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

Valdez CA, Saavedra JE, Showalter BM, Davies KM, Wilde TC, Citro ML, Barchi JJ, Deschamps JR, Parrish D, El-Gayar S, Schleicher U, Bogdan C, Keefer LK - J. Med. Chem. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.

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.

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Related in: MedlinePlus

Nitrite yields as a reflection of NO generation on incubating 5a, 9a, and 9b in PBS, in cell culture medium containing 2.5% fetal calf serum, or in the serum-containing medium while being used to culture macrophages for 24 h at 37 °C. When the glycoside solutions were assayed immediately after they were dissolved, no nitrite was detected using the Griess test. Data shown are mean values of triplicates. Standard deviations were <5%. Shown is one of two comparable experiments.
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fig2: Nitrite yields as a reflection of NO generation on incubating 5a, 9a, and 9b in PBS, in cell culture medium containing 2.5% fetal calf serum, or in the serum-containing medium while being used to culture macrophages for 24 h at 37 °C. When the glycoside solutions were assayed immediately after they were dissolved, no nitrite was detected using the Griess test. Data shown are mean values of triplicates. Standard deviations were <5%. Shown is one of two comparable experiments.

Mentions: The relatively high susceptibility of GlcNAc derivative 9a to hydrolysis at pH 7.4 was confirmed by following the accumulation of the nitric oxide auto-oxidation product, nitrite ion, in both phosphate-buffered saline (PBS) and cell culture medium containing 2.5% fetal calf serum. As shown in Figure 2, there was little difference between the PBS and culture medium results, with each one engendering cleavage of 9a to NO and thence to nitrite in 10−20% recovery during a 24 h incubation. By contrast, mannose derivative 5a generated little or no nitrite under the same conditions.


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

Valdez CA, Saavedra JE, Showalter BM, Davies KM, Wilde TC, Citro ML, Barchi JJ, Deschamps JR, Parrish D, El-Gayar S, Schleicher U, Bogdan C, Keefer LK - J. Med. Chem. (2008)

Nitrite yields as a reflection of NO generation on incubating 5a, 9a, and 9b in PBS, in cell culture medium containing 2.5% fetal calf serum, or in the serum-containing medium while being used to culture macrophages for 24 h at 37 °C. When the glycoside solutions were assayed immediately after they were dissolved, no nitrite was detected using the Griess test. Data shown are mean values of triplicates. Standard deviations were <5%. Shown is one of two comparable experiments.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2574667&req=5

fig2: Nitrite yields as a reflection of NO generation on incubating 5a, 9a, and 9b in PBS, in cell culture medium containing 2.5% fetal calf serum, or in the serum-containing medium while being used to culture macrophages for 24 h at 37 °C. When the glycoside solutions were assayed immediately after they were dissolved, no nitrite was detected using the Griess test. Data shown are mean values of triplicates. Standard deviations were <5%. Shown is one of two comparable experiments.
Mentions: The relatively high susceptibility of GlcNAc derivative 9a to hydrolysis at pH 7.4 was confirmed by following the accumulation of the nitric oxide auto-oxidation product, nitrite ion, in both phosphate-buffered saline (PBS) and cell culture medium containing 2.5% fetal calf serum. As shown in Figure 2, there was little difference between the PBS and culture medium results, with each one engendering cleavage of 9a to NO and thence to nitrite in 10−20% recovery during a 24 h incubation. By contrast, mannose derivative 5a generated little or no nitrite under the same conditions.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.

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.

Show MeSH
Related in: MedlinePlus