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.
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Carlos A
CA
Valdez
Joseph E
JE
Saavedra
Brett M
BM
Showalter
Keith M
KM
Davies
Thomas C
TC
Wilde
Michael L
ML
Citro
Joseph J
JJ
Barchi
Jeffrey R
JR
Deschamps
Damon
D
Parrish
Stefan
S
El-Gayar
Ulrike
U
Schleicher
Christian
C
Bogdan
Larry K
LK
Keefer
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