Abstract
The synthesis of a series of berberine, phenantridine and isoquinoline derivatives was realized to explore their Rho GTPase nucleotide inhibitory activity. The compounds were evaluated in a nucleotide binding competition assay against Rac1, Rac1b, Cdc42 and in a cellular Rac GTPase activation assay. The insertion of 19 AA in the splice variant Rac1b is shown to be sufficient to introduce a conformational difference that allows compounds 4, 21, 22, and 26 to exhibit selective inhibition of Rac 1b over Rac1.
MeSH terms
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Amino Acid Sequence
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Berberine / chemical synthesis
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Berberine / chemistry
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Berberine / pharmacology
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Binding Sites
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Computer Simulation
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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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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Nucleotides / chemistry*
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Protein Binding
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Structure-Activity Relationship
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rac1 GTP-Binding Protein / antagonists & inhibitors*
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rac1 GTP-Binding Protein / metabolism
Substances
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Enzyme Inhibitors
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Isoquinolines
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Nucleotides
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Protein Isoforms
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Berberine
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rac1 GTP-Binding Protein
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isoquinoline