6,6-Spiroimine analogs of (−)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptorsElectronic supplementary information (ESI) available. CCDC reference numbers 828699. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1ob06257c

• Main Authors: Duroure, Leslie, Jousseaume, Thierry, Aráoz, Rómulo, Barré, Elvina, Retailleau, Pascal, Chabaud, Laurent, Molgó, Jordi, Guillou, Catherine
• Format: Journal Article
• Language: English
• Published: 10.11.2011
• ISSN: 1477-0520; 1477-0539
• 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 β-ketoester to acrolein, whereas the asymmetric allylic alkylation of the same β-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 α4β2) or having incorporated ( Torpedo α1 2 βγδ) 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. Synthetic spiroimine analogs of (−)-gymnodimine A inhibit nicotinic acetylcholine receptors, but are less potent than the natural toxin.