DNA Binding To Guide the Development of Tetrahydroindeno[1,2-b]pyrido[4,3,2-d e]quinoline Derivatives as Cytotoxic Agents

The tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline chromophore was initially designed as a DNA intercalating unit because of its planar structure. Unexpectedly, one molecule (15d) bearing two N-methylpiperazine chains on both sides of this condensed pentacyclic skeleton fits into the minor groove...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-07, Vol.47 (14), p.3665-3673
Main Authors: Catoen-Chackal, Sarah, Facompré, Michael, Houssin, Raymond, Pommery, Nicole, Goossens, Jean-François, Colson, Pierre, Bailly, Christian, Hénichart, Jean-Pierre
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Division - drug effects
Cell Line, Tumor
Circular Dichroism
DNA - chemistry
DNA Footprinting
Drug Screening Assays, Antitumor
Fluorometry
General aspects
Humans
Intercalating Agents - chemical synthesis
Intercalating Agents - chemistry
Intercalating Agents - pharmacology
Medical sciences
Pharmacology. Drug treatments
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacology
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Structure-Activity Relationship
Transition Temperature
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Summary:The tetrahydroindeno[1,2-b]pyrido[4,3,2-de]quinoline chromophore was initially designed as a DNA intercalating unit because of its planar structure. Unexpectedly, one molecule (15d) bearing two N-methylpiperazine chains on both sides of this condensed pentacyclic skeleton fits into the minor groove of DNA and preferentially recognizes AT-rich sequences. The monosubstituted compound 16d was identified as a potent cytotoxic DNA intercalator, whereas the disubstituted analogue 15d represents a new structural motif for the development of DNA sequence-reading small molecules.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0400193