title: 5'-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls.
abstract: Pyridoxamine (PM) is a prospective drug for the treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of nonionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side chain of arginine, alkyl-PMs were shown to be more effective than PM in reducing the modification of N-α-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.
authors.affiliation: †Department of Pathology, Microbiology and Immunology, ‡Division of Clinical Pharmacology, §Department of Medicine, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.affiliation: †Department of Pathology, Microbiology and Immunology, ‡Division of Clinical Pharmacology, §Department of Medicine, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Amarnath
authors.affiliation: †Department of Pathology, Microbiology and Immunology, ‡Division of Clinical Pharmacology, §Department of Medicine, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Avance
authors.affiliation: †Department of Pathology, Microbiology and Immunology, ‡Division of Clinical Pharmacology, §Department of Medicine, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Stec
authors.affiliation: †Department of Pathology, Microbiology and Immunology, ‡Division of Clinical Pharmacology, §Department of Medicine, and ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
mesh_terms: D055162:Biocatalysis; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D009113:Muramidase / Q000378:metabolism; D011733:Pyridoxamine / Q000138:chemical synthesis / Q000737:chemistry*; D011765:Pyruvaldehyde / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D005609:Free Radicals; D008565:Membrane Proteins; D011733:Pyridoxamine; D011765:Pyruvaldehyde; D006735:Horseradish Peroxidase; D013482:Superoxide Dismutase; D009113:Muramidase; D005947:Glucose