Abstract
We designed and synthesized small-molecule activator protein-1 (AP-1) inhibitors based on a three-dimensional (3D) pharmacophore model that we had previously derived from a cyclic decapeptide exhibiting AP-1 inhibitory activity. New AP-1 inhibitors with a 1-thia-4-azaspiro[4.5]decane or a benzophenone scaffold, which inhibit the DNA-binding and transactivation activities of AP-1, were discovered using a "lead hopping" procedure. An additional investigation of the benzophenone analogues confirmed the reliability of the pharmacophore model, its utility to discover AP-1 inhibitors, and the potency of the benzophenone derivatives as a lead series.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzophenones / chemical synthesis
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Benzophenones / chemistry*
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Benzophenones / pharmacology
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Computer Simulation
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Crystallography, X-Ray
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DNA / 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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Mice
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Models, Molecular
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Molecular Structure
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NIH 3T3 Cells
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Protein Conformation
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Quantitative Structure-Activity Relationship*
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology
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Transcription Factor AP-1 / antagonists & inhibitors*
Substances
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Benzophenones
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Enzyme Inhibitors
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Spiro Compounds
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Transcription Factor AP-1
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benzophenone
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DNA