Derivatives of Hemimellitic Acid. A Synthesis of Erythrocentaurin<sup>1</sup>

Wenkert, Ernest; Johnston, David B.; Dave, K. G.

doi:10.1021/jo01032a012

Cited by 36 publications

(18 citation statements)

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“…This method leads to a higher yield of 5-AIQ than that previously reported (Wenkert et al, 1964). Suto et al (1991) and Watson et al (1998) reported an IC 50 of 240 nM when 5-AIQ was evaluated in an in vitro cell-free system consisting of PARP isolated from calf thymus, which is broadly comparable with other potent 5-substituted isoquinolinones.…”

mentioning

confidence: 77%

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Genovese¹,

Mazzon²,

Paola³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with inflammation. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury and apoptosis (measured by Annexin V coloration). An increase of immunoreactivity to nitrotyrosine and PARP, as well as a significant loss of body weight and mortality, was observed in the lung of bleomycin-treated mice. Administration of the two PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) edema formation, and 5) histological evidence of lung injury. Administration of 3-AB and 5-AIQ also markedly reduced nitrotyrosine formation and PARP activation. These results demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events induced by bleomycin administration in the mice.

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confidence: 77%

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Genovese¹,

Mazzon²,

Paola³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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“…Suto et al in 1991 to inhibit PARP activity in a cell-free preparation from calf thymus (IC 50 240 nM) [26]. As 5-AIQ was not commercially available then, we optimised its synthetic route (previously described by Wenkert et al [125]) and then converted it to its highly water-soluble hydrochloride salt, 5-AIQ.HCl [46]. This enabled us, in collaboration with several other research groups, to investigate for the first time, its pharmacological effects in a wide range of diseases in vivo, including animal models of myocardial infarction [52], ischaemia-reperfusion of the liver [51] and kidney [50] and acute lung inflammation [74].…”

Section: The Need For Water-soluble Parp-1 Inhibitorsmentioning

confidence: 99%

Poly(ADP-ribose)polymerase Inhibition - Where Now?

Woon

Threadgill

2005

CMC

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The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD(+) to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD(+) and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through pro-drug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.

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“…This method leads to a higher yield of 5-AIQ than that previously reported [35]. Suto et al [34] and Watson, Whish, and Threadgill [43] reported an IC 50 of 240 nmol/L when 5-AIQ was evaluated in an in vitro cell free system consisting of PARP isolated from calf thymus, which is broadly comparable with other potent 5-substituted isoquinolinones.…”

Section: Discussionmentioning

confidence: 56%

“…Twelve years ago, Suto et al [34] used a cell-free preparation of PARP (purified 900-fold from calf thymus) to demonstrate that 5-aminoisoquinolinone [5-aminoisoquinolin-1(2 H)-one] (5-AIQ) is a water-soluble inhibitor of PARP activity. As previously published reports of the synthesis of 5-AIQ reported problems of low yield and unreliability [34,35], we recently developed a novel and more efficient method for the synthesis of 5-AIQ [36]. We have previously demonstrated that 5-AIQ can reduce I/R injury of the heart and liver [37,38] and 5-AIQ has been shown to provide beneficial effects in rodent models of heart transplantation [39] and lung injury [40].…”

mentioning

confidence: 99%

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion

Chatterjee¹,

Chatterjee²,

Pedersen³

et al. 2004

Kidney International

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Derivatives of Hemimellitic Acid. A Synthesis of Erythrocentaurin¹

Cited by 36 publications

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Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Poly(ADP-ribose)polymerase Inhibition - Where Now?

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion

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Derivatives of Hemimellitic Acid. A Synthesis of Erythrocentaurin1

Cited by 36 publications

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Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Poly(ADP-ribose)polymerase Inhibition - Where Now?

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion

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Derivatives of Hemimellitic Acid. A Synthesis of Erythrocentaurin¹