Aldose Reductase Inhibitory Compounds from Xanthium strumarium

As part of our ongoing search for natural sources of therapeutic and preventive agents for diabetic complications, we evaluated the inhibitory effects of components of the fruit of Xanthium strumarium (X. strumarium) on aldose reductase (AR) and galactitol formation in rat lenses with high levels of glucose. To identify the bioactive components of X. strumarium, 7 caffeoylquinic acids and 3 phenolic compounds were isolated and their chemical structures were elucidated on the basis of spectroscopic evidence and comparison with published data. The abilities of 10 X. strumarium-derived components to counteract diabetic complications were investigated by means of inhibitory assays with rat lens AR (rAR) and recombinant human AR (rhAR). From the 10 isolated compounds, methyl-3,5-di-O-caffeoylquinate showed the most potent inhibition, with IC₅₀ values of 0.30 and 0.67 μM for rAR and rhAR, respectively. In the kinetic analyses using Lineweaver–Burk plots of 1/velocity and 1/substrate, methyl-3,5-di-O-caffeoylquinate showed competitive inhibition of rhAR. Furthermore, methyl-3,5-di-O-caffeoylquinate inhibited galactitol formation in the rat lens and in erythrocytes incubated with a high concentration of glucose, indicating that this compound may be effective in preventing diabetic complications.     

Development of potent aldose reductase inhibitors having a hydantoin structure

Seventeen hydantoin derivatives were tested as inhibitors of aldose reductase, an enzyme believed to participate in the initiation of diabetic complications. Nine compounds with high inhibitory activities (IC50 values against purified rat lens aldose reductase less than or equal to 1.06 X 10(-6)M) were tested further for their abilities to prevent sorbitol accumulation induced by exposure of excised rat lens and sciatic nerve to a high glucose concentration (50 mM). Seven active compounds among them inhibited sorbitol accumulation by about 50% or more at a concentration of 10(-5)M. These seven compounds were given orally to streptozotocin-induced diabetic rats at a dose of 50 mg/kg/day and were assessed for their abilities to prevent both sorbitol accumulation in two tissues (lens and sciatic nerve) and myo-inositol depletion in the sciatic nerve. 1-[(2,4,5-Trichlorophenyl)sulfonyl]hydantoin, 1-[(2,5-dichlorophenyl)sulfonyl]hydantoin, and 1-[(beta-naphthyl)sulfonyl]hydantoin were found to be the most effective: they inhibited sorbitol accumulation in the sciatic nerve completely and that in the lens by more than 92%. It is conceivable from this study that the three compounds are promising for further investigation targeted to the treatment of diabetic complications.     

Potential use of aldose reductase inhibitors to prevent diabetic complications

Reviewed are (1) the biochemical basis and pathophysiology of diabetic complications and (2) the structure-activity relationships, pharmacology, pharmacokinetics, clinical trials, and adverse effects of aldose reductase inhibitors (ARIs). ARIs are a new class of drugs potentially useful in preventing diabetic complications, the most widely studied of which have been cataracts and neuropathy. ARIs inhibit aldose reductase, the first, rate-limiting enzyme in the polyol metabolic pathway. In nonphysiological hyperglycemia the activity of hexokinase becomes saturated while that of aldose reductase is enhanced, resulting in intracellular accumulation of sorbitol. Because sorbitol does not readily penetrate the cell membrane it can persist within cells, which may lead to diabetic complications. ARIs are a class of structurally dissimilar compounds that include carboxylic acid derivatives, flavonoids, and spirohydantoins. The major pharmacologic action of an ARI involves competitive binding to aldose reductase and consequent blocking of sorbitol production. ARIs delay cataract formation in animals, but the role of aldose reductase in cataract formation in human diabetics has not been established. The adverse effects of ARIs include hypersensitivity reactions. Although the polyol pathway may not be solely responsible for diabetic complications, studies suggest that therapy with ARIs could be beneficial. Further research is needed to determine the long-term impact and adverse effects of ARIs in the treatment of diabetic complications.     

Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues

Aldose reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of aldose reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of aldose reductase from the rhizomes of Belamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens aldose reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong aldose reductase inhibition. Tectoridin and tectorigenin, exhibited the highest aldose reductase inhibitory potency, their IC50 values, being 1.08 x 10(-6) M and 1.12 x 10(-6) M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.     

Inhibition of sorbitol formation in human erythrocytes by calcium dobesilate

The effects of calcium dobesilate (Doxium, a drug already known to prevent or reverse the retinal microvascular lesions of diabetes mellitus) on sorbitol formation in human erythrocytes was studied, and compared with the effects of tetramethylene glutaric acid (TMGA), a specific aldose reductase inhibitor. Both compounds inhibited sorbitol formation. In a 29 mmol/l glucose medium, calcium dobesilate in concentrations of 2 and 10 mmol/l caused, 50 and 100% inhibition of sorbitol formation, respectively, whereas TMGA completely inhibited sorbitol formation at a concentration of 0.1 mmol/l. These results suggest that calcium dobesilate may exert, at least in part, its beneficial effect on diabetic microangiopathy by inhibiting the formation of sorbitol. The inhibition of sorbitol synthesis may be mediated by an inhibitory action of calcium dobesilate on aldose reductase.     

Effects of novel aldose reductase inhibitors, M16209 and M16287, on streptozotocin-induced diabetic neuropathy in rats.

We investigated the effects of novel aldose reductase inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), on neuropathy in streptozotocin-induced (STZ) diabetic rats. Both compounds (3-100 mg/kg per day, p.o.) dose dependently improved the decreased motor nerve conduction velocity in the sciatic nerve during a 14-day treatment period. These compounds also partially ameliorated the diabetes-induced histological changes in the sciatic nerve. A distinct increase in sorbitol content and a slight decrease in myo-inositol content was observed in the sciatic nerve of STZ diabetic rats, and the sorbitol accumulation was dose dependently suppressed by treatment with M16209 and M16287. Treatment started at an earlier period was more effective in the suppression of sorbitol accumulation. There was a significant correlation between motor nerve conduction velocity and nerve sorbitol content, whereas there was none between motor nerve conduction velocity and myo-inositol content. The present study indicates that M16209 and M16287 are potent aldose reductase inhibitors expected to be useful for the treatment of diabetic complications.     

Synthesis and biological evaluation of 2'-oxo-2,3-dihydro-3'H- spiro[chromene-4,5'-[1,3]oxazolidin]-3'yl]acetic acid derivatives as aldose reductase inhibitors

Aldose reductase (ARL2) is the first enzyme in the polyol pathway which catalyzes the NADPH-dependent reduction of glucose to sorbitol. Its involvement on diabetic complications makes this enzyme a challenge therapeutic target widely investigated to limit and/or prevent them. On this basis, a limited series of 4-spiro-oxazolidinone-benzopyran derivatives (1-7) were synthesized to evaluate them as potential ARL2 inhibitors. The activity was determined spectrophotometrically by monitoring the oxidation of NADPH catalyzed by ALR2. Within the series of compounds, the 4-methoxy derivative 1b showed to be the most active compound, exhibiting inhibitory levels in the submicromolar range. In addition, the activity against the aldehyde reductase isoform (ARL1) was also evaluated. Unlike sorbinil (reference drug) that lack of selectivity towards the two enzyme all the tested compounds resulted to be devoid of ARL1 inhibitory activity (IC(50) > 10 μM), thus proving to be selective.     

Inhibition effects of quinones on aldose reductase: Antidiabetic properties

Diabetes mellitus is a chronic metabolic disease characterized by abnormal glucose metabolism. Aldose reductase (AR) is the first enzyme in the polyol pathway and converts glucose to sorbitol. It plays a vital role as a glucose reducing agent and is involved in the pathophysiology of diabetic complications. In this study, we purified AR from sheep kidney with a specific activity of 2.00 EU/mg protein and 133.33- fold purification After the purification of the AR enzyme, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed and the molecular weight of the enzyme was found approximately as 38 kDa. The inhibition effects of eight quinones were studied against AR. The quinones were potent inhibitors of AR with K_i values in the range of 0.07–20.04 μM. Anthraquinone showed the best potential inhibitory effects against AR. All compounds exhibited noncompetitive inhibition against AR. These compounds may be selective inhibitors of this enzyme. AR inhibition is an essential strategy for the attenuation and prevention of diabetic complications.     

Galloyl glucoses from the seeds of Cornus officinalis with inhibitory activity against protein glycation, aldose reductase, and cataractogenesis ex vivo

In an ongoing project directed toward the discovery of novel treatments for diabetic complications from traditional herbal medicines, six galloyl glucoses, 1,2,3-tri-O-galloyl-β-D-glucose (1), 1,2,6-tri-O-galloyl-β-D-glucose (2), 1,2,3,6-tetra-O-galloyl-β-D-glucose (3), 1,2,4,6-tetra-O-galloyl-β-D-glucose (4), 1,2,3,4,6-penta-O-galloyl-β-D-glucose (5), and tellimagrandin II (6), and two phenolic acids, gallic acid 4-O-β-D-glucoside (7) and gallic acid 4-O-β-D-(6'-O-galloyl)-glucoside (8), were isolated from an EtOAc-soluble fraction of the seeds of Cornus officinalis (Cornaceae). The structures of the compounds were identified using physical and spectroscopic methods, as well as by comparison of their data with values reported in the literature. All the isolates were evaluated in vitro for inhibitory activity against the formation of advanced glycation end-products (AGEs) and rat lens aldose reductase (RLAR). Compounds 1-6 were subjected to further bioassay to examine their inhibitory effects on AGE cross-linking. The opacity of lenses was significantly prevented when treated with 3 in an ex vivo experiment.     

Preliminary evaluation of rat kidney aldose reductase inhibitory activity of 2-phenylindole derivatives: affiliation to antioxidant activity

Diabetic complications including nephropathy, neuropathy, and cataract are leading causes of end-stage renal diseases and neurological disorders. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, catalyzes the reduction of glucose to sorbitol via NADPH. Excessive accumulation of intracellular sorbitol found in various tissues of diabetic animals and in cells cultured under high glucose conditions has been proposed to be an important factor for the pathogenesis of diabetic complications. Indole ring–containing AR inhibitors have received considerable attention as potential treatments for diabetic complications. However, these agents have not achieved worldwide use because of limited efficacy or unacceptable adverse effects. In this study, a series of 2-phenylindole derivatives were evaluated via an in vitro spectrophotometric assay for their ability to inhibit rat kidney AR. In addition, the antioxidant and AR inhibitory activities of the compounds under study were compared.     

Patent Evaluation: The Use of Aldose Reductase Inhibitors in the Treatment of Diabetes

Summary

Novelty: Novel biphenyl carboxylic acid derivatives are disclosed. These compounds are claimed to be aldose reductase inhibitors and are potentially useful for the treatment of diabetic complications such as cataract, retinal diseases, neuropathy, corneal and disorders diabetic ureitis.

Biology: The disclosed compounds were evaluated for inhibition of aldose reductase and for suppression of sorbitol accumulation in lens and sciatic nerves. The specified compound provided 63% inhibition of aldose reductase at a concentration of 0.1γ. At 2.5γ, sorbitol accumulation (lens) was inhibited by 85%.

Chemistry: 2,2′-Dimethoxy-5,5′-bis(3-carboxypropyl)biphenyl is one of three specifically claimed compounds.

Structure:      

Aldose reductase inhibitors

The present management of diabetes consists of attempting to control blood sugar tightly in the normal range and to treat individual complications such as neuropathy and retinopathy as they appear. Whereas these measures are perhaps effective in slowing the progress of diabetic complications, they do not cure the underlying process. The aldose reductase inhibitors have been investigated as possible remedies for various diabetic complications. Aldose reductase is an enzyme present in several human tissues that reduces glucose to sorbitol. In animal models there is evidence that the production of sorbitol is associated with the development of diabetic complications. Animal and human studies have tested the ability of aldose reductase inhibitors to halt or reverse diabetic complications. The weight of evidence leads to two conclusions: first, that aldose reductase inhibitors may bring significant relief to patients with certain diabetic complications; and second, that the current approach to proving clinical efficacy may not be adequate for these drugs.     

Inhibitory effects of isorhamnetin-3-O-beta-D-glucoside from Salicornia herbacea on rat lens aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues

The inhibitory effects of compounds from Salicornia herbacea (Chenopodiaceae) on rat lens aldose reductase (RLAR) and sorbitol accumulation in streptozotocin-induced diabetic rat tissues were investigated. The various fractions from the MeOH extract of S. herbacea were tested for their effects on RLAR in vitro. Among them, the EtOAc fraction was found to exhibit a potent RLAR inhibition (IC(50)=0.75 microg/ml), from which an active principle as a potent AR inhibitor was isolated and its chemical structure was elucidated as isorhamnetin-3-O-beta-D-glucoside (1) by spectral analysis. Compound 1 exhibited a potent RLAR inhibition in vitro, its IC(50) being 1.4 microM. Compound 1, when administered orally at 25 mg/kg in streptozotocin (STZ)-induced diabetic rats, caused not only a significant inhibition of serum glucose concentration but also sorbitol accumulation in the lenses, red blood cells (RBC), and sciatic nerves. These results indicate that compound 1 from S. herbacea is a leading compound for further study as a new drug for the prevention and/or treatment of diabetes and its complications.     

Spiro hydantoin aldose reductase inhibitors

Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus. Spiro hydantoins derived from five- and six-membered ketones fused to an aromatic ring or ring system inhibit aldose reductase isolated from calf lens. In vivo these compounds are potent inhibitors of sorbitol formation in sciatic nerves of streptozotocinized rats. Optimum in vivo activity is reached in spiro hydantoins derived from 6-halogenated 2,3-dihydro-4H-1-benzopyran-4-ones (4-chromanones). In 2,4-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione, the activity resides exclusively in the 4S isomer, compound 115 (CP-45,634, USAN: sorbinil). This compound is currently being used to test, in humans, the value of aldose reductase inhibitors in the therapy of diabetic complications.     

Phenylpropanoid glycosides from Orobanche caerulescens

Two new phenylpropanoid glycosides, caerulescenoside ( 1), and 3'-methyl crenatoside ( 2), as well as five known phenylpropanoid glycosides [acteoside ( 3), isoacteoside ( 4), campneoside II ( 5), crenatoside ( 6), and desrhamnosyl acteoside ( 7)] were isolated from the whole plant of Orobanche caerulescens. The antioxidative effects of compounds 1 - 7 on human low-density lipoprotein were evaluated. All these compounds suppress concentration-dependently conjugated diene formation with IC (50) values of 1.25 +/- 0.06, 2.97 +/- 0.31, 0.31 +/- 0.01, 1.01 +/- 0.05, 1.15 +/- 0.04, 1.69 +/- 0.15, and 0.64 +/- 0.03 microM, respectively. Comparison of their antioxidative activities with that of resveratrol (IC (50) : 6.75 +/- 1.05 microM), a natural phenolic antioxidant isolated from grape, demonstrated that the prolonged effect on lag-time and the damping effect on oxidative rate by compounds 1 - 7 were all more potent.     

Presence of aldose reductase inhibitors in tea leaves

Water extract from commercial English tea has a potent inhibitory activity against human placenta aldose reductase (NADPH oxidoreductase, E.C.1.1.1.21.). Inhibitory activity was separated into five major fractions by one-step chromatography with a C-18 reverse phase column. The most active fraction was further subjected to reverse phase column chromatography. As a result, a well-known flavone-glycoside, isoquercitrin, was isolated as the most potent chemical. The inhibitory character of isoquercitrin for aldose reductase was a mix of uncompetitive and noncompetitive inhibitions, and its IC50 was 1 x 10(-6) M. In rat sciatic nerve tissue preparations, sorbitol accumulation in the presence of high concentrations of glucose (30 mM) was inhibited by 38% at 5 x 10(-4) M of isoquercitrin. The flavone-glycoside isoquercitrin is the active inhibitor of aldose reductase inhibitor present in English tea. Given the ability of aldose reductase inhibitors to prevent diabetic complications, an epidemiological study of the effect of tea consumption on the pathogenesis and progression of diabetic complications would be interesting.     

Antiproliferative activity of the main constituents from Phyllanthus emblica

Eighteen main compounds, including four norsesquiterpenoids (1-4) and 14 phenolic compounds (5-18) isolated previously from Phyllanthus emblica, together with a main constituent, proanthocyanidin polymers (19) identified at this time from the roots, were estimated for their antiproliferative activities against MK-1 (human gastric adenocarcinoma), HeLa (human uterine carcinoma), and B16F10 (murine melanoma) cells using an MTT method. All of the phenolic compounds including the major components 5-8 from the fruit juice, 8, 9, and 12 from the branches and leaves, and 19 from the roots showed stronger inhibition against B16F10 cell growth than against HeLa and MK-1 cell growth. Norsesquiterpenoid glycosides 3 and 4 from the roots exhibited significant antiproliferative activities, although their aglycon 1 and monoglucoside 2 showed no inhibitory activity against these tumor cells.     

Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β₂ inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications.     

Preventive effect of chlorogenic acid on lens opacity and cytotoxicity in human lens epithelial cells

The present study reveals the pharmacological effect of chlorogenic acid, a major phenolic compound in plants, food, and coffee, on diabetic cataracts. Chlorogenic acid examined the inhibitory effects upon rat lens aldose reductase (AR) activity and xylose-induced rat lens opacity. The effect of chlorogenic acid on high glucose-induced cytotoxicity in lens epithelial cells was also examined. Chlorogenic acid showed potential inhibitory activity against rat lens AR, with an IC?? value of 0.95 μM. The xylose-induced opacity of lenses was significantly improved after treatment with chlorogenic acid in a dose-dependent manner. Chlorogenic acid prevented high glucose-induced cytotoxicity in human lens epithelial (HLE-B3) cells in a dose-dependent manner. These results suggest that chlorogenic acid may provide a potential therapeutic approach for prevention of diabetic complications, such as cataracts.