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Hydrolytic reactivity trends among potential prodrugs of the O2-glycosylated diazeniumdiolate family. Targeting nitric oxide to macrophages for antileishmanial activity.

ABSTRACT: Glycosylated diazeniumdiolates of structure R 2NN(O)NO-R' (R' = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R 2NN(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 2NN(O)NO-GlcNAc (where R 2N = 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.

SUBMITTER: Valdez CA

PROVIDER: S-EPMC2574667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cell-permeable esters of diazeniumdiolate-based nitric oxide prodrugs.

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Project description:Nitric oxide (NO)-releasing xerogel materials were synthesized using N-diazeniumdiolate-modified silane monomers that were subsequently co-condensed with an alkoxysilane. The NO-release characteristics were tuned by varying the aminosilane structure and concentration. The resulting materials exhibited maximum NO release totals and durations ranging from 0.45-3.2 μmol cm(-2) and 20-90 h, respectively. The stability of the xerogel networks was optimized by varying the alkoxysilane backbone identity, water to silane ratio, base catalyst concentration, reaction time, and drying conditions. The response of glucose biosensors prepared using the NO-releasing xerogel (15 mol % N-diazeniumdiolate-modified N-2-(aminoethyl)-aminopropyltrimethoxysilane) as an outer sensor membrane was linear (R(2) = 0.979) up to 24 mM glucose. The sensitivity (3.4 nA mM(-1)) of the device to glucose was maintained for 7 days in phosphate buffered saline. The facile sol-gel synthetic route, along with the NO release and glucose biosensor characteristics, demonstrates the versatility of this method for biosensor membrane applications.

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