Stereoselective Synthesis, Configurational Assignment and Biological Evaluations of the Lipid Mediator RvD2_{n‐3 DPA}

Abstract

Herein we report the first total synthesis of RvD2n‐3 DPA, an endogenously formed mediator biosynthesized from the omega‐3 fatty acid n‐3 docosapentaenoic acid. The key steps are the Midland Alpine borane reduction, Sonogashira cross‐coupling reactions, and a Z‐selective alkyne reduction protocol, yielding RvD2n‐3 DPA methyl ester in 13 % yield over 12 steps (longest linear sequence). The physical property data (UV chromophore, chromatography and MS/MS fragmentation) of the synthetic lipid mediator matched those obtained from biologically produced material. Moreover, synthetic RvD2n‐3 DPA also carried the potent biological activities of enhancing macrophage uptake of Staphylococcus aureus and zymosan A bioparticles.

Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators

“…The stereochemistry of RvD1was proved to be 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and that of AT-RvD1 was established as 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid [93] .Furthermore, the second pathway for biosynthesis of RvD1 and AT-RvD1 involves the oxygenation of 17-hydro(peroxy) product at the C-7 position by 5-LOX to yield 17S-hydro(peroxy)-7S-HDHA, which is then converted by enzymatic epoxidation to16,17S-epoxy-7S-HDHA intermediate. This 16(17)-epoxide upon enzymatic hydrolysis at C-1,10 yields RvD1, or AT-RvD1 if acetylated COX-2 is involved [108] , [109] .Additionally, RvD1 n-3 can be synthesized from 7(S),17(S)-diHpDPA, which is enzymatically converted to 7S,8R-epoxy 17S-HDPA,an epoxide intermediate,which upon hydroxylation yields RvD1 n-3 [110] . The complete stereochemistry of RvD1 n-3DPA is 7S,8R,17S-trihydoxy-9E,11E,13Z,15E,19Z-docosapentaenoic acid [111] .…”

“…This SPM is formed after two consecutive lipoxygenation reactions, first lipoxygenation occurs via 15-LOX and forms 17(S)-HpDPA, while the second lipoxygenation step occurs in the presence of 5-LOX and yields 7(S),17(S)-diHpDPA and epoxide formation, followed by ring opening of the epoxide by a hydrolytic enzyme. The stereochemistry of this oxygenated SPM was established as RvD2 n-3 DPA 7S,16R,17S-trihydroxydocosa-8E,10Z,12E,14E,19Z-pentaenoic acid [110] , [115] .…”

“…The intermediate thus generated is (17S,4Z,7Z,10Z,13Z,15E,19Z)-17-hydroperoxydocosahexaenoic acid (17S-HpDHA), which is reduced to 17S-hydroxyDHA (17S-HDHA) by a peroxidase. Subsequent lipoxygenation at C-7 by 5-LOX, followed by peroxidase catalysis generates RvD5 (7S, 17S-dihydroxy-docosa-4Z, 8E, 10Z, 13Z, 15E, 19Z-hexaenoic acid) [122] , [93] .The Aspirin-triggered Resolvin D5(AT-RvD5) is formed from DHA catalyzed by acetylated COX-2 in presence of aspirin or CYP450.Here the upstream pathway involving formation of AT-RvDs is similar.The stereochemaical structure of Aspirin-triggered Resolvin D5(AT-RvD5) is 7S,17R-Dihydroxy-docosa-5Z,8E,10Z,13Z,15E,19Z-hexaenoic acid [114] .Alternatively, SPM RvD5 n-3 DPA is produced from 17-hydroperoxy-8Z,10Z,13Z,15E,19Z-docosapentaenoic acid (17-HpDPA) intermediate, which undergoes a subsequent lipoxygenation to yield RvD5 n-3 DPA [110] .The complete stereochemistry of RvD5n-3 DPA 7S,17S-dihydroxy-8E,10Z,13Z,15E,19Z-docosapentaenoic acid [115] .…”

Micellar Mechanisms for Desymmetrization Reactions in Aqueous Media

“…These reactions were among the first examples of water-mediated desymmetrization reactions. Half-esters produced in these reactions are very versatile building blocks applied to the synthesis of pharmaceuticals, natural products, and polymers. − These reactions can produce the corresponding half-esters even in near-quantitative yields in many cases.…”

Stereoselective Synthesis, Pro-resolution, and Anti-inflammatory Actions of RvD5n-3 DPA

“…As of today, stereoselective total syntheses of RvD1 n‑3 DPA and RvD2 n‑3 DPA have been achieved (Figure ). Recently, it was reported that RvD5 n‑3 DPA ( 1 ) binds to and activates GPR101, exerting tissue-protective actions during inflammatory arthritis .…”