Abstract
Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.
Highlights
Diabetes mellitus (DM) is a worldwide health problem affecting approximately 415 millions of people and is expected that this number will grow rapidly in the two decades[1]
The enzyme catalyses the NADPH-dependent reduction of glucose to sorbitol which is subsequently oxidised to fructose by sorbitol dehydrogenase (SDH) through a NADþ dependent reaction
As a continuation of our recent results aimed at searching new potential ALR2 inhibitors[15] from these 1,5-dicarbonyl substrates, we studied their reaction with O-(arylmethyl)hydroxylamines hydrochlorides (Figure 3)
Summary
Diabetes mellitus (DM) is a worldwide health problem affecting approximately 415 millions of people and is expected that this number will grow rapidly in the two decades[1]. On the contrary, in cells where glucose up-take is independent of insulin, ALR2 operates the conversion of glucose into sorbitol leading to an accumulation of intracellular sorbitol This determines an alteration of the osmolality and the oxidative stress with consequent production of reactive oxygen species (ROS) able of triggering ischaemic and inflammatory processes responsible for diabetic complications. Fructose phosphorylation can lead to the formation of AGE (Advanced Glycation End-products) and the subsequent binding of AGEs to their receptors can lead to ROS production Based on these considerations, reduction of the polyol pathway by the inhibition of the aldose reductase has long been considered a valid strategy to counteract or at least delay the onset of diabetic complications
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