Resistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)

Griffin, Roger J.; Srinivasan, S.; Bowman, Karen J.; Calvert, A. Hilary; Curtin, Nicola J.; Newell, David R.; Pemberton, LC; Golding, BT

doi:10.1021/jm980273t

Cited by 127 publications

(71 citation statements)

References 31 publications

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“…Even 10, with the very long 4′-group, showed good selectivity (>70-fold TNKS-1 vs. PARP-1, >110-fold TNKS-2 vs. PARP-1). These modest activities vs. PARP-1 correlate well with data for 7a,c−e,j,k reported by Griffin et al 29 who investigated quinazolin-4-ones as PARP-1 inhibitors. The known inhibitor 1 and our new potent tankyrase inhibitors were counterscreened against IMPDH2, an oxidoreductase that uses NAD + , to examine selectivity further.…”

supporting

confidence: 89%

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Nathubhai

Wood

Lloyd

et al. 2013

ACS Med. Chem. Lett.

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Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC 50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4′-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

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supporting

confidence: 89%

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Nathubhai

Wood

Lloyd

et al. 2013

ACS Med. Chem. Lett.

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“…Recently, potent and selective inhibitors of PARP have been developed (10,12,40). These agents diminish brain damage after focal cerebral ischemia (10,12) and myocardial ischemia (T. Walles, P. Wang, A.A.P., S.H.S., and J. L. Zweier, unpublished report).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Pieper

Brat

Krug

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

277

180

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Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD ؉ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP ؊͞؊), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP ؉͞؊ animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.Type I diabetes (insulin-dependent diabetes mellitus) is a chronic metabolic disorder characterized by a loss of pancreatic islet B cell mass, decreased serum insulin, and hyperglycemia. Although the pathogenic mechanisms of this disease have not been fully characterized, genetic, environmental, and autoimmune factors have been postulated. In particular, development of this disorder is postulated to proceed through generation of oxygen radicals during prediabetic pancreatic islet inflammation (1, 2). One possible mechanism is that autoimmune activation of macrophages damages B cells through release of massive amounts of NO after inducible NO synthase activation, as damage elicited when islets are cocultured with macrophages is prevented by inhibition of NO synthase (3).Focal cerebral ischemic damage is also associated with NO release leading to DNA damage elicited by reactive oxygen species, including peroxynitrite formed from NO. Downstream of this DNA damage, the enzyme poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is stimulated. Nuclear PARP is activated by DNA fragments to transfer branched chains of up to 200 ADP ribose groups from NAD ϩ to acceptor proteins in the nucleus, including histones and PARP itself. PARP activation plays a role in DNA repair, particularly the base excision repair process (4-8), in response to moderate amounts of DNA damage. With excessive DNA damage, however, PARP is so highly activated that its substrate NAD ϩ is critically depleted (9). NAD ϩ is an important enzyme in energy metabolism, and its depletion results in lower ATP production. As ATP is also consumed in efforts to resynthesize NAD ϩ , cells can die from energy loss. Cerebral ischemic damage is greatly diminished in mice with targeted deletion of PARP (PARP Ϫ͞Ϫ) (10, 11) and in animals treated with PARP inhibitors (12, 13). A role of PARP activation in pancreatic damage is also suggested by protection through PARP inhibition of pancreatic islet cells from NO-mediated killing (14, 15). Furthermore, in vitro pancreatic islet cells from PARP Ϫ͞Ϫ mice are resistant to NAD ϩ depletion after exposure to either NO or other reactive oxygen intermediates generated th...

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“…As medicines, many of them display antifungal 1 , antimicrobial 2 , anti-HIV 3 , antitubercular 4 , anticancer 5 , antiinflammatory 6 , anticonvulsant 7 , antidepressant 8 , hypolipidemic 9 , antiulcer 10 , analgesic 11 or immu-notropic activities 12 and are also known to act as thymidyalate synthase 13 , poly(ADP-ribose) polymerase (PARP) 14 , and protein tyrosine kinase 15 inhibitors. As pesticides, they are used as insecticides 16 and fungicides 17 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Spectroscopic Characterization and X-Ray Analysis of 6-Nitroquinazoline-2,4(1h,3h)-Dione

Kesternich

Pérez-Fehrmann

Ortíz

et al. 2013

J. Chil. Chem. Soc.

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In this work, 6-nitroquinazoline-2,4(1H,3H)-dione was obtained in two step with good yields using a facile synthetic method. Its structure was characterized by X-ray single crystal diffraction technique (XRD), IR, 1D-NMR ( 1 H-NMR and 13 C-NMR) and 2D-NMR (H-H COSY and H-C HMBC) spectroscopy. All N and O carbonyl atoms are involved in hydrogen bonding, with an average H···O distance of 1.89 (2)

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Resistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP)

Cited by 127 publications

References 31 publications

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Synthesis, Spectroscopic Characterization and X-Ray Analysis of 6-Nitroquinazoline-2,4(1h,3h)-Dione

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