RESUMO
New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.
Assuntos
Anti-Inflamatórios/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Graxos Insaturados/química , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Teoria Quântica , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , EstereoisomerismoRESUMO
PD1n-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 PD1n-3 DPA from n-3 docosapentaenoic acid, the epoxy acid 16(S),17(S)-epoxy-PDn-3 DPA, herein named ePDn-3 DPA, was prepared by stereoselective total synthesis. The synthetic material of ePDn-3 DPA allowed investigations of its role in the biosynthesis of PD1n-3 DPA. The obtained results establish that the biosynthesis of PD1n-3 DPA in neutrophils occurs with ePDn-3 DPA as the intermediate, and that 15-LOX produces ePDn-3 DPA from n-3 docosapentaenoic acid. Furthermore, support for the involvement of a hydrolytic enzyme in the biosynthetic conversion of ePDn-3 DPA to PD1n-3 DPA was found. In addition, ePDn-3 DPA was found to regulate the formation of the potent neutrophil chemoattractant LTB4 with equal potencies to that obtained with PD1n-3 DPA.