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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

  1. Author:
    Valdez, C. A.
    Saavedra, J. E.
    Showalter, B. M.
    Davies, K. M.
    Wilde, T. C.
    Citro, M. L.
    Barchi, J. J.
    Deschamps, J. R.
    Parrish, D.
    El-Gayar, S.
    Schleicher, U.
    Bogdan, C.
    Keefer, L. K.

  2. Author Address

    Valdez, Carlos A.; Showalter, Brett M.; Wilde, Thomas C.; Keefer, Larry K.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Saavedra, Joseph E.; Citro, Michael L.] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. [Davies, Keith M.] George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. [Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Frederick, MD 21702 USA. [Deschamps, Jeffrey R.; Parrish, Damon] USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. [El-Gayar, Stefan, Schleicher, Ulrike, Bogdan, Christian] Univ Klinikum Erlangen, Mikrobiol Inst Klin Mikrobiol Immunol & Hyg, D-91054 Erlangen, Germany. [Schleicher, Ulrike, Bogdan, Christian] Univ Freiburg Klinikum, Abt Mikrobiol & Hyg, Inst Med Mikrobiol & Hyg, D-79104 Freiburg, Germany.
    1. Year: 2008
  2. Journal: Journal of Medicinal Chemistry
    1. 51
    2. 13
    3. Pages: 3961-3970
  4. Type of Article: Article
  1. Abstract:

    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-1-yl and GlcNAc = N-acetylglucosamin-1-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.

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External Sources

  1. PMID: 18533711

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