Abstract
A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Crystallography, X-Ray
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Dacarbazine / analogs & derivatives*
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Dacarbazine / pharmacology
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Drug Design
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Drug Screening Assays, Antitumor
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Drug Synergism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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NAD / metabolism
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / metabolism
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Structure-Activity Relationship
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Temozolomide
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Topotecan / pharmacology
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Indoles
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Isoquinolines
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Poly(ADP-ribose) Polymerase Inhibitors
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NAD
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Dacarbazine
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Topotecan
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Poly(ADP-ribose) Polymerases
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Temozolomide