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
Exonhit Therapeutics, 65 Boulevard Massena, F-75013 Paris, France.
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5594-8. doi: 10.1016/j.bmcl.2009.08.037. Epub 2009 Aug 13.
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.
为了探索一系列小檗碱、菲啶和异喹啉衍生物的Rho GTPase核苷酸抑制活性，实现了它们的合成。这些化合物在针对Rac1、Rac1b、Cdc42的核苷酸结合竞争试验以及细胞Rac GTPase激活试验中进行了评估。结果表明，剪接变体Rac1b中19个氨基酸的插入足以引入构象差异，使化合物4、21、22和26对Rac 1b表现出比Rac1更强的选择性抑制作用。
