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

[Image: see text] Glycosylated diazeniumdiolates of structure R(2)NN(O)=NO−R′ (R′ = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R(2)NN(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 R(2)NN(O)=NO−GlcNAc (where R(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.