Three-component, one-flask synthesis of rhodanines (thiazolidinones)

5-(Z)-alkylidene-2-thioxo-1,3-thiazolidin-4-ones (rhodanine derivatives) were prepared by reaction of in situ generated dithiocarbamates with recently reported racemic α-chloro-β,γ-alkenoate esters. This multicomponent sequential transformation performed in one reaction flask represents a general route to this medicinally valuable class of sulfur/nitrogen heterocycles. Using this convergent procedure, we prepared an analogue of the drug epalrestat, an aldose reductase inhibitory rhodanine.     

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).     

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.     

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.     

Gaussian field-based comparative 3D QSAR modelling for the identification of favourable pharmacophoric features of chromene derivatives as selective inhibitors of ALR2 over ALR1

Structural Chemistry - Aldehyde reductase (ALR1) and aldose reductase (ALR2) are both oxo-reductase enzymes of aldo-keto reductase (AKR) superfamily involved in several cellular processes. ALR1...     

Structural requirements of flavonoids and related compounds for aldose reductase inhibitory activity

The methanolic extracts of several natural medicines and medicinal foodstuffs were found to show an inhibitory effect on rat lens aldose reductase. In most cases, flavonoids were isolated as the active constituents by bioassay-guided separation, and among them, quercitrin (IC(50)=0.15 microM), guaijaverin (0.18 microM), and desmanthin-1 (0.082 microM) exhibited potent inhibitory activity. Desmanthin-1 showed the most potent activity, which was equivalent to that of a commercial synthetic aldose reductase inhibitor, epalrestat (0.072 microM). In order to clarify the structural requirements of flavonoids for aldose reductase inhibitory activity, various flavonoids and related compounds were examined. The results suggested the following structural requirements of flavonoid: 1) the flavones and flavonols having the 7-hydroxyl and/or catechol moiety at the B ring (the 3',4'-dihydroxyl moiety) exhibit the strong activity; 2) the 5-hydroxyl moiety does not affect the activity; 3) the 3-hydroxyl and 7-O-glucosyl moieties reduce the activity; 4) the 2-3 double bond enhances the activity; 5) the flavones and flavonols having the catechol moiety at the B ring exhibit stronger activity than those having the pyrogallol moiety (the 3',4',5'-trihydroxyl moiety).     

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.     

5-Arylmethylene-2,4-imidazolidinediones and 5-arylmethylene-2-thioxo-4-imidazolidinones derivatives: stereochemistry elucidation by H and C NMR

Derivatives of 5-arylmethylene-2,4-imidazolidinediones and 5-arylmethylene-2-thioxo-4-imidazolidinones were synthesized as potential aldose reductase inhibitors (ARI). The Z/E configuration was elucidated by homonuclear NOE difference spectra and by proton-carbon coupling constant measurement from ¹³C coupled spectra using GATEDEC and SFDEC programs.     

Improvement of nerve conduction velocity in mutant diabetic mice by aldose reductase inhibitor without affecting nerve myo-inositol content

The sciatic motor nerve conduction velocity of mutant diabetic C57BL/Ks mice was significantly improved from 30.0 +/- 1.4 to 38.0 +/- 4.6 m/s by treatment with the aldose reductase inhibitor 1-[(beta-naphthyl)sulfonyl]hydantoin (30 mg/kg/d) for 2 weeks. The treatment, however, did not cause any significant change in myo-inositol concentration in the sciatic nerve. The results indicate that the ameliorating effect of the aldose reductase inhibitor on nerve conduction velocity in mutant diabetic mice is not due to alteration of myo-inositol content in the nerve.     

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.     

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.     

Preparation of 5-alkyl-3-carboxymethylrhodanines and their aldose reductase inhibitory activity.

5-Alkyl-3-carboxymethylrhodanines (2) were prepared from 5-alkylmethylidene-3-carboxymethylrhodanines (1). The exo double bond of 1 was successfully reduced with NaBH4. The 1,4-addition reaction path was confirmed on the basis of proton nuclear magnetic resonance spectrum of the product (4b) obtained from the reduction of 3 using NaBD4. Optical resolution of the tert-butyl compound (2i) was achieved upon epimerization-crystallization method using L-3-amino-epsilon-caprolactam. The alkyl compounds (2) and the optical active compounds ((+)-2i, (-)-2i) were evaluated for aldose reductase inhibitory potency.     

Atmospheric chemistry of the Z and E isomers of CF3CF=CHF; kinetics, mechanisms, and products of gas-phase reactions with Cl atoms, OH radicals, and O3

Smog chamber/FTIR techniques were used to study the atmospheric chemistry of the Z and E isomers of CF3CF=CHF, which we refer to as CF3CF=CHF(Z) and CF3CF=CHF(E). The rate constants k(Cl + CF3CF=CHF(Z)) = (4.36 +/- 0.48) x 10-11, k(OH + CF3CF=CHF(Z)) = (1.22 +/- 0.14) x 10-12, and k(O3 + CF3CF=CHF(Z)) = (1.45 +/- 0.15) x 10-21 cm3 molecule-1 s-1 were determined for the Z isomer of CF3CF=CHF in 700 Torr air diluent at 296 +/- 2 K. The rate constants k(Cl + CF3CF=CHF(E)) = (5.00 +/- 0.56) x 10-11, k(OH + CF3CF=CHF(E)) = (2.15 +/- 0.23) x 10-12, and k(O3 + CF3CF=CHF(E)) = (1.98 +/- 0.15) x 10-20 cm3 molecule-1 s-1 were determined for the E isomer of CF3CF=CHF in 700 Torr air diluent at 296 +/- 2 K. Both the Cl-atom and OH-radical-initiated atmospheric oxidation of CF3CF=CHF give CF3C(O)F and HC(O)F in molar yields indistinguishable from 100% for both the Z and E isomer. CF3CF=CHF(Z) has an atmospheric lifetime of approximately 18 days and a global warming potential (100 year time horizon) of approximately 6. CF3CF=CHF(E) has an atmospheric lifetime of approximately 10 days and a global warming potential (100 year time horizon) of approximately 3. CF3CF=CHF has a negligible global warming potential and will not make any significant contribution to radiative forcing of climate change.     

Medicinal flowers. VI. Absolute stereostructures of two new flavanone glycosides and a phenylbutanoid glycoside from the flowers of Chrysanthemum indicum L.: their inhibitory activities for rat lens aldose reductase

Two new flavanone glycosides, (2S)- and (2R)-eriodictyol 7-O-beta-D-glucopyranosiduronic acids, and a new phenylbutanoid glycoside, (2S, 3S)-1-phenyl-2,3-butanediol 3-O-beta-D-glucopyranoside, were isolated from the flowers of Chrysanthemum indicum L. cultivated in China together with eight flavonoids. The absolute stereostructures of the new compounds were determined on the basis of chemical and physicochemical evidence. Both of the new flavanone glycosides were found to show inhibitory activity for rat lens aldose reductase.     

Intramolecularly sensitized precipitons: a model system for application to metal sequestration

We have investigated light-triggered or catalytically activated precipitation agents and have proposed the name "precipiton" for such molecules or molecular fragments. A phase separation is induced when the precipiton isomerizes to a low-solubility form. In this paper we describe the first intramolecularly activated precipitons. The isomerization process is induced by intramolecular triplet energy transfer from a covalently attached metal complex. As expected, intramolecular sensitization leads to a more rapid isomerization than can be achieved by intermolecular sensitization at accessible concentrations. Two isomeric bichromophoric precipiton species, each containing [Ru(bpy)(3)](2+) and 1,2-bis(biphenyl)ethene units covalently linked together by an ether tether, have been synthesized and characterized, and their photochemical properties have been investigated. The rates of photoisomerization of these complexes, [((Z)-1,2-bis(biphenyl)ethene-bpy)Ru(bpy)(2)](PF(6))(2) (2Z) and [((E)-1,2-bis(biphenyl)ethene-bpy)Ru(bpy)(2)](PF(6))(2) (2E), were compared to those of their untethered analogues, (Z)-1,2-bis(biphenyl)ethene-OTBS (1Z) and (E)-1,2-bis(biphenyl)ethene-OTBS (1E), where ruthenium sensitization occurred through an intermolecular pathway. Upon irradiation with visible light (lambda > or = 400 nm) in degassed solution, 2Z/E and 1Z/E obeyed reversible first-order rate kinetics. The intramolecularly sensitized precipiton 2Z isomerized 250 times faster (k(2Z-->2E) = 1.0 x 10(-3) s(-1) with a 51% neutral density filter) than the intermolecular case 1Z (k(1Z-->1E) = 0.80 x 10(-5) s(-1)). For 1E and 2E, the isomerization rates were k(1E-->1Z) = 11.0 x 10(-5) s(-1) and k(2E-->2Z) = 1.6 x 10(-3) s(-1), respectively. The average Z/E mole ratio at the photostationary state was 62/38 for 2Z/E and 93/7 for 1Z/E. The impetus for this study was our desire to evaluate the possibility of using metal-binding precipitons that would precipitate only upon metal-to-precipiton binding and would be inert to visible light in the absence of metals.     

Proteome analysis of rat hepatomas: carcinogen-dependent tumor-associated protein variants

Proteome analysis led to the identification and characterization of tumor-associated protein variants by two-dimensional electrophoresis and mass spectrometry. We focused on comparing the influence of genotoxic nitroso compounds N-methyl-N-nitrosourea, diethylnitrosamine and N-nitrosomorpholine and the nongenotoxic peroxisome proliferator Nafenopin as tumor-inducing agents on the protein pattern of rat hepatomas. We found several tumor-associated variants that represent members of the aldo-keto reductase superfamily. Their induction and/or inhibition was specifically related to the carcinogen used for tumor induction. The most prominent tumor-associated protein, rat aldose reductase-like protein-1 (rARLP-1) (69% sequence identity to lens aldose reductase) and three additional types of rARLP-1 were detected in nitroso compound-induced rat hepatomas, while rat aldo-keto reductase protein-c (Rak-c), a novel tumor-associated variant (65% sequence identity with 3alpha-hydroxysteroid dehydrogenase) was discovered in N-methyl-N-nitrosourea-induced hepatomas only. 3Alpha-hydroxysteroid dehydrogenase and delta4-3-ketosteroid-5beta-reductase, both liver-specific enzymes, were reduced in amount in all hepatomas investigated, independent of their mode of induction. We conclude, that detoxification enzymes like 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) and delta4-3-ketosteroid-5beta-reductase (5beta-Red) might be replaced in hepatomas by tumor-associated proteins that are often present in the embryonal state, like the rARLPs or the Rak-c protein. Their induction appears to reflect an altered constitutive pattern of detoxification enzymes, detoxifying toxic aldehydes being induced by nitroso compounds. In contrast, members of the aldo-keto reductase superfamily have not been found in Nafenopin-induced hepatomas. The pattern of tumor-associated protein variants is apparently characteristic for a given group of initiating carcinogens. The hypothesis is proposed that carcinogens leave specific fingerprints at the proteome level of manifest liver tumors.     

Atmospheric chemistry of (Z)-CF3CH═CHCF3: OH radical reaction rate coefficient and global warming potential

Rate coefficients, k, for the gas-phase reaction of the OH radical with (Z)-CF(3)CH═CHCF(3) (cis-1,1,1,4,4,4-hexafluoro-2-butene) were measured under pseudo-first-order conditions in OH using pulsed laser photolysis (PLP) to produce OH and laser-induced fluorescence (LIF) to detect it. Rate coefficients were measured over a range of temperatures (212-374 K) and bath gas pressures (20-200 Torr; He, N(2)) and found to be independent of pressure over this range of conditions. The rate coefficient has a non-Arrhenius behavior that is well-described by the expression k(1)(T) = (5.73 ± 0.60) × 10(-19) × T(2) × exp[(678 ± 10)/T] cm(3) molecule(-1) s(-1) where k(1)(296 K) was measured to be (4.91 ± 0.50) × 10(-13) cm(3) molecule(-1) s(-1) and the uncertainties are at the 2σ level and include estimated systematic errors. Rate coefficients for the analogous OD radical reaction were determined over a range of temperatures (262-374 K) at 100 Torr (He) to be k(2)(T) = (4.81 ± 0.20) × 10(-19) × T(2) × exp[(776 ± 15)/T], with k(2)(296 K) = (5.73 ± 0.50) × 10(-13) cm(3) molecule(-1) s(-1). OH radical rate coefficients were also measured at 296, 345, and 375 K using a relative rate technique and found to be in good agreement with the PLP-LIF results. A room-temperature rate coefficient for the O(3) + (Z)-CF(3)CH═CHCF(3) reaction was measured using an absolute method with O(3) in excess to be <6 × 10(-21) cm(3) molecule(-1) s(-1). The atmospheric lifetime of (Z)-CF(3)CH═CHCF(3) due to loss by OH reaction was estimated to be ~20 days. Infrared absorption spectra of (Z)-CF(3)CH═CHCF(3) measured in this work were used to determine a (Z)-CF(3)CH═CHCF(3) global warming potential (GWP) of ~9 for the 100 year time horizon. A comparison of the OH reactivity of (Z)-CF(3)CH═CHCF(3) with other unsaturated fluorinated compounds is presented.     

Bioactive constituents from Chinese natural medicines. XXXII. aminopeptidase N and aldose reductase inhibitors from Sinocrassula indica: structures of sinocrassosides B(4), B(5), C(1), and D(1)-D(3)

From the methanolic extract of the whole plant of Sinocrassula indica (Crassulaceae), six new flavonol glycosides, sinocrassosides B(4) (1), B(5) (2), C(1) (3), D(1) (4), D(2) (5), and D(3) (6), were isolated together with 30 compounds. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. In addition, several constituents were found to show inhibitory effects on aminopeptidase N and aldose reductase.     

A facile preparation of 1-(6-hydroxyindol-1-yl)-2,2-dimethylpropan-1-one

An effective synthesis of 1-(6-hydroxyindol-1-yl)-2,2-dimethylpropan-1-one (4) was developed starting from 1H-indole (2). The key step involved suitable utilization of 4-(1-pyrrolidino)pyridine for the removal of the chloroacetyl moiety from chloroacetic acid 1-(2,2-dimethylpropionyl)-1H-indol-6-yl ester (3); a possible mechanism is, also, presented. Compound 4 might lead to selectively substituted derivatives, either on the phenolic-OH or the indolyl-NH, with putative biological interest. In this respect, we found that the core structure of 1H-indol-6-ol (1) possesses a degree of aldose reductase inhibitory potential, at a concentration of 100 microM.