Hydrolytic reactivity trends among potential prodrugs of the O2-glycosylated diazeniumdiolate family. Targeting nitric oxide to macrophages for antileishmanial activity.
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.
Valdez
Carlos A
CA
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Saavedra
Joseph E
JE
Showalter
Brett M
BM
Davies
Keith M
KM
Wilde
Thomas C
TC
Citro
Michael L
ML
Barchi
Joseph J
JJ
Deschamps
Jeffrey R
JR
Parrish
Damon
D
El-Gayar
Stefan
S
Schleicher
Ulrike
U
Bogdan
Christian
C
Keefer
Larry K
LK
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry; D018360:Crystallography, X-Ray; D006031:Glycosylation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D018320:Leishmania major; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis*; D010100:Oxygen / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D001391:Azo Compounds; D002241:Carbohydrates; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D010100:Oxygen