CONFORMATIONAL-ANALYSIS OF ISOLATED DOCOSAHEXAENOIC ACID (22 6 N-3) AND ITS 14-(S) AND 11-(S) HYDROXY DERIVATIVES BY FORCE-FIELD CALCULATIONS/

Docosahexaenoic acid (DHA) and two of its lipoxygenase end-products, t he 11- and 14-hydroxy derivatives, of biological relevance were studie d for their privileged conformations using molecular mechanics. As an isolated molecule, DHA adopted helical conformations. However, a more extended helical conformation would fit better with the hydrophobic in teractions expected with DHA esterified within glycerophospholipids. T he most stable conformations of the hydroxy derivatives of DHA appeare d as coiled ones where an intramolecular hydrogen bond occurs between the carboxylic and the hydroxy groups. Among the latter conformations, one for each hydroxy derivative would fit better with the requirement of the largest distance between the hydrophobic and hydrophilic cente rs within the molecule for being inserted in membrane phospholipids wh ere the hydroxy derivatives are likely to be located in their unesteri fied form. As thromboxane A(2) (TXA(2)) antagonist, DHA and its hydrox y derivatives were compared with minimized conformations of TXA(2) and one of its potent antagonist recently described, (R)-(+)-TCV-144. Int erestingly, the 14-hydroxy derivative of DHA, previously reported as t he most potent TXA(2) antagonist among the DHA derivatives, exhibited stable conformations quite similar to those of TXA(2) and (R)-(+)-TCV- 144.