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Hydrolytic Reactivity Trends among Potential Prodrugs of the O 2 -Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity

2008; American Chemical Society; Volume: 51; Issue: 13 Linguagem: Inglês

10.1021/jm8000482

1520-4804

Carlos A. Valdez, Joseph E. Saavedra, Brett M. Showalter, Keith M. Davies, Thomas Wilde, Michael L. Citro, Joseph J. Barchi, Jeffrey R. Deschamps, Damon A. Parrish, Stefan El-Gayar, Ulrike Schleicher, Christian Bogdan, Larry K. Keefer,

Trypanosoma species research and implications

Glycosylated diazeniumdiolates of structure R2NN(O)═NO−R′ (R′ = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)═NO− ion. Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8−4.6 as background for further developing both the protecting group application and the ability to target NO pharmacologically to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)═NO−GlcNAc (where R2N = diethylamino or pyrrolidin-l-yl and GlcNAc = N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity.