Synthesis and biological activity of N-sulfonylphosphoramidates: probing the electrostatic preferences of alkaline phosphatase.
N-Sulfonylphosphoramidates have been synthesized to investigate the electrostatic requirements for binding to alkaline phosphatase. Alkyl- and aryl N-benzylated sulfonamides were phosphorylated with bromophosphates or synthesized via phosphoramidite chemistry in moderate yields (44-77%.) The resulting tribenzylated N-sulfonylphosphoramidates may be deprotected in one step to give the free acids in quantitative yields. Physical data of N-sulfonylphosphoramidates, including pK(a)'s and stability toward hydrolysis, were determined. Inhibition data suggests that AP does not bind trianionic N-sulfonylphosphoramidates better than dianionic N-sulfonylphosphoramidates, although N-sulfonylphosphoramidates are bound tighter than N-phenylphosphoramidate. k(cat) for the hydrolysis of N-sulfonylphosphoramidates by bovine and E. coli alkaline phosphatases is 10-60% that of p-nitrophenyl phosphate.
Burlingham
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Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Widlanski
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D000469:Alkaline Phosphatase / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D004926:Escherichia coli / Q000201:enzymology; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D027805:Phaseolus / Q000201:enzymology; D055672:Static Electricity; D013379:Substrate Specificity; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
D001593:Benzyl Compounds; D010755:Organophosphates; D013449:Sulfonamides; D000469:Alkaline Phosphatase