Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation

Abstract

Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.

α‐linolenic acid interconversion is sufficient as a source of longer chain ω‐3 polyunsaturated fatty acids in humans: An opinion

“…The relative proportions of individual PUFA can also modulate cell function by influencing the pattern of lipid second messengers produced in response to stimulation including oxylipins such as eicosanoids and leukotrienes (Wada et al, 2007), and phospholipid‐derived mediators, for example diacylglycerol (Kamiya et al, 2016) and phosphatidic acid (Heung & Postle, 1995a, 1995b). EPA and DHA are substrates for synthesis of specialized pro‐resolving mediators that are important for immune homeostasis (Calder, 2017; Ferreira et al, 2022). Moreover, ω‐3 PUFA can influence transcription by acting as ligands for transcription factors, for example the peroxisome proliferator‐activated receptor (PPAR) family (Forman et al, 1997), and by modifying epigenetic processes (Burdge & Lillycrop, 2014; Perez‐Mojica et al, 2020).…”

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

“…The synthesis of propargyl bromide intermediate 4 is detailed in Scheme 3. This synthesis employed D-erythrose (9) as a chiral feedstock. However, in our recent and separate study 8 postdating the current synthesis, we found D-erythronolactone as a more suitable chiral synthon than 9 due to its high cost and handling difficulties.…”

Contribution of n-3 Long-Chain Polyunsaturated Fatty Acids to the Prevention of Breast Cancer Risk Factors

“…The anti-inflammatory properties of n-3 LC-PUFAs have been known for a long time, and are thought to occur (i) by the replacement of ARA by DHA in cellular membranes, lowering the production of pro-inflammatory eicosanoids from ARA by COX and lipoxygenase; (ii) the fact that DHA is preferred to ARA as a substrate of COX-2 enzyme; and (iii) by the synthesis of lipidic specialized pro-resolving mediators (SPMs), namely, resolvins, protectins, and maresins, which are enzymatically oxygenated PUFAs (or oxylipins) acting as lipid mediators to suppress inflammation by clearing neutrophils and macrophages from inflammatory sites [82][83][84][85][86] (Figure 3). However, the synthesis of SPMs in humans is not clearly linked to n-3 LC-PUFA dietary supplementation [87].…”