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Synthesis of chemically edited derivatives of the endogenous regulator of inflammation 9-PAHSA


Fatty acid esters of hydroxy fatty acids (FAHFAs) are a growing class of natural products found in organisms ranging from plants to humans. The roles these endogenous derivatives of fatty acids play in biology and their novel pathways for controlling inflammation have increased our understanding of basic human physiology. FAHFAs incorporate diverse fatty acids into their structures, however, given their recent discovery non-natural derivatives have not been a focus and as a result structure-activity relationships remain unknown. The importance of the long chain hydrocarbons extending from the ester linkage as they relate to anti-inflammatory activity is unknown. Herein the systematic removal of carbons from either the hydroxy fatty acid or fatty acid regions of the most studied FAHFA, palmitic acid ester of 9-hydroxystearic acid (9-PAHSA), was achieved and these synthetic, abridged analogs were tested for their ability to attenuate IL-6 production. Reduction of the carbon chain lengths of the 9-hydroxystearic acid portion or palmitic acid hydrocarbon chain resulted in lower molecular weight analogs that maintained anti-inflammatory activity or in one case enhanced activity.

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This study is dedicated to Professor Samuel Danishefsky for his tireless efforts to advance the field of organic chemistry and his tremendous scientific contributions to the exploration of structurally complex, and biologically important, natural products.

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This work was supported by the National Institutes of Health Grants R56 DK110150 (to D. S. and A. S.). The authors thank Brendan Duggan for assistance with NMR spectroscopy. This work was supported by the University of California, San Diego.

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The authors declare that they have no conflict of interest.

Correspondence to Dionicio Siegel.

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