Compounds that Combine Aldose Reductase Inhibitory Activity and Ability to Prevent the Glycation (Glucation and/or Fructation) of Proteins as Putative Pharmacotherapeutic Agents

Diabetes mellitus exacts a huge toll in money and human suffering. At its present rate of increase, within few decades it will be one of the world's commonest diseases and biggest public-health problem, with an estimated minimum of half-a-billion cases. The diabetic individual is prone to late onset complications that are largely responsible for the morbidity and mortality observed in the patients. It has been demonstrated that the more severe and sustained the degree of hyperglycaemia, the more likely it is that the chronic complications of diabetes will develop. Pharmaceutical intervention of hyperglycaemia-induced diabetic complications is actively pursued since it is very difficult to maintain normoglycaemia by any means in patients with diabetes mellitus. Aldose reductase enzyme (AR, ALR2, E.C. 1.1.1.21) of the polyol metabolic pathway was first found to be implicated in the aetiology of secondary complications of diabetes. AR inhibitors (ARIs) have therefore been noted as possible pharmacotherapeutic agents. Although several ARIs have progressed to the clinical level, only one is currently on the market. However, the inhibition of the polyol pathway is considered to be a promising approach to control diabetes complications as well as a number of other pathological conditions like ischemia, abnormal vascular smooth muscle cell proliferation, cancers, and mood disorders. Thus, attention is currently targeted to discover ARIs of distinct chemical structures, being derivatives of neither hydantoin nor carboxylic acid, which are known to cause either toxicity, or posses narrow spectrum of tissue activity. Glucose and, especially, fructose can react with proteins to form alpha keto-amines via Amadori rearrangements. This can lead, through Maillard type reactions, to advanced glycation end products (AGEs) and damage of proteins. Glucose and fructose can undergo transition metal catalyzed oxidations, which contribute to acceleration of modifications in the tissues. AGEs thus formed by the above mentioned non-enzymatic reactions between monosaccharides and proteins, have been implicated as a major pathogenesis process leading, for example, to diabetic complications, atherosclerosis, Alzheimer's disease and Creutzfeldt-Jakob disease. In the present review, the data that will be presented will aim to support the notion that compounds which combine aldose reductase inhibitory activity and ability to prevent the glycation of proteins posses' pharmacotherapeutic potential.