Palmyrolide (PalA) is a neuroactive macrolide with rare structural features, isolated from a cyanobacteral assemblage collected at Palmyra Atoll. Initial studies revealed PalA to be a potent inhibitor of calcium ion oscillations in murine cerebrocortical neurons and to possess sodium ion channel blocking ability in neuroblastoma cells with no cytotoxicity. In 2011 we designed a flexible synthetic strategy that resulted in the first total synthesis of ent-PalA. This report was followed by our second-generation synthesis that produced PalA in ten linear operations exploiting no protecting groups. We now report our progress on the design and synthesis of a library of synthetic PalA derivatives that will allow for one-step analog development. Each can be produced using our current synthetic route, and by utilizing a strategy of rapid analog development, we are now generating a library for biological evaluation. This work may lead to a better understanding of calcium dependent neurological disorders.

Design and synthesis of neuroactive derivatives of the palmyrolide A macrolide

245th National Meeting (2013)

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