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 Citations (Scopus)

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

Fingerprint

Sodium Channel Blockers
evaluation
Macrolides
synthesis
Biological Products
analogs
Voltage-Gated Sodium Channel Blockers
plasma oscillations
electric potential
products
Veratridine
Voltage-Gated Sodium Channels
Calcium Signaling
Sodium Channels
calcium
drugs
Drug Discovery
Scaffolds
Libraries
preparation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection. / Philkhana, Satish Chandra; Mehrotra, Suneet; Murray, Thomas F.; Reddy, D. Srinivasa.

In: Organic and Biomolecular Chemistry, Vol. 14, No. 36, 2016, p. 8457-8473.

Research output: Contribution to journalArticle

Philkhana, Satish Chandra ; Mehrotra, Suneet ; Murray, Thomas F. ; Reddy, D. Srinivasa. / Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection. In: Organic and Biomolecular Chemistry. 2016 ; Vol. 14, No. 36. pp. 8457-8473.
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