We designed and synthesized the molecular framework of 3,5-disubstituted isoxazoles containing privileged substructures with various substituents which uniquely display polar surface area in a diverse manner. A library of 3,5-disubstituted isoxazoles were systematically prepared via 1,3-dipolar cycloaddition of alkynes with nitrile oxides prepared by two complementary synthetic routes; method A utilized a halogenating agent with a base and method B utilized a hypervalent iodine reagent. Through the biological evaluation of corresponding isoxazoles via three independent phenotypic assays, the different pattern of biological activities was shown according to the type of privileged substructure and substituent. These results demonstrated the significance of molecular design via introducing privileged substructures and various substituents to make a diverse arrangement of polar surface area within a similar 3-dimensional molecular framework.
A new fluorescent core skeleton containing pyrazolo[1,5-a]pyridine-fused pyrimidine, called fluoremidine (FD), was discovered. FD analogues were prepared via a one-pot silver-catalyzed cascade cyclization. An N,N-dimethylamino group at the R(1)- and R(2)-positions plays important roles in controlling fluorescence brightness and emission wavelength. An N-acetyl group at the R(3) position contributes to red shifting of the emission wavelength. FD shows excellent solvatochromism with turn-on fluorescence in the lipophilic environment, which was utilized to design a fluorescent probe, FD13, for visualizing lipid droplets in living cells.
α-Galactosylceramide (α-GalCer) is a typical antigen for invariant natural killer T cells that are a subset of T cells and play critical roles in regulating immune responses. To selectively induce the secretion of certain cytokines via introducing hydrogen-bonding interaction with polar amino acid residues in the binding pocket of CD1d, a series of α-GalCer analogues with diether moiety in the acyl chain were designed and synthesized. The subsequent in vitro biological evaluation of these analogues revealed the structure−activity relationship for the selective IL-17 secretion. Analogues 5 and 6 induced the significantly increased IL-17 secretion over other cytokines, suggesting protective effects against pathogens. In contrast, analogue 7 showed the highly reduced IL-17 secretion, which may indicate potential anti-inflammatory effects.
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