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 language | English (US) |
|---|---|
| Pages (from-to) | 8457-8473 |
| Number of pages | 17 |
| Journal | Organic and Biomolecular Chemistry |
| Volume | 14 |
| Issue number | 36 |
| DOIs | |
| State | Published - 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection
AU - Philkhana, Satish Chandra
AU - Mehrotra, Suneet
AU - Murray, Thomas F.
AU - Reddy, D. Srinivasa
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84988353339&partnerID=8YFLogxK
U2 - 10.1039/c6ob01372d
DO - 10.1039/c6ob01372d
M3 - Article
C2 - 27536802
AN - SCOPUS:84988353339
VL - 14
SP - 8457
EP - 8473
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
SN - 1477-0520
IS - 36
ER -