Abstract
A small library of synthetic (-)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (-)-palmyrolide A and analogues to antagonize veratridine-stimulated Na+ influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (-)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (-)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.
| Original language | English |
|---|---|
| Pages (from-to) | 2553-2560 |
| Number of pages | 8 |
| Journal | Journal of Natural Products |
| Volume | 77 |
| Issue number | 11 |
| DOIs | |
| State | Published - Oct 24 2014 |
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All Science Journal Classification (ASJC) codes
- Drug Discovery
- Pharmacology
- Pharmaceutical Science
- Analytical Chemistry
- Organic Chemistry
- Molecular Medicine
- Complementary and alternative medicine
Cite this
Detailed analysis of (-)-palmyrolide A and some synthetic derivatives as voltage-gated sodium channel antagonists. / Mehrotra, Suneet; Duggan, Brendan M.; Tello-Aburto, Rodolfo; Newar, Tara D.; Gerwick, William H.; Murray, Thomas F.; Maio, William A.
In: Journal of Natural Products, Vol. 77, No. 11, 24.10.2014, p. 2553-2560.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Detailed analysis of (-)-palmyrolide A and some synthetic derivatives as voltage-gated sodium channel antagonists
AU - Mehrotra, Suneet
AU - Duggan, Brendan M.
AU - Tello-Aburto, Rodolfo
AU - Newar, Tara D.
AU - Gerwick, William H.
AU - Murray, Thomas F.
AU - Maio, William A.
PY - 2014/10/24
Y1 - 2014/10/24
N2 - A small library of synthetic (-)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (-)-palmyrolide A and analogues to antagonize veratridine-stimulated Na+ influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (-)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (-)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.
AB - A small library of synthetic (-)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (-)-palmyrolide A and analogues to antagonize veratridine-stimulated Na+ influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (-)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (-)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.
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U2 - 10.1021/np500644k
DO - 10.1021/np500644k
M3 - Article
VL - 77
SP - 2553
EP - 2560
JO - Journal of Natural Products
JF - Journal of Natural Products
SN - 0163-3864
IS - 11
ER -