Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid found in plants, exerts neuroprotection and anti-inflammatory effects in chronic and acute CNS disease models. However, the underlying mechanisms are not yet understood. Since ALA is not incorporated into the brain, the observed health benefits may result from some of its metabolites. The putative formation of dihydroxylated ALA derivatives (called linotrins) was recently shown in vitro in the presence of lipoxygenases. However, the in vitro biosynthesis of linotrins was neither stereoselective nor quantitatively efficient for studying their physiological roles as enantiomeric pure forms. Herein, we report the first stereo-controlled synthesis that features regio- and stereoselective hydrometalations of alkynes for assembling the sensitive E,Z,E-conjugated trienes, as well as LC-MS investigations that provide evidence of linotrins occurrence in plants. Moreover, strong anti-inflammatory effects on microglia highlight the potential physiological importance of linotrins and open new perspectives in search of CNS therapeutics.
Keywords: Conjugated triène; Cytokine; Inflammation; Linolenic acid; Microglial cell; Total synthesis.
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