Stereocontrolled total synthesis of Resolvin D4 and 17()-Resolvin D4.

The total synthesis of Resolvin D4 and its 17()-hydroxy-epimer is reported. These lipid-based natural products are biosynthesized from docosahexaenoic acid (DHA, C22:6) during the body's rapid cellular and chemical response to injurious stimuli and are part of a large class of bioactive molecules that resolve inflammation. Our convergent synthesis employed a chiral pool strategy starting from glycidol derivatives and D-erythrose to introduce stereogenic centers.

Synergistic Neuroprotection by a PAF Antagonist Plus a Docosanoid in Experimental Ischemic Stroke: Dose-Response and Therapeutic Window.

Objective: We tested the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAFR) with LAU-0901 (LAU) plus administering a selected docosanoid, aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways after middle cerebral artery occlusion (MCAo), would lead to neurological recovery. Dose-response and therapeutic window were investigated.

Materials And Methods: Male SD rats were subjected to 2 hours of MCAo.

First stereoselective total synthesis of 4(),5()-oxido-17()-hydroxy-6(),8(),10(),13(),15(),19()-docosahexaenoic acid, the biosynthetic precursor of resolvins D3 and D4.

The first total convergent synthesis of 4(),5()-oxido-17()-hydroxy-6(),8(),10(),13(),15(),19()-docosahexaenoic acid (1) is described. The reported synthesis led to confirmation of the native epoxydocosahexaenoic acid as the biosynthetic precursor of lipid mediators resolvin D3 and resolvin D4. These potent enzymatic products of docosahexaenoic acid (DHA) are important signaling molecules in the resolution of inflammation.

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.

Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures and ultra-large libraries of virtual compounds. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries, new approaches to compound screening are needed. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds.

Human leukocytes selectively convert 4,5-epoxy-resolvin to resolvin D3, resolvin D4, and a cys-resolvin isomer.

Human phagocytes have key functions in the resolution of inflammation. Here, we assessed the role of the proposed 4,5-epoxy-resolvin intermediate in the biosynthesis of both resolvin D3 and resolvin D4. We found that human neutrophils converted this synthetic intermediate to resolvin D3 and resolvin D4.