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.

Modular Total Synthesis of (–)‐Palmyrolide A and (+)‐(5S,7S)‐Palmyrolide A via Ring‐Closing Metathesis and Alkene Isomerization†

“…The anti ‐Me/ t ‐Bu structural motif has been reported for apratoxin A albeit in (5 S ,7 S )‐configuration. [ 11 ] Three types of intramolecular processes were used to construct the trans ‐ N ‐methyl enamide subunit of 1a / 1b : (a) a CuI‐catalyzed macroenamidation of a primary amide with a trans ‐alkenyl iodide followed by N ‐methylation [ 4a,b,d,f,h,5b ] or employing an N ‐methyl amide in the macroenamidation; [ 4g ] (b) a ring‐closing metathesis (RCM) [ 12 ] reaction of an N ‐allyl‐ N ‐methyl amide with an alkene followed by ruthenium hydride‐catalyzed alkene isomerization; [ 4c,f ] and (c) a TFA‐mediated dehydrative cyclization of an aldehyde with an N ‐methyl amide. [ 4e ] We reported total synthesis of two laingolide B stereoisomers and assigned the (2 S ,9 R ) absolute configuration for the naturally occurring 4 .…”

“…[ 1 ] It is interesting to observe some trans ‐ N ‐methyl enamide‐containing macrolides possessing a tert ‐butyl carbinol moiety. [ 2 ] This small group of unique macrolides as depicted in Figure 1 includes palmyrolide A ( 1 ), [ 3‐5 ] laingolide ( 2 ), [ 6 ] laingolide A ( 3 ), [ 7‐8 ] laingolide B ( 4 ), [ 9‐10 ] and madangolide (structure not shown). [ 7 ] Palmyrolide A was isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf .…”

Synthesis of Bioactive 1,2,3-Triazole-Fused Macrocycles via Azide-Alkyne Cycloaddition

“…anticancer, antibacterial, antifungal, immunosuppressant and more and thus have proven themselves to be extremely effective in the field of medicine. 3 In particular, 1,2,3-triazole-fused macrocycles have exhibited promising biological activities like anticancer [4][5][6] , antibacterial 7 , anti-inflammatory 8 , antiviral 9 and more [10][11][12] , and hence, the synthesis of triazole-based macrocycles has become a hot topic for researchers. Literature reports revealed that significant efforts have been attributed towards the synthesis of triazole scaffold involving Ag(I)-, Cu(I)-, Ru(II)-catalyzed azide-alkyne cycloaddition (AAC) reactions, microwave assisted reactions, ultrasound-promoted reactions etc.…”

Total Synthesis and Structural Reassignment of Laingolide A

“…In 2010, Gerwick and co-workers reported the isolation of palmyrolide A ( 5 ), a structurally closely related 15-member macrolide from a cyanobacterial assemblage comprised of Leptolyngbya and Oscillatoria species collected at Palmyra Atoll, south of Hawaii [ 6 ]. One of the absolute configurations present in palmyrolide A was correctly assigned upon its initial isolation [ 15 ], and the absolute configurations of the remaining stereocentres were later established via total syntheses [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. The structurally intriguing laingolides have attracted considerable attention from the synthetic community [ 25 , 26 , 27 ].…”