Activation of prostanoid
EP2 receptor exacerbates neuroinflammatory
and neurodegenerative pathology in central nervous system diseases
such as epilepsy, Alzheimer’s disease, and cerebral aneurysms.
A selective and brain-permeable EP2 antagonist will be useful to attenuate
the inflammatory consequences of EP2 activation and to reduce the
severity of these chronic diseases. We recently developed a brain-permeable
EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory
and neuroprotective actions in rodent models of status epilepticus.
However, this compound exhibited moderate selectivity to EP2, a short
plasma half-life in rodents (1.7 h) and low aqueous solubility (27
μM), limiting its use in animal models of chronic disease. With
lead-optimization studies, we have developed several novel EP2 antagonists
with improved water solubility, brain penetration, high EP2 potency,
and selectivity. These novel inhibitors suppress inflammatory gene
expression induced by EP2 receptor activation in a microglial cell
line, reinforcing the use of EP2 antagonists as anti-inflammatory
agents.
We previously described a new organocatalytic oxidation-reduction-condensation for amide/peptide construction. The reaction system relies on triethylphosphite as the stoichiometric reductant and organocatalytic benzoisothiazolone/O in air as the oxidant. The reaction was assumed to generate catalytic quantities of S-acylthiosalicylamides as electrophiles, which are rapidly intercepted by amine reactants to generate amides/peptides and o-mercaptobenzamides. The latter are then gently reoxidized to the benzoisothiazolones under Cu-catalyzed aerobic conditions to complete the catalytic cycle. To gain a mechanistic understanding, we describe herein our studies of the stoichiometric generation of S-acylthiosalicylamides under oxidation-reduction-condensation conditions from a variety of benzoisothiazolones and carboxylic acids using triethylphosphite as the terminal reductant. These studies have revealed the presence of more than one reaction pathway when benzoisothiazolones react with triethylphosphite (including a rapid, direct deoxygenation of certain classes of benzoisothiazolones by triethylphosphite) and allow the identification of optimal reaction characteristics (benzoisothiazolone structure and solvent) for the generation of thioesters. These explorations will inform our efforts to develop highly effective and robust organocatalytic oxidation-reduction-condensation reactions that are based on the benzoisothiazolone and related motifs.
International audienceAn efficient and eco-friendly method for the synthesis of substituted pyrroles has been developed via ruthenium-catalyzed multicomponent reaction of ketone, amine, and ethylene glycol in PEG-400 as solvent medium without using any external ligand. The catalytic system and solvent can be recycled with the same, as well as different, ketones with minimum loss of Ru-catalyst activity
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