01879nas a2200169   4500008004100000245012000041210006900161260000800230300001400238490000700252520122400259100003101483700002101514700002301535700002101558856013001579       2016                        eng d00aSynthesis and biological evaluation of palmyrolide a macrocycles as sodium channel blockers towards neuroprotection0 aSynthesis and biological evaluation of palmyrolide a macrocycles  cAUG  a8457-84730 v143 a<p>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.</p>1 aPhilkhana, Satish, Chandra1 aMehrotra, Suneet1 aMurray, Thomas, F.1 aReddy, Srinivasa  uhttp://library.ncl.res.in/content/synthesis-and-biological-evaluation-palmyrolide-macrocycles-sodium-channel-blockers-towards