Issue 23, 2011

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

Abstract

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 Xenopusoocytes either expressing (human α4β2) or having incorporated (Torpedo α12βγδ) 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.

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

Supplementary files

Article information

Article type
Paper
Submitted
26 Jul 2011
Accepted
05 Sep 2011
First published
06 Sep 2011

Org. Biomol. Chem., 2011,9, 8112-8118

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

L. Duroure, T. Jousseaume, R. Aráoz, E. Barré, P. Retailleau, L. Chabaud, J. Molgó and C. Guillou, Org. Biomol. Chem., 2011, 9, 8112 DOI: 10.1039/C1OB06257C

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