The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
Ac hiral dinuclear zincc omplexc an effectively catalyse the direct aldol reactions of pyruvic acid ester with various chiral sugar aldehydes,t hus functionally mimicking the pyruvate-dependent type II aldolases.A pplication of sterically hindered aryl estersa llows for the elusive aldolr eactiono ft he pyruvate donor with controlled anti-selectivity en route to the shorta nd efficient synthesis of 3-deoxy-2-ulosonic acids.Pyruvic acid ester is here used as achemical equivalent of phosphoenol pyruvate (PEP) in imitation of the synthetic principle used in nature. Thep resented biomimetic methodologies use enol formation for the highly efficient and flexiblef ormation of various C 6 -C 9 ulosonic acids.Particularly,efficient and concise syntheses of 3-deoxy-d-erythrohex-2-ulosonica cid (KDG,o verall5 0% yield), 3-deoxy-d-ribo-hept-2-ulosonic acid (DRH, overall 53% yield) and3 -deoxy-d-glycero-d-talo-non-2-ulosonic acid (4-epi-KDN,o verall 78% yield) are described. This direct efficienta pplication of pyruvic estersd oes not require additional demasking steps and thus surpassess previously methodologies utilising masked pyruvic synthons such 2-acetylthiazole and pyruvic aldehyde dimethyl acetal.
Asymmetric hetero‐Diels‐Alder reactions of Danishefsky's diene and glyoxylate/pyruvate esters catalyzed by readily available zinc triflate complex with BOX ligand afforded the corresponding adduct which upon treatment with trifluoroacetic acid furnished the hetero‐Diels‐Alder product in 91 % enantiomeric excess and 87 % isolated yield. This reaction was applied to the concise synthesis of six‐membered ulosonic acid C‐glycoside.
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