberg

2005

Pflugers Arch - Eur J Physiol

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Within the transient receptor potential (Trp) superfamily of ion channels, three members of the Trp (melastatin) (TRPM) subfamily stand out as their amino acid sequences indicate that they possess both ion channel and enzymatic functions. Recently, progress has been made in understanding the relationships between these disparate functionalities for two of these proteins, TRPM2 and TRPM7. TRPM2 appears to have adapted an ADP-ribose hydrolase (ADPRibase) enzyme's structure as a means of binding ADP-ribose and conveying information about the accumulation of ADP-ribose to the cell via the activation of Na(+)/Ca(2+) entry through the channel domain. While the ADPRibase activity of TRPM2's enzymatic domain is not required for channel gating, whether a converse relationship exists, wherein channel gating or ion flow modulates the enzymatic domain's ADPRibase activity, is not known. In contrast, TRPM7 appears to have evolved to place a Mg(2+)-regulated protein kinase domain in close proximity to a Mg(2+)-permeant ion channel, such that the kinase domain's phosphotransferase activity is able respond to local changes in free Mg(2+) occurring as the result of the flux of Mg(2+) through the channel. As with TRPM2, the activity of TRPM7's enzymatic domain is not required for gating of its channel domain, although evidence exists that it may have an alternative means of influencing channel gating. These insights into the functional relationships between the channel and enzymatic domains of TRPM2 and TRPM7 suggest informative models for their roles in vertebrate cell physiology.

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Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. part 4: Biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries

Cited by 57 publications

References 36 publications

Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels

Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels

Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury

TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors

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