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

Satish Chandra Philkhana, Suneet Mehrotra, Thomas F. Murray, D. Srinivasa Reddy

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8457-8473
Number of pages17
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number36
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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