title: Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress.
abstract: Tissue deterioration and aging have long been associated with the accumulation of chemically induced protein and DNA damage. Reactive oxygen species (ROS) and reactive carbonyl species (RCS), especially alpha-dicarbonyl compounds, are key mediators of damage caused by oxidative stress, glycation, and UV-irradiation. The toxic effects of ROS are counteracted in vivo by antioxidants and antioxidant enzymes, and the deleterious effects of one RCS, methylglyoxal, are counteracted by a ubiquitous glyoxalase system. Carbonyl stress as a result of toxic effects of various mono-dicarbonyls (e.g. 4-hydroxynonenal) and alpha-dicarbonyls (e.g. glyoxal and deoxyosones) cannot be directly antagonized by antioxidants, and only a small number of biological carbonyl scavengers like glutathione (GSH) have been identified to date. We have developed a new screening method for the identification of carbonyl scavengers using a rapid glycation system that proceeds independent of oxygen and therefore, excludes identification of inhibitory compounds acting as antioxidants. Using this screening assay adapted to 96-well microtiter plates, we have identified the cysteine derivative 3,3-dimethyl-D-cysteine as a potent inhibitor of non-oxidative advanced glycation. Comparative kinetic analyses demonstrated the superior alpha-oxoaldehyde-scavenging activity of D-penicillamine over that of aminoguanidine. D-Penicillamine traps alpha-oxoaldehydes by forming a 2-acylthiazolidine derivative as shown by structure elucidation of reaction products between D-penicillamine and methylglyoxal or phenylglyoxal. We demonstrated that upon co-incubation, D-penicillamine protects human skin keratinocytes and fibroblasts (CF3 cells) against glyoxal- and methylglyoxal-induced carbonyl toxicity. Our research qualifies alpha-amino-beta-mercapto-beta,beta-dimethyl-ethane as a promising pharmacophore for the development of related alpha-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.forename: Daniel
authors.initials: D
authors.lastname: Cervantes-Laurean
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Roberts
authors.forename: Jaber G
authors.initials: JG
authors.lastname: Qasem
authors.forename: Moonsun
authors.initials: M
authors.lastname: Kim
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Jacobson
authors.forename: Myron K
authors.initials: MK
authors.lastname: Jacobson
mesh_terms: D002478:Cells, Cultured; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D006037:Glyoxal / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D010396:Penicillamine / Q000737:chemistry / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D006037:Glyoxal; D011765:Pyruvaldehyde; D010396:Penicillamine; C004479:pimagedine