Online citations, reference lists, and bibliographies.
← Back to Search

Design, Synthesis, And Bioactivation Of O-Glycosylated Prodrugs Of The Natural Nitric Oxide Precursor N(ω)-Hydroxy-l-arginine.

Felix-A Litty, Julia Gudd, U. Girreser, B. Clement, D. Schade
Published 2016 · Chemistry, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
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.
This paper references
10.1039/c0ob01117g
Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): synthetic approaches and physicochemical characterization.
D. Schade (2011)
10.1002/ARDP.19943271208
Synthesis of 15Nω‐Hydroxy‐L‐arginine and ESR and 15N‐NMR Studies for the Elucidation of the Molecular Mechanism of Enzymic Nitric Oxide Formation from L‐Arginine
B. Clement (1994)
10.3109/14756366.2011.573480
Designing modulators of dimethylarginine dimethylaminohydrolase (DDAH): A focus on selectivity over arginase
J. Kotthaus (2012)
10.1038/sj.bjp.0706458
The discovery of nitric oxide and its role in vascular biology
S. Moncada (2006)
10.1016/S0008-6215(00)00283-4
Anomalous Zemplén deacylation reactions of α- and β-D-mannopyranoside derivatives
Károly Ágoston (2001)
10.1016/j.pharmthera.2010.02.005
Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease.
D. Schade (2010)
N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.
D. Stuehr (1991)
10.1016/J.FREERADBIOMED.2004.06.031
Alternative nitric oxide-producing substrates for NO synthases.
D. Mansuy (2004)
10.1016/S0040-4039(01)01614-8
Expedient synthesis of aminooxylated-carbohydrates for chemoselective access of glycoconjugates
O. Renaudet (2001)
10.1246/BCSJ.36.1214
Studies of the Pyrimidine Derivatives. XXV. The Reaction of Alkoxycarbonylthiocyanates and Related Compounds with the Sodium Salt of Thiamine
TakamizawaAkira (1963)
10.1055/S-2008-1067165
Efficient Synthesis of OpticallyPure Nω-Alkylated l-Arginines
D. Schade (2008)
10.1124/dmd.107.016428
Human Enteric Microsomal CYP4F Enzymes O-Demethylate the Antiparasitic Prodrug Pafuramidine
M. Z. Wang (2007)
10.1006/BBRC.1994.2371
N omega-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase.
J. L. Boucher (1994)
10.1002/(SICI)1521-3773(19980605)37:10<1402::AID-ANIE1402>3.0.CO;2-6
Combinatorial Solid-Phase Synthesis of Structurally Complex Thiazolylhydantoines.
J. Stadlwieser (1998)
10.1111/bph.12559
The contribution of VEGF signalling to fostamatinib‐induced blood pressure elevation
M. Skinner (2014)
10.1111/j.1440-1681.2007.04638.x
ARGINASE: A CRITICAL REGULATOR OF NITRIC OXIDE SYNTHESIS AND VASCULAR FUNCTION
W. Durante (2007)
10.1002/ANIE.198404361
The Allyloxycarbonyl (Aloc) Moiety—Conversion of an Unsuitable into a Valuable Amino Protecting Group for Peptide Synthesis†
H. Kunz (1984)
10.1002/ANIE.197805221
Simple Method for the Esterification of Carboxylic Acids
B. Neises (1978)
10.1055/S-0035-1561303
An Efficient Synthesis of Optically Pure Nδ-Monomethylated l-Arginine and l-Ornithine
Felix-A. Litty (2016)
10.1016/J.NUMECD.2005.11.012
Endothelial dysfunction and oxidative stress in arterial hypertension.
P. Ferroni (2006)
10.1021/BI992992V
Recognition of alpha-amino acids bearing various C=NOH functions by nitric oxide synthase and arginase involves very different structural determinants.
C. Moali (2000)
10.1016/J.BMCL.2006.11.042
Synthesis and biological evaluation of the suberoylanilide hydroxamic acid (SAHA) beta-glucuronide and beta-galactoside for application in selective prodrug chemotherapy.
Mickaël Thomas (2007)
10.1021/JM060005S
Galactosyl derivatives of L-arginine and D-arginine: synthesis, stability, cell permeation, and nitric oxide production in pituitary GH3 cells.
D. Melisi (2006)
10.1016/J.NIOX.2006.03.011
Nitric oxide and atherosclerosis: an update.
C. Napoli (2006)
10.1042/BJ0830331
Almond-emulsin β-d-glucosidase and β-d-galactosidase
R. Heyworth (1962)
10.1021/BI00335A022
Reversible inhibitors of beta-glucosidase.
M. Dale (1985)
10.1021/AC9801723
Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins.
H. Kojima (1998)
10.1002/CBER.19851180905
15N‐NMR‐Studien an 2‐Hydroxyguanidinen und Amidoximen
B. Clement (1985)
10.1002/(SICI)1521-3773(19991102)38:21<3209::AID-ANIE3209>3.0.CO;2-6
Fluorescent Indicators for Imaging Nitric Oxide Production.
Kojima (1999)
10.1111/j.1751-7176.2008.06632.x
Vascular System: Role of Nitric Oxide in Cardiovascular Diseases
K. Bian (2008)



This paper is referenced by
Semantic Scholar Logo Some data provided by SemanticScholar