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Issue 36, 2016
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Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection

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Abstract

Palmyrolide A is a neuroprotective macrolide isolated by Gerwick and coworkers in 2010. This natural product is known to suppress neuronal spontaneous calcium ion oscillations through its voltage-gated sodium channel blocking ability which is of significant interest in CNS drug discovery. Herein, we give a detailed account on total synthesis of (+)-palmyrolide A and synthesis of a focused library of macrocycles around the scaffold, followed by their biological evaluation. Use of the chiral pool approach, Zhu's oxidative homologation, access to unnatural cis-palmyrolide A, preparation of 18 new analogues and identification of macrolides with improved sodium channel blocking activity are the important features of the present paper. As a measure of potency as voltage-gated sodium channel blockers, all the synthesized analogues were profiled for their ability to inhibit the veratridine-stimulated Na+ influx in murine primary neuronal cultures. Four macrocycles were found to be more potent or comparable to that of the natural product (−)-palmyrolide A. The most potent compound from this series 20 was structurally simplified and readily accessible in good quantities for further biological profiling.

Graphical abstract: Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection

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Supplementary files

Article information


Submitted
25 Jun 2016
Accepted
08 Aug 2016
First published
09 Aug 2016

Org. Biomol. Chem., 2016,14, 8457-8473
Article type
Paper

Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection

S. C. Philkhana, S. Mehrotra, T. F. Murray and D. S. Reddy, Org. Biomol. Chem., 2016, 14, 8457
DOI: 10.1039/C6OB01372D

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