Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress.
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.
Wondrak
Georg T
GT
Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Cervantes-Laurean
Daniel
D
Roberts
Michael J
MJ
Qasem
Jaber G
JG
Kim
Moonsun
M
Jacobson
Elaine L
EL
Jacobson
Myron K
MK
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
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D006037:Glyoxal; D011765:Pyruvaldehyde; D010396:Penicillamine; C004479:pimagedine