Stereocontrolled synthesis and investigation of the biosynthetic transformations of 16(S),17(S)-epoxy-PDn-3 DPA

Abstract

PD1_{n-3 DPA} is a specialized pro-resolving lipid mediator that displays potent anti-inflammatory properties and pro-resolving bioactivities. Such naturally occurring compounds are of current interest in biomolecular chemistry and drug discovery. To investigate the involvement of an epoxide intermediate in the biosynthesis of PD1_{n-3 DPA} from n-3 docosapentaenoic acid, the epoxy acid 16(S),17(S)-epoxy-PD_{n-3 DPA}, herein named ePD_{n-3 DPA}, was prepared by stereoselective total synthesis. The synthetic material of ePD_{n-3 DPA} allowed investigations of its role in the biosynthesis of PD1_{n-3 DPA}. The obtained results establish that the biosynthesis of PD1_{n-3 DPA} in neutrophils occurs with ePD_{n-3 DPA} as the intermediate, and that 15-LOX produces ePD_{n-3 DPA} from n-3 docosapentaenoic acid. Furthermore, support for the involvement of a hydrolytic enzyme in the biosynthetic conversion of ePD_{n-3 DPA} to PD1_{n-3 DPA} was found. In addition, ePD_{n-3 DPA} was found to regulate the formation of the potent neutrophil chemoattractant LTB₄ with equal potencies to that obtained with PD1_{n-3 DPA}.