Laurence Balas

The Handy Use of Brown’s P2‐Ni Catalyst for a Skipped Diyne Deuteration: Application to the Synthesis of a [D4]‐Labeled F4t‐Neuroprostane

Browns P2-Ni does the job: An efficient synthesis of tetradeuterated neuroprostane (see structure) has been accomplished by using an eneˆdiyne stereoselective mots cles : 15-D2-IsoP; 15-E2t-IsoP; total synthesis; selective enzymatic chemical differentiation of a non-meso-1,5-diols

Total Synthesis of the Four Enantiomerically Pure Diasteroisomers of the Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes

Syntheses of the four enantiomerically pure diastereoisomers of the phytoprostanes E1 type II and 15-E2t-isoprostanes (1-4) are described. The key steps included the preparation of the Freïmanis (+/-)-hydroxycyclopentenone 5, enzymatic resolution of this racemic hydroxycyclopentenone, Wittig and Horner-Wadsworth-Emmons (HWE) coupling reactions and finally enantioselective reductions.

Confusion between protectin D1 (PD1) and its isomer protectin DX (PDX). An overview on the dihydroxy-docosatrienes described to date.

There is currently a growing interest in docosahexaenoic acid (DHA) oxygenated metabolites. Among them, protectin D1 (PD1), an endogenous dihydroxylated and non-cyclic docosatriene made through lipoxygenation and hydrolysis of an epoxide intermediate, shows appealing biological effects. However, with the present paper we wish to point out that results are sometimes assigned to PD1 while they are indeed related to its isomer protectin DX (PDX) made through double lipoxygenation only. These misleading conclusions urge us to review herein the structural/chemical and biological differences in the docosatrienes reported to date in the literature i.e. PD1, the related PD1n-3 DPA, AT-NPD1, maresin 1 (MaR1) and MaR1n-3 DPA, as well as their poxytrin analogs such as PDX, and some synthetic diastereoisomers. Hopefully, this will avoid further mistakes and confusion in the future.

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z‐Triene

A versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers.

DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: Putative mechanisms through PPAR activation

ABSTRACT Whereas the anti‐inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose‐dependent and comparative study in human primary macrophages aiming to compare the anti‐inflammatory activity of two types of DHA‐derived oxylipins including the well‐described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14‐A4t‐ and 4‐F4t‐NeuroP) formed through free‐radical mediated oxygenation and expected to be new anti‐inflammatory mediators. Considering the potential ability of these DHA‐derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL‐6 and TNF‐&agr;, however not at the same doses. NPD1 showed the most effect at 0.1 &mgr;M (−14.9%, p<0.05 for IL‐6 and −26.7%, p<0.05 for TNF‐&agr;) while the three other molecules had greater effects at 10 &mgr;M, with the strongest result due to the cyclopentenone neuroprostane, 14‐A4t‐NeuroP (−49.8%, p<0.001 and −40.8%, p<0.001, respectively). Part of the anti‐inflammatory properties of the DHA‐derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPAR&ggr;, with 14‐A4t‐NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPAR&agr;. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti‐inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti‐inflammatory effects of DHA. Graphical abstract Figure. No Caption Available. HighlightsBoth Neuroprostanes and Protectins attenuate inflammatory response of macrophages.Cyclopentenone neuroprostanes have the most potent anti‐inflammatory properties.Protectin D1 is active at low dose and loses its bioactivity at high dose.Neuroprostanes and Protectins might act through PPAR activation.Neuroprostanes preferentially activate PPAR&ggr; while Protectins mainly activate PPAR&agr;.

Hemisynthesis and preliminary evaluation of novel endocannabinoid analogues.

Three new endocannabinoid analogues in which amide moiety was replaced either by oxomethylene group or ester moiety with simultaneous substitution of both alpha-hydrogens with methyl groups were synthesized and their abilities to interact with CB1-receptor and FAAH were investigated.

Total synthesis of neuroprotectin D1 analogues derived from omega-6 docosapentaenoic acid (DPA) and adrenic acid (AdA) from a common pivotal, late-stage intermediate.

The first total synthesis of three omega-6 dihydroxylated (E,E,Z)-docosatrienes has been successfully achieved employing a flexible strategy. The key features encompass a Boland semireduction, to create the (E,E,Z)-triene via an (E,E)-ynediene, and a selective deprotection of a tris(tert-butyldimethylsilyl) ether. The main advantage of the present strategy over previous syntheses of noncyclic dihydroxylated PUFA metabolites derived from docosahexaenoic and arachidonic acids comes from the introduction of the polar head chain at the very end of the synthesis from an advanced, pivotal aldehyde. In terms of divergency this enables late-stage modification of the head group.

Levels of palmitic acid ester of hydroxystearic acid (PAHSA) are reduced in the breast milk of obese mothers

To achieve optimal development of a newborn, breastfeeding is extensively recommended, but little is known about the role of non-nutritive bioactive milk components. We aimed to characterize the fatty acid esters of hydroxy fatty acids (FAHFAs), namely palmitic acid hydroxystearic acids (PAHSAs)-endogenous lipids with anti-inflammatory and anti-diabetic properties, in human breast milk. Breast milk samples from 30 lean (BMI=19-23) and 23 obese (BMI>30) women were collected 72h postpartum. Adipose tissue and milk samples were harvested from C57BL/6J mice. FAHFA lipid profiles were measured using reverse phase and chiral liquid chromatography-mass spectrometry method. PAHSA regioisomers as well as other FAHFAs were present in both human and murine milk. Unexpectedly, the levels of 5-PAHSA were higher relative to other regioisomers. The separation of both regioisomers and enantiomers of PAHSAs revealed that both R- and S-enantiomers were present in the biological samples, and that the majority of the 5-PAHSA signal is of R configuration. Total PAHSA levels were positively associated with weight gain during pregnancy, and 5-PAHSA as well as total PAHSA levels were significantly lower in the milk of the obese compared to the lean mothers. Our results document for the first time the presence of lipid mediators from the FAHFA family in breast milk, while giving an insight into the stereochemistry of PAHSAs. They also indicate the negative effect of obesity on 5-PAHSA levels. Future studies will be needed to explore the role and mechanism of action of FAHFAs in breast milk.

Synthesis of 5-(mercaptomethyl)-3(E)-undecene-1,11-dioic acid, a non-peptide glutathione analog

The key step in the synthesis of the title compound is a Julia reaction to create the E-double bond by introducing a functionalized C3 carbon chain.

Dihydroxylated E,E,Z-docosatrienes. An overview of their synthesis and biological significance.

Dihydroxylated E,E,Z-docosatrienes are acyclic lipoxygenase metabolites of 22-carbon atom polyunsaturated fatty acids (PUFAs) containing a conjugated E,E,Z-triene flanked by two secondary allylic alcohols. The two main metabolites, protectin D1 (PD1) and its regioisomer maresin 1 (MaR1), were shown to be actively involved in the resolution and more specifically the termination of the inflammation process. Studies directed at the synthesis of E,E,Z-docosatrienes have been undertaken to resolve stereochemical ambiguities, and provide standards for biological evaluation and reference samples for in-vivo detection and lipidomic analyses. In this review we provide a brief update of the literature on the biological significance of E,E,Z-docosatrienes and the role that synthetic organic chemists has played in the development of these lipids, providing an overview and comparison of the different strategies employed to access synthetic E,E,Z-docosatriene standards.