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

Glycosylated diazeniumdiolates of structure R sub(2)NN(O)=NOaRa2 (Ra2 = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R sub(2)NN(O)=NO super(a) 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 3.8a4.6 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 R sub(2)NN(O)=NOaGlcNAc (where R sub(2)N = 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.