RESUMO
Protectin D1 is a specialized pro-resolving mediator with potent pro-resolving and anti-inflammatory effects in vivo in several human disease models. Herein the preparation of the first synthetic analog of protectin D1, named 22-F-PD1, is presented together with data from in vivo investigations. This analog showed potent pro-resolving and anti-inflammatory properties. These results inspired the preparation of the radiotracer 22-[18F]F-PD1-ME that was used in a positron emission tomography proof of concept study. Altogether, the findings presented contribute to new knowledge on the biomolecular properties of protectin D1 analogs. In addition, an improved formal synthesis of the metabolite 22-OH-PD1 is reported.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Anti-Inflamatórios/química , Encéfalo/diagnóstico por imagem , Técnicas de Química Sintética , Ácidos Docosa-Hexaenoicos/química , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Tomografia por Emissão de Pósitrons , Traçadores RadioativosRESUMO
A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao's chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material.
