Abstract
On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase I-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenoisoquinoline 5. The desired compound 14a was synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in a series of human leukemia, ovarian, and breast cancer cells.
Publication types
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Research Support, N.I.H., Extramural
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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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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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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Indenes / chemical synthesis
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Indenes / chemistry*
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Indenes / pharmacology*
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry*
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Isoquinolines / pharmacology*
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Thermodynamics
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Topoisomerase I Inhibitors*
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Indenes
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Isoquinolines
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Topoisomerase I Inhibitors