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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.Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions.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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Chemiluminescence trace showing the time course of NO release from 0.39 µM 9a at 37 °C in 50 mM citrate buffer (pH 5.0) with 1.6 µg/mL of jack bean β-N-acetylglucosaminidase.
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fig4: Chemiluminescence trace showing the time course of NO release from 0.39 µM 9a at 37 °C in 50 mM citrate buffer (pH 5.0) with 1.6 µg/mL of jack bean β-N-acetylglucosaminidase.

Mentions: The above results suggested that the macrophages may harbor factors capable of accelerating the conversion of glycosides 9a and especially 9b to NO. As one possibility, Wu, et al. have reported on the rapid enzymatic cleavage of 5b and certain other diazeniumdiolated carbohydrates by the corresponding glycosidases.(8) To determine whether N-acetylglucosamine derivatives 9a and 9b are similarly susceptible, we incubated them with N-acetylglucosaminidases isolated from jack bean and from human placenta. As summarized in Table 3, both enzymes hydrolyzed both substrates with rates and efficiencies that were comparable to those of the reference compound, 1-(p-nitrophenyl)-2-deoxy-2-(N-acetyl)-β-d-glucosamine. The time course of NO release in a typical hydrolysis is illustrated in Figure 4. Negligible NO generation was seen in a parallel incubation of mannose derivative 5a, which was not expected to be hydrolyzed by an N-acetylglucosaminidase.


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)

Chemiluminescence trace showing the time course of NO release from 0.39 µM 9a at 37 °C in 50 mM citrate buffer (pH 5.0) with 1.6 µg/mL of jack bean β-N-acetylglucosaminidase.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig4: Chemiluminescence trace showing the time course of NO release from 0.39 µM 9a at 37 °C in 50 mM citrate buffer (pH 5.0) with 1.6 µg/mL of jack bean β-N-acetylglucosaminidase.
Mentions: The above results suggested that the macrophages may harbor factors capable of accelerating the conversion of glycosides 9a and especially 9b to NO. As one possibility, Wu, et al. have reported on the rapid enzymatic cleavage of 5b and certain other diazeniumdiolated carbohydrates by the corresponding glycosidases.(8) To determine whether N-acetylglucosamine derivatives 9a and 9b are similarly susceptible, we incubated them with N-acetylglucosaminidases isolated from jack bean and from human placenta. As summarized in Table 3, both enzymes hydrolyzed both substrates with rates and efficiencies that were comparable to those of the reference compound, 1-(p-nitrophenyl)-2-deoxy-2-(N-acetyl)-β-d-glucosamine. The time course of NO release in a typical hydrolysis is illustrated in Figure 4. Negligible NO generation was seen in a parallel incubation of mannose derivative 5a, which was not expected to be hydrolyzed by an N-acetylglucosaminidase.

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.Moreover, cleaving the acid-stable glycosides under alkaline conditions provides a convenient protecting group strategy for diazeniumdiolate ions.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