6,6-Spiroimine analogs of (-)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptors

作者：Duroure Leslie; Jousseaume Thierry; Araoz Romulo; Barre Elvina; Retailleau Pascal; Chabaud Laurent^*; Molgo Jordi; Guillou Catherine

来源：Organic and Biomolecular Chemistry, 2011, 9(23): 8112-8118.

DOI：10.1039/c1ob06257c

Simple models of the spiroimine core of (-)-gymnodimine A have been synthesized in racemic and optically active forms. The quaternary carbon of the racemic spiroimines was created by Michael addition of a beta-ketoester to acrolein, whereas the asymmetric allylic alkylation of the same b-ketoester was used to access the spiroimines in an enantioselective fashion. Both racemic and enantio-enriched mixtures were tested for their biological activities on Xenopus oocytes either expressing (human alpha 4 beta 2) or having incorporated (Torpedo alpha 1(2)beta gamma delta) nicotinic acetylcholine receptors (nAChRs). These spiroimine analogs of (-)-gymnodimine A inhibited acetylcholine-evoked nicotinic currents, but were less active than the phycotoxin. Our results reveal that the 6,6-spiroimine moiety is important for the blockade of nAChRs and support the hypothesis that it is one of the pharmacophores of this group of toxins.

• 出版日期2011