Detailed Analysis of (-)-Palmyrolide A and Some Synthetic Derivatives as Voltage-Gated Sodium Channel Antagonists

TitleDetailed Analysis of (-)-Palmyrolide A and Some Synthetic Derivatives as Voltage-Gated Sodium Channel Antagonists
Publication TypeJournal Article
Year of Publication2014
AuthorsMehrotra S., Duggan BM, Tello-Aburto R., Newar T.D, Gerwick WH, Murray T.F, Maio W.A
JournalJournal of Natural Products
Volume77
Pagination2553-2560
Date Published2014/11
Type of ArticleArticle
ISBN Number0163-3864
Accession NumberWOS:000345472100030
Keywordscyanobacteria; cyclopeptide alkaloids; cytotoxic macrolides; laingolide; lobatamides; lyngbya-bouillonii; neurons; palmyrolide; revision; visualization
Abstract

A small library of synthetic (-)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (-)-palmyrolide A and analogues to antagonize veratridine-stimulated Na(+) influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (-)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (-)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.

DOI10.1021/np500644k
Short TitleJ. Nat. Prod.
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