Studies on α-glucosidase,aldose reductase and glycation inhibitory properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith

Eight known phytochemicals, four sesquiterpenes and four flavonoids of Zingiber zerumbet were screened against α-glucosidase enzyme, aldose reductase enzyme and antiglycation property under in vitro conditions. The results established kaempferol-3-O-methylether as a potent inhibitor of α-glucosidase enzyme with an IC₅₀ value of 7.88 μM. In aldose reductase enzyme inhibition assay, all the compounds except zerumbone epoxide showed good to excellent inhibition properties. Among these, the flavonoid compounds were found to be potent aldose reductase inhibitors compared with the four sesquiterpenes. In addition, compounds such as α-humulene, kaempferol, kaempferol-3-O-methylether and 3″,4″-O-diacetylafzelin displayed potent antiglycation properties. From overall results, we found that kaempferol and kaempferol-3-O-methylether are potent inhibitors of α-glucosidase enzyme, aldose reductase enzyme and glycation reaction, the three main targets of drugs for the treatment of diabetes and its complications.     

Characterization of aldose reductase and aldehyde reductase from the medulla of rat kidney

Aldose reductase and aldehyde reductase from the medulla of the rat kidney have been purified to homogeneity by using affinity chromatography, gel filtration and chromatofocusing. The molecular weights of aldose reductase and aldehyde reductase by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis were found to be 37000 and 39000, respectively. The isoelectric points of aldose reductase and aldehyde reductase were found to be 5.4 and 6.2 by chromatofocusing, respectively. The major differences of amino acid compositions between both enzymes were found in serine, alanine and aspartic acid. Substrate specificity studies showed that aldose reductase utilized aldo-sugars such as D-glucose and D-galactose, but aldehyde reductase did not use them. The Km values of aldose reductase for various substrates were lower than those of aldehyde reductase. Aldose reductase utilized both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and reduced nicotinamide adenine dinucleotide (NADH) as coenzymes, whereas aldehyde reductase utilized only NADPH. The presence of the sulfate ion resulted in a dramatic activation of aldose reductase whereas it did not affect aldehyde reductase activity. These enzymes were strongly inhibited by the known aldose reductase inhibitors. However, aldose reductase was more susceptible than aldehyde reductase to inhibition by the aldose reductase inhibitors.     

The Efficiency of RP-TLC for Lipophilicity Assessment. A Comparative Study on a Series of Pyrrolyl-Acetic Acid Derivatives,Inhibitors of Aldose Reductase

JPC – Journal of Planar Chromatography – Modern TLC - The lipophilicity of a series of pyrrolyl-acetic acid derivatives, inhibitors of the aldose reductase enzyme, was assessed by...     

Synthesis and activity of a new series of (Z)-3-phenyl-2-benzoylpropenoic acid derivatives as aldose reductase inhibitors

During the course of studies directed towards the discovery of novel aldose reductase inhibitors for the treatment of diabetic complications, we synthesized a series of new (Z)-3-phenyl-2-benzoylpropenoic acid derivatives and tested their in vitro inhibitory activities on rat lens aldose reductase. Of these compounds, (Z)-3-(3,4-dihydroxyphenyl)-2-(4-methylbenzoyl)propenoicacid (3k) was identified as the most potent inhibitor, with an IC50 of 0.49 microM. The theoretical binding mode of 3k was obtained by simulation of its docking into the active site of the human aldose reductase crystal structure.     

Synthesis and aldose reductase inhibitory activity of triazine derivatives possessing acetic acid group.

N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-6) M less than or equal to IC50 less than or equal to 10(-4) M). Furthermore, biological activity (log 1/IC50) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC50 = 2 x 10(-6) M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.     

Properties of novel aldose reductase inhibitors, M16209 and M16287, in comparison with known inhibitors, ONO-2235 and sorbinil

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.     

Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: synthesis and biological activity

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human palcenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development.     

Resolving isoforms of aldose reductase by preparative isoelectric focusing in the Rotofor

We have resolved and characterized isoforms of aldose reductase from bovine and porcine lenses by preparative isoelectric focusing with narrow pH gradients using the Rotofor. Both bovine and porcine lens aldose reductases were resolved as two enzyme isoforms. The bovine isoforms were Mr40400 +/- 445 polypeptides of pI4.71 and 5.19. Porcine isoforms were Mr41500 +/- 450 polypeptides of pI 4.90 and 5.30. Staphylococcus aureus V-8 protease digestion patterns for each set of isoforms were essentially identical and all isoforms probably contain blocked amino terminal amino acids. Antiserum to bovine lens aldose reductase cross-reacted with porcine lens aldose reductase. Each isoform displayed substrate preferences characteristic of mammalian aldose reductases. With purification, both bovine and porcine lens aldose reductases became less sensitive to inhibition by 6-fluoro-spiro-(chroman-4.4'-imidazolidine)-2',5'-dione (sorbinil).     

Antidiabetic principles of natural medicines. IV. Aldose reductase and qlpha-glucosidase inhibitors from the roots of Salacia oblonga Wall. (Celastraceae): structure of a new friedelane-type triterpene, kotalagenin 16-acetate

The aqueous methanolic extract of an Indian natural medicine, the roots of Salacia oblonga Wall. (Celastraceae), was found to show inhibitory activity on the increase in serum glucose level in sucrose- and maltose-loaded rats. The water-soluble and ethyl acetate-soluble portions from the aqueous methanolic extract showed inhibitory activities on alpha-glucosidase and aldose reductase, respectively. From the water-soluble portion, potent alpha-glucosidase inhibitors, salacinol and kotalanol, were isolated, together with nine sugar related components, while a new friedelane-type triterpene, kotalagenin 16-acetate, was isolated from the ethyl acetate-soluble portion along with known diterpenes and triterpenes. The structure of kotalagenin 16-acetate was elucidated on the basis of physicochemical evidence. Principal components from this natural medicine were examined in terms of inhibitory activity on aldose reductase, and the diterpene and triterpene constituents, including the new kotalagenin 16-acetate, were found to be responsible components for the inhibitory activity on aldose reductase.     

Predictive ADMET study of rhodanine-3-acetic acid chalcone derivatives

Considered one of the chronic diseases in a global state of emergency, diabetes mellitus (DM) may cover an area of 629 million people affected by 2045. The main route of hyperglycemia in the human body is associated with the action of the enzyme aldose reductase on glucose molecules, resulting in the accumulation of sorbitol in blood and tissue cells. Thus, the present study is a high-throughput virtual screening (HTS) of the various molecular datasets available online, as well as an investigation of the pharmacokinetic properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET) and enzyme inhibition aldose reductase from a series of derivatives of rhodanine-3-acetic acid chalcones (D1-8). Four derivatives (D1-4) showed greater oral bioavailability, as they are anions of low relative polarity, showing better viability to interact with the aldose reductase target with a low toxic response to the host.     

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.     

Exploring structural feature of aldose-reductase inhibition by 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives employing Fujita-Ban and Hansch approach

Designing of a highly selective, potent and safe inhibitor of aldose reductase (ALR) capable of potentially blocking the excess glucose flux through the polyol pathway that prevails under diabetic condition has been a long standing challenge. In our study, we did quantitative structure-activity relationship (QSAR) analysis, based on Fujita-Ban and classical Hansch approach, on 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives. Study gave structural insight into the binding mode of the molecules to the aldose reductase enzyme. The Fujita-Ban approach revealed that benzylidene thiazolidine nucleus is more potent as compare to naphthyl-methylene thiazolidine analogs. The bulkierness of naphthyl-methylene might be inquisitive with receptor. Hansch approach suggested that electron-withdrawing groups are conducive to aldose reductase inhibitory activity.     

Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase inhibitory effect of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas.

The hot water extracts of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas, were found to have potent inhibitory activity towards lens aldose reductase (AR). Ellagic acid (4) was isolated from C. morifolium and I. batatas, isoscutellarein (7) from B. orellana and 3,5-dicaffeoylquinic acid (10) from I. batatas, respectively, as potent inhibitors.     

Aldose reductase inhibitors from natural sources

This review covers aldose reductase inhibitors (ARIs) isolated from natural sources. Compounds in the review are grouped according to the source from which they have been isolated: terrestrial, marine, or microorganism and the in vitro inhibitory activity of the compounds is also showed. The literature, both journals and patents, up to June 2002 is reviewed and 86 references are cited.     

Synthesis of 3-aminorhodanine derivatives as aldose reductase inhibitors

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.     

A series of diarylsubstituted oximes as potential substrate for new aldose reductase inhibitors

In the course of our research aimed at the discovery of new compounds acting as aldose reductase inhibitors, we tested a series of some (E)‐ and (Z)‐ω‐[[(aryldiazinylmethylene)amino]oxy]alkanoic acids, which were found to have moderate in vitro inhibitory activity. On this basis we have now prepared several new derivatives modified both at the length of the chain and at its terminal carboxylic group, together with compounds carrying various substituents at the phenyl ring. This paper describes their synthesis and biological properties.     

Liquid chromatographic measurement of hydrophobicity constants for N-arylsulfonylglycine aldose reductase inhibitors

The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k' data is used to estimate the capacity factor in 100% water (log k'w) for each compound. The log k'w values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953. The same procedure is then used to estimate the log k'w values for a large group of ARIs and their log P values, calculated from the established relationship between log k'w and log P from the reference compounds. An initial analysis of the aldose reductase inhibitory activity of these compounds as a function of hydrophobicity alone fails to reveal a clear relationship, demonstrating the need for a multivariant approach for quantitative structure-activity analysis in this series of compounds.     

Aldose reductase inhibitory, anti-cataract and antioxidant potential of selected medicinal plants from the Marathwada region, India

The water, ethanol and chloroform extracts of selected plants such as Adhatoda vasica (L.) (Acanthaceae), Caesalpinia bonduc (L.), Cassia fistula (L.) (Caesalpiniaceae) and Biophytum sensitivum (L.) (Oxalidaceae) were evaluated for rat lens aldose reductase inhibitory (RLAR) potential, anti-cataract and antioxidant activities. All the samples inhibited the aldose reductase considerably and exhibited anti-cataract activity, while C. fistula (IC(50), 0.154 mg mL(-1)) showed significant RLAR inhibitory activity as compared to the other tested samples, and was further found to be more effective in maintaining sugar-induced lens opacity in the rat lens model. The antioxidant potential of plant extracts was determined using DPPH (2,2-diphenyl-1-picryl hydrazine), hydroxyl (OH), nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) scavenging activities, along with determination of reducing power, ferrous ion chelating ability and inhibition of polyphenol oxidase (PPO). The extracts of the tested plant showed significant free radical scavenging activities and inhibited the activity of enzyme PPO, a model oxidising enzyme. The plant samples were found to possess considerable amounts of vitamin C, total polyphenols and flavonoids.