Structure–activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 19; pp. 5594 - 5598
• Main Authors: Beausoleil, Eric, Chauvignac, Cédric, Taverne, Thierry, Lacombe, Sandrine, Pognante, Laure, Leblond, Bertrand, Pallares, Diego, Oliveira, Catherine De, Bachelot, Florence, Carton, Rachel, Peillon, Hélène, Coutadeur, Séverine, Picard, Virginie, Lambeng, Nathalie, Désiré, Laurent, Schweighoffer, Fabien
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2009; Elsevier
• Subjects: Alkaloid; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Berberine - chemical synthesis; Berberine - chemistry; Berberine - pharmacology; Binding Sites; Biological and medical sciences; Computer Simulation; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; GTP binding protein; Hydrolases; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Medical sciences; Miscellaneous; Molecular docking; Nucleotides - chemistry; Pharmacology. Drug treatments; Protein Binding; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Rac; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - metabolism; Rho GTPase; Structure-Activity Relationship; Alkaloid; GTP binding protein; Rac; Rho GTPase; Molecular docking; Organic cation; Enzyme; Iminium compounds; Angular nitrogen heterocycle; Nitrogen heterocycle; Isozyme; Inhibitor enzyme complex; Selectivity; Tetracyclic compound; In vitro; Modeling; Structure activity relation; Molecular model; Bicyclic compound; Hydrolases; Aromatic compound; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.08.037

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.