title: Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection.
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.
authors.affiliation: CSIR-National Chemical Laboratory, Dr HomiBhabha Road, Pune, 411008, India. ds.reddy@ncl.res.in.
authors.forename: Satish Chandra
authors.initials: SC
authors.lastname: Philkhana
authors.forename: Suneet
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
authors.forename: D Srinivasa
authors.initials: DS
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047028:Macrocyclic Compounds; D018942:Macrolides; D018696:Neuroprotective Agents; D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; C572829:palmyrolide A