Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase

Potent cytoprotective and antishock agents

Prakash Jagtap, Francisco Garcia Soriano, László Virág, Lucas Liaudet, Jon Mabley, Éva Szabó, György Haskó, Anita Marton, Clara Batista Lorigados, Ferenc Gallyas, Balázs Sümegi, Dale G. Hoyt, Erkan Baloglu, John VanDuzer, Andrew L. Salzman, Garry J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Objective: To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. Design: Randomized, prospective laboratory study. Setting: Research laboratory. Subjects: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. Interventions: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. Measurements and Main Results: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-α, interleukin-1β, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). Conclusions: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.

Original languageEnglish (US)
Pages (from-to)1071-1082
Number of pages12
JournalCritical Care Medicine
Volume30
Issue number5
StatePublished - 2002
Externally publishedYes

Fingerprint

Ligases
Adenosine
Lipopolysaccharides
Viscera
Thymocytes
Poly Adenosine Diphosphate Ribose
Reperfusion
Peroxynitrous Acid
Macrophages
Malondialdehyde
Peroxidase
Blood Vessels
Wistar Rats
Shock
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Necrosis
Endothelial Cells
Multiple Trauma
Bleomycin
Liver Failure

Keywords

  • Endothelial
  • Endotoxin
  • Gut
  • Liver
  • Lung
  • Malondialdehyde
  • Myeloperoxidase
  • Shock
  • Vascular

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase : Potent cytoprotective and antishock agents. / Jagtap, Prakash; Garcia Soriano, Francisco; Virág, László; Liaudet, Lucas; Mabley, Jon; Szabó, Éva; Haskó, György; Marton, Anita; Batista Lorigados, Clara; Gallyas, Ferenc; Sümegi, Balázs; Hoyt, Dale G.; Baloglu, Erkan; VanDuzer, John; Salzman, Andrew L.; Southan, Garry J.; Szabo, Csaba.

In: Critical Care Medicine, Vol. 30, No. 5, 2002, p. 1071-1082.

Research output: Contribution to journalArticle

Jagtap, P, Garcia Soriano, F, Virág, L, Liaudet, L, Mabley, J, Szabó, É, Haskó, G, Marton, A, Batista Lorigados, C, Gallyas, F, Sümegi, B, Hoyt, DG, Baloglu, E, VanDuzer, J, Salzman, AL, Southan, GJ & Szabo, C 2002, 'Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase: Potent cytoprotective and antishock agents', Critical Care Medicine, vol. 30, no. 5, pp. 1071-1082.
Jagtap, Prakash ; Garcia Soriano, Francisco ; Virág, László ; Liaudet, Lucas ; Mabley, Jon ; Szabó, Éva ; Haskó, György ; Marton, Anita ; Batista Lorigados, Clara ; Gallyas, Ferenc ; Sümegi, Balázs ; Hoyt, Dale G. ; Baloglu, Erkan ; VanDuzer, John ; Salzman, Andrew L. ; Southan, Garry J. ; Szabo, Csaba. / Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase : Potent cytoprotective and antishock agents. In: Critical Care Medicine. 2002 ; Vol. 30, No. 5. pp. 1071-1082.
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title = "Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase: Potent cytoprotective and antishock agents",
abstract = "Objective: To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. Design: Randomized, prospective laboratory study. Setting: Research laboratory. Subjects: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. Interventions: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. Measurements and Main Results: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-α, interleukin-1β, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). Conclusions: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.",
keywords = "Endothelial, Endotoxin, Gut, Liver, Lung, Malondialdehyde, Myeloperoxidase, Shock, Vascular",
author = "Prakash Jagtap and {Garcia Soriano}, Francisco and L{\'a}szl{\'o} Vir{\'a}g and Lucas Liaudet and Jon Mabley and {\'E}va Szab{\'o} and Gy{\"o}rgy Hask{\'o} and Anita Marton and {Batista Lorigados}, Clara and Ferenc Gallyas and Bal{\'a}zs S{\"u}megi and Hoyt, {Dale G.} and Erkan Baloglu and John VanDuzer and Salzman, {Andrew L.} and Southan, {Garry J.} and Csaba Szabo",
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TY - JOUR

T1 - Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphateribose) synthetase

T2 - Potent cytoprotective and antishock agents

AU - Jagtap, Prakash

AU - Garcia Soriano, Francisco

AU - Virág, László

AU - Liaudet, Lucas

AU - Mabley, Jon

AU - Szabó, Éva

AU - Haskó, György

AU - Marton, Anita

AU - Batista Lorigados, Clara

AU - Gallyas, Ferenc

AU - Sümegi, Balázs

AU - Hoyt, Dale G.

AU - Baloglu, Erkan

AU - VanDuzer, John

AU - Salzman, Andrew L.

AU - Southan, Garry J.

AU - Szabo, Csaba

PY - 2002

Y1 - 2002

N2 - Objective: To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. Design: Randomized, prospective laboratory study. Setting: Research laboratory. Subjects: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. Interventions: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. Measurements and Main Results: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-α, interleukin-1β, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). Conclusions: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.

AB - Objective: To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5′-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. Design: Randomized, prospective laboratory study. Setting: Research laboratory. Subjects: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. Interventions: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. Measurements and Main Results: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-α, interleukin-1β, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). Conclusions: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.

KW - Endothelial

KW - Endotoxin

KW - Gut

KW - Liver

KW - Lung

KW - Malondialdehyde

KW - Myeloperoxidase

KW - Shock

KW - Vascular

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