Detailed Analysis of (−)-Palmyrolide A and Some Synthetic Derivatives as Voltage-Gated Sodium Channel Antagonists

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.

Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against Na V

“…Following earlier work from our laboratory (19) and others (44,45), we questioned whether the enantiomer form of BTX would bind with high affinity to Na V with analogous functional effects. Such a question can only be answered with the availability of a de novo synthesis of the toxin.…”

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

“…We next focused on the synthesis of macrocycles with an increase in the size of the ring. While we were working on this, the structure activity relationship studies on palmyrolide A were reported 21 and provided valuable insights into the structural features contributing to voltage-gated sodium channel (VGSC) blocking activity. According to that report, both the enantiomers of palmyrolide A showed a similar activity.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…139) for preparation of a lagunamide A segment [457]; (8) acrylamide or acryloyl chloride with alkenealcohols for total synthesis of palmyrolide A and stereoisomeric compounds [458]; and (9) acrolein or acrylonitrile with various 1-alkenes [459]. Several examples employing the cross metathesis of simple inexpensive low molecular weight functionalized allylic derivatives with more precious alkenes were reported in 2014, including: (1) cis 1,4-diacetoxy-2-butene with an alkene-alcohol for synthesis of trans oxepanes [460], and with various homoallylic alcohols for synthesis of substituted pyrans [461]; (2) Boc-protected cis 2-buten-1,4-diol and a homoallylic alcohol [462]; (3) 1-phenylallyl acetate and various monosubstituted alkenes [463];…”