A nonhydrolyzable analogue of phosphotyrosine, and related aryloxymethano- and aryloxyethano-phosphonic acids as motifs for inhibition of phosphatases

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 23; pp. 5931 - 5935
• Main Authors: Iyer, Subashree, Younker, Jarod M., Czyryca, Przemyslaw G., Hengge, Alvan C.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.12.2004; Elsevier
• Subjects: Biological and medical sciences; Inhibition; Medical sciences; Miscellaneous; Organophosphonates - chemistry; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Phosphatase; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Phosphotyrosine - analogs & derivatives; Phosphotyrosine - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Substrate analogue; Phosphatase; Substrate analogue; Inhibition; Alkaline phosphatase; Stereoisomer; Ether; Enzyme; Mimetic; Active site; Yersinia; Phosphonic acids; Enzyme inhibitor; Phosphoric monoester hydrolases; Esterases; Competitive inhibition; Biological activity; Phosphorus Organic compounds; Organic sulfide; Substrate; Bacteria; Hydrolases; Aromatic compound; Chemical synthesis; Enterobacteriaceae; Protein-tyrosine-phosphatase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.09.008

[Display omitted] Nonhydrolyzable analogues of both stereoisomers of phosphotyrosine, and a series of related aryloxy (or thio) methyl and aryloxy (or thio) ethyl phosphonic acids of the general formula RX–(CH 2) n –PO 3H 2 (where X = O or S and n = 1 or 2), have been tested as nonhydrolyzable mimetics of phosphatase substrates. These compounds were tested against a panel of phosphatases (two alkaline phosphatases, a protein–tyrosine phosphatase, and two serine/threonine phosphatases) with different active site motifs. The compounds exhibit competitive inhibition toward all enzymes tested, with the best inhibition expressed toward the Ser/Thr phosphatases. The stereoisomers of the phosphotyrosine analogues exhibited an unexpected difference in their inhibitory properties toward the protein–tyrosine phosphatase from Yersinia. The K i for the d isomer is 33-fold lower than that of the l isomer, and is more than an order of magnitude lower than the reported K m of the substrate l-phosphotyrosine.