Tricyclic Benzimidazoles as Potent Poly(ADP-ribose) Polymerase-1 Inhibitors

Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measu...

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Veröffentlicht in:	Journal of medicinal chemistry 2003-01, Vol.46 (2), p.210-213
Hauptverfasser:	Skalitzky, Donald J, Marakovits, Joseph T, Maegley, Karen A, Ekker, Anne, Yu, Xiao-Hong, Hostomsky, Zdenek, Webber, Stephen E, Eastman, Brian W, Almassy, Robert, Li, Jianke, Curtin, Nicola J, Newell, David R, Calvert, A. Hilary, Griffin, Roger J, Golding, Bernard T
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - pharmacology Binding Sites Biological and medical sciences Cell Line Crystallography, X-Ray Dacarbazine - analogs & derivatives Dacarbazine - metabolism Dacarbazine - pharmacology Drug Resistance, Neoplasm Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Humans Medical sciences Models, Molecular Pharmacology. Drug treatments Poly(ADP-ribose) Polymerase Inhibitors Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Stereoisomerism Structure-Activity Relationship temozolomide topotecan Topotecan - metabolism Topotecan - pharmacology
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Zusammenfassung:	Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measurement of NAD+ depletion and ADP-ribose polymer formation caused by chemically induced DNA damage.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0255769