Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the Modification of Indeno[1,2-<i>c</i>]isoquinolinone

Jagtap, Prakash G.; Baloglu, Erkan; Southan, Garry J.; Mabley, Jon G.; Li, Hongshan; Zhou, Jing; Duzer, John van; Salzman, and Andrew L.; Szabó, Csaba

doi:10.1021/jm0502891

Cited by 78 publications

(61 citation statements)

References 15 publications

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“…Some of these compounds, including the INO-1001, are in phase I and II. Clinical trials for myocardial infarction and for other indications appear to be well tolerated clinically (17).…”

mentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Leprdb/dbMice

et al. 2006

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(1). Characteristic morphological lesions of diabetic nephropathy initially present in the renal glomerulus; these include glomerular hypertrophy, thickening of the basement membrane, and mesangial expansion (2). Several interventions have been shown to slow the progression of diabetic nephropathy, including tight glucose and blood pressure control and the blockade of the renin-angiotensin system (3-5). However, none of these can cure or prevent the development of diabetic nephropathy.Recent observations indicate important roles for glomerular epithelial cells (podocytes) in the pathogenesis of diabetic nephropathy (6 -9). The density of glomerular visceral epithelial cells is reduced in kidneys of individuals with diabetic nephropathy. Among various glomerular morphological characteristics, the decreased podocyte density is one of the strongest predictors of disease progression (10). Apoptosis and detachment of podocytes have been implicated as a potential mechanism of podocyte loss in animal models of diabetic nephropathy (7,11). We recently reported increased apoptosis of podocytes in type 1 diabetic Akita and type 2 diabetic Lepr db/db mice at the time of development of hyperglycemia. In vitro treatment of podocytes with high glucose also leads to increased apoptosis rate (7,12). Podocyte apoptosis seems to contribute significantly to the development of diabetic nephropathy, as prevention of podocyte apoptosis in vivo was associated with a decrease in albuminuria and mesangial expansion in the Lepr db/db model of type 2 diabetes. Brownlee (13) has pioneered the concept that hyperglycemia-induced overproduction of superoxide is the single unifying link to diabetes complications, including cellular activation of protein kinase C, hexosamine pathway, and advanced glycation formation, which are the major pathways of hyperglycemic damage in endothelial cells. This process occurs via inhibition of glyceraldehyde-3-phosphate dehydrogenase activity, which is likely to be the consequence of poly(ADP) ribosylation of the enzyme by active poly(ADP-ribose) polymerase (PARP)-1 (14). Since uncoupling protein 1 or manganese superoxide dismutase overexpressions blocked the activation of PARP-1, it has been hypothesized that the high-glucose-induced PARP-1 activation is the consequence of the increased intracellular reactive oxygen species (ROS) and subsequent DNA breakage in endothelial cells (14).PARP-1 is one of the most abundant nuclear proteins. The catalytic function of PARP-1 relates to its role as a DNA damage sensor and signaling molecule. The zinc C.S. is a stockholder of Inotek Pharmaceuticals, a firm involved in the development of PARP inhibitors.Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.ELISA, enzyme-linked immunosorbent assay; IB␣, inhibitor of B␣; NFB; nuclear factor-B; PARP, poly(ADP-ribose) polymerase; PAS, periodic acid Schiff; ROS, reactive oxygen species.

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“…Some of these compounds, including the INO-1001, are in phase I and II. Clinical trials for myocardial infarction and for other indications appear to be well tolerated clinically (17).…”

mentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Leprdb/dbMice

et al. 2006

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“…The residue was then purified by flash column chromatography (hexane:ethyl acetate = 1:5) to afford the title compound 11 as a yellow solid (2.5 g, 21%, 2 step). Ethyl 6-oxo-5,6,7,8,9,10-hexahydrophenanthridin-2-carboxylate (12) 6-Oxo-5,6,7,8,9,10-hexahydrophenanthridin-2-carboxylic acid (13). To a stirred solution of carboxylate 12 (1.0 g, 3.68 mmol) in MeOH (12 mL) was added aqueous 1N NaOH solution (18.4 mL).…”

Section: Methodsmentioning

confidence: 99%

“…6,[8][9][10][11][12][13][14][15] Most PARP-1 inhibitors are competitive with NAD + and these structures are typically nicotinamide or benzamide analogs (Fig. 1).…”

Section: -7mentioning

confidence: 99%

Synthesis and Evaluation of Tricyclic Derivatives Containing a Non-Aromatic Amide as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors

Park

Chun

Choi

et al. 2011

Bulletin of the Korean Chemical Society

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A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors were successfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one 23c displayed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC 50 = 0.142 µM, ED 50 = 0.90 µM) with good water solubility. Further, molecular modeling studies confirmed the obtained biological results.

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“…Each compound was identified as its ZINC database ID, experimental binding affinities (IC 50 ) [45][46][47][48][49][50][51][52] , and estimated docking scores were reported for individual compounds. While docking results showed higher (absolute) docking scores for PARP-1 active inhibitors, inactive PARP-1 molecules showed lower docking scores (Table 1).…”

Section: Molecular Dockingmentioning

confidence: 99%

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

Salmas

Ünlü

Yurtsever

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.

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Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the Modification of Indeno[1,2-c]isoquinolinone

Cited by 78 publications

References 15 publications

Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Leprdb/dbMice

Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Leprdb/dbMice

Synthesis and Evaluation of Tricyclic Derivatives Containing a Non-Aromatic Amide as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

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