ABSTRACT
[reaction: see text]. A library of potential bisubstrate analogue inhibitors (1) targeting sulfotransferase enzymes was generated by the chemoselective ligation of the PAPS mimic 2 with a panel of 447 aldehydes. Preliminary screening has identified compounds that inhibit estrogen sulfotransferase (EST), an enzyme relevant to breast cancer.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Sulfotransferases/antagonists & inhibitors , Aldehydes/chemistry , Enzyme Inhibitors/chemistry , Phosphoadenosine Phosphosulfate/chemistry , Substrate SpecificityABSTRACT
[reaction: see text] Here we report a novel modification of our previously reported "Staudinger ligation" that generates an amide bond from an azide and a specifically functionalized phosphine. This method for the selective formation of an amide bond, which does not require the orthogonal protection of distal functional groups, should find general utility in synthetic and biological chemistry.
Subject(s)
Amides/chemical synthesis , Amides/chemistry , Chromatography, High Pressure Liquid , Indicators and Reagents , Molecular ConformationABSTRACT
Sulfated biomolecules regulate a diverse array of normal and pathological cellular communication events. The participation of these bioconjugates in a variety of disease states has sparked interest in the enzyme class that installs the sulfate esters: the sulfotransferases. Recent advances in the cloning and characterization of sulfotransferase enzymes and our understanding of the role of sulfated biomolecules in disease states have prompted the search for specific sulfotransferase inhibitors. Evidence for the participation of sulfated carbohydrates and proteins in acute and chronic inflammation, tumor progression and microbial pathogenesis is presented herein, followed by a discussion of sulfotransferase mechanism and approaches to inhibiting sulfotransferase activity.
