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Novel inhibitors of advanced glycation endproducts

Communicated by Monnier
https://doi.org/10.1016/j.abb.2003.08.009Get rights and content

Abstract

A number of natural or synthetic compounds as AGE inhibitors have been proposed, discovered or currently being advanced by others and us. We have identified two new classes of aromatic compounds; aryl- (and heterocyclic) ureido and aryl (and heterocyclic) carboxamido phenoxyisobutyric acids, and benzoic acid derivatives and related compounds, as potential inhibitors of glycation and AGE formation. Some of these novel compounds also showed “AGE-breaking” activities in vitro. Current evidence is that chelation of transition metals and/or trapping or indirect inhibition of formation of reactive carbonyl compounds are involved in the mechanisms of action of these novel AGE inhibitors and breakers. Here, we review the inhibitors of glycation and AGE-breakers published to date and present the results of our in vitro and in vivo investigations on a number of these novel AGE inhibitors. These AGE-inhibitors and AGE-breakers may find therapeutic use in the treatment of diseases that AGE formation and accumulation may be responsible for their pathogenesis such as diabetes, Alzheimer’s, rheumatoid arthritis, and atherosclerosis.

Section snippets

Oxidative stress

…It would appear that life originated as a result of free radical reactions (FRRs), selected FRRs to play major metabolic roles, and used them to provide for aging, mutation, and death, thereby assuring evolution. Further, life span evolved in parallel with the ability of organisms to cope with damaging free radical reactions. In short, the origin and evolution of life may be due to free radical reactions and, in particular, to their ability to induce random change. If so, it is remarkable that

Glycation

Glycation is a spontaneous non-enzymatic amino-carbonyl reaction between reducing sugars and long-lived proteins and lipids that are a major form of chemical modifications of biomolecules that compromise their function. These chemical damages are detectable in the form of advanced glycation and lipoxidation endproducts (AGE, ALE); amino acids modified by ROS, chlorine, and nitrogen; and racemized amino acids [38]. Glycation is a major source of ROS and reactive α-dicarbonyl intermediates that

Carbonyl stress

Carbonyl stress (Fig. 2) is an imbalance of reactive carbonyl species (RCS) production and carbonyl scavening mechanisms that originate from a multitude of mechanistically related pathways, like glycation [10], [51], [52], autooxidation of sugars [53], amino acid metabolism [51], lipid peroxidation [54], and UV damage [49]. An important step in the glycation reactions is the generation of reactive intermediate products in the course of all stages and pathways of glycation. These compounds are

Natural defense mechanism against AGE and cell signaling pathways

Nature has devised several humoral and cellular defense mechanisms to protect tissues from deleterious effects of carbonyl stress and accumulation of AGE. These include the glyoxylase system (I and II) and aldose reductase that catalyze the deglycation of methylglyoxal (MG), the most common reactive intermediates of AGE to d-lactate [66], [74]. Additionally, a novel class of enzymes found in Aspergillus called amadoriases was found to catalyze the deglycation of Amadori products [75]. Most

Dietary antioxidants

A dietary antioxidant can be defined as “a substance in food that significantly decrease the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans”[13]. Antioxidant compounds such as vitamin C, vitamin E (α-tocopherol and the carotenoids including α-carotene, β-carotene, β-cryptoxantin, lutein, lycopene, and zeaxanthine) have been shown to have vascular-related effects that prevent or reverse nerve conduction velocity (NCV)

Synthetic and natural AGE-inhibitors

Historically, nearly a century ago, high-dose salicylate treatment was found to reduce the glycosuria in diabetic patients [95]. The amino acid lysine and N-acetyllysine also demonstrated beneficial effects in reducing albuminuria in diabetic subjects [96]. However, the first compound which has been extensively studied in vitro and in vivo to be a powerful inhibitor of AGE formation is aminoguanidine [97]. In the original study, aminoguanidine inhibited the cross-linking and fluorescence of

Novel AGE-inhibitors

In the past seven years, our laboratory in collaboration with Dr. I. Lalezari, an organic chemist at Chemiphar, New York, has been involved in the design and synthesis of compounds with possible AGE inhibitory effects. These aromatic compounds, mostly derivatives of aryl (and heterocyclic) ureido, and aryl (and heterocyclic) carboxaminido phenoxy isobutyric acids, were screened and evaluated using several well-established in vitro assay methods. Drug candidates examined in this screen were

Conclusion

There is a considerable body of evidence implicating formation and accumulation of advanced glycation end products as a major factor in the development of diabetic complications, atherosclerosis, Alzheimer’s disease, and the normal aging process. The significance of this phenomenon becomes more evident where tight association of lipoxidation reactions, over-production of reactive oxygen species (oxidant stress), and over-generation of RCS (carbonyl-stress) with the process of AGE formation are

Acknowledgements

This work was supported in part by research grants from R.W. Johnson Pharmaceutical Research Institute and the Ella Fitzgerald Charitable Foundation. The authors are grateful to Eileen Sepulveda for preparation of the manuscript.

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