Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics.

The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress.

Catalytic Room-Temperature C-N Coupling of Amides and Isocyanates by Using Mechanochemistry.

A mechanochemical route is developed for room-temperature and solvent-free derivatization of different types of amides into carbamoyl isatins (up to 96 % conversion or yield), benzamides (up to 81 % yield), and imides (up to 92 % yield). In solution, this copper-catalyzed coupling either does not take place or requires high temperatures at which it may also be competing with alternative thermal reactivity, highlighting the beneficial role of mechanochemistry for this reaction. Such behavior resembles the previously investigated coupling with sulfonamide substrates, suggesting that this type of C-N coupling is an example of a mechanochemically favored reaction, for which mechanochemistry appears to be a favored environment over solution.

Rapid Metabolization of Protectin D1 by β-Oxidation of Its Polar Head Chain.

Protectin D1 [neuroprotectin D1 (), PD1] has been proposed to play a key role in the resolution of inflammation. Aside from its ω-monohydroxylated metabolite, little has been reported on its metabolic fate. Upon incubation in HepG2 cells, liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the formation of two main metabolites, identified as and by comparison with standards obtained through demanding total chemical syntheses.

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.

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).

Deprotonative metallation of ferrocenes using mixed lithium-zinc and lithium-cadmium combinations.

A mixed lithium-cadmium amide and a combination of lithium and zinc amides were reacted with a range of ferrocenes; deprotonative mono- or dimetallation in general occurred chemoselectively at room temperature, as evidenced by subsequent quenching with iodine.