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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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-01, Vol.46 (2), p.210-213
Main Authors: 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: Article
Language:English
Subjects:
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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Summary: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