Production of 2-methyl-4(3H)-quinazolinone, an inhibitor of poly(ADP-ribose) synthetase, by bacterium.

Yoshida, Shigemi; Aoyagi, Takaaki; Harada, S.; Matsuda, Naoko; Ikeda, Takako; Naganawa, Hiroshi; Hamada, Masa; Takeuchi, Tomio

doi:10.7164/antibiotics.44.111

Cited by 68 publications

(28 citation statements)

References 5 publications

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“…The compounds 3,4-dihydro-5-methyl-isoquinolin-1(2H)-one and benzoxazole-4-carboxamide are examples of this approach (Griffin et al, , 1996. Dihydroisoquinolin-1(2H)-nones, 1,6-naphthyridine-5(6H)-ones, quinazolin-4(3H)-ones, thieno[3,4-c]pyridin-4(5H)ones and thieno[3,4-d]pyrimidin-4(3H)ones, 1,5-dihydroxyisoquinoline, and 2-methyl-quinazolin-4[3H]-one are also potent inhibitors of PARP (Yoshida et al, 1991;Watson et al, 1998;.…”

Section: Pharmacological Inhibition Of Parpmentioning

confidence: 99%

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,280

1,246

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.

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Section: Pharmacological Inhibition Of Parpmentioning

confidence: 99%

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,280

1,246

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“…2‐Methyl‐4( 3H )‐quinazolinone ( 245 ) (Fig. ) from the culture broth of the micro‐organism B. cereus BMH225‐mF1 strongly inhibited poly(ADP‐ribose) synthetase (IC 50 1.10 μM) and was competitive with the substrate . It also had low acute toxicity, and the mice tolerated i.p.…”

Section: Bioactivities Of Quinoline and Quinazoline Alkaloidsmentioning

confidence: 99%

Biologically active quinoline and quinazoline alkaloids part I

Shang

Morris‐Natschke

Liu

et al. 2017

Medicinal Research Reviews

307

166

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Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

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“…(2) shows the structures of examples of known potent inhibitors, together with the structure of the consensus pharmacophore containing the benzamide with the amide N-H held cis to the amide carbonyl either by incorporation into a covalent fivemembered ring (in isoindolones), covalent six-membered rings (isoquinolin-1-ones [26,46,[48][49][50][51][52]95,96], 3,4-dihydroisoquinolin-1-ones [26,97], quinazolin-4-ones [24,48,[97][98][99][100], thienoisoquinolinones [48], phthalazin-1-ones [95,97], phthalazine-1,4-diones [95], phenanthridin-6-ones [94,95], naphthalimides [95]) and covalent sevenmembered rings (benzazepin-1-ones [48] and the highly potent tricyclic inhibitors recently reported by the Newcastle group [20,21] and the Guilford group [49]). Ingeniously, intramolecular hydrogen bonds have also been used by this group to maintain the required planar benzamide conformation in their potent benzoxazole-4-carboxamides [97] and benzimidazole-4-carboxamides [22] and by a Japanese group in the new lead inhibitor FR261529, a quinoxaline-5-carboxamide [24,101]. Cantoni et al had claimed the benzene ring was essential in the pharmacophore and could not be replaced by thiophene [102] but this orthodoxy has been challenged by the observation of potent inhibitory activity for series of aminothiophenecarboxamides, thieno [3,4-c]pyridin-4(5H)-ones, thieno [3,4-d]pyrimidin-4(3H)-ones [103] and thieno [2...…”

Section: Introductionmentioning

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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Production of 2-methyl-4(3H)-quinazolinone, an inhibitor of poly(ADP-ribose) synthetase, by bacterium.

Cited by 68 publications

References 5 publications

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Biologically active quinoline and quinazoline alkaloids part I

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

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