title: Design, Synthesis, and Bioactivation of O-Glycosylated Prodrugs of the Natural Nitric Oxide Precursor N(ω)-Hydroxy-l-arginine.
abstract: Naturally occurring N(ω)-hydroxy-l-arginine (NOHA, 1) is the best substrate of NO synthases (NOS). The development of stable and bioavailable prodrugs would provide a pharmacologically valuable strategy for the treatment of cardiovascular diseases that are associated with endothelial dysfunction. To improve NOHAs druglike properties, we demonstrate that O-substitution by (glycosylic) acetal formation greatly increased the chemical stability of the hydroxyguanidine moiety and provided a nontoxic group that could be easily bioactivated by glycosidases. A straightforward synthetic concept was devised and afforded a series of diversely substituted prodrugs by O-conjugation of the hydroxyguanidine moiety with different monosaccharides. Systematic exploration of their bioactivation profile revealed that glucose-based prodrugs were more efficiently bioactivated than their galactose counterparts. NOS-dependent cytosolic NO release was quantified by automated fluorescence microscopy in a cell-based assay with murine macrophages. Glucose-based prodrugs performed particularly well and delivered cellular NO levels comparable to 1, demonstrating proof-of-concept.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Felix-A
authors.initials: FA
authors.lastname: Litty
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Gudd
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Girreser
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, 24118 Kiel, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
authors.affiliation: Department of Chemistry and Chemical Biology, TU Dortmund , Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D005690:Galactose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006031:Glycosylation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020030:Nitric Oxide Donors; D011355:Prodrugs; D009569:Nitric Oxide; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D005947:Glucose; D005690:Galactose