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ChemMedChem Jun 20212,4-Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur-containing heterocycle is... (Review)
Review
2,4-Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur-containing heterocycle is a versatile pharmacophore that confers a diverse range of pharmacological activities. TZD has been shown to exhibit biological action towards a vast range of targets interesting to medicinal chemists. In this review, we attempt to provide insight into both the historical conventional and the use of novel methodologies to synthesise the TZD core framework. Further to this, synthetic procedures utilised to substitute the TZD molecule at the activated methylene C and N position are reviewed. Finally, research into developing clinical agents, which act as modulators of peroxisome proliferator-activated receptors gamma (PPARγ), protein tyrosine phosphatase 1B (PTP1B) and aldose reductase 2 (ALR2), are discussed. These are the three most targeted receptors for the treatment of diabetes mellitus (DM).
Topics: Aldehyde Reductase; Animals; Chemistry, Pharmaceutical; Diabetes Mellitus; Humans; Hypoglycemic Agents; PPAR gamma; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Thiazolidinediones
PubMed: 33844475
DOI: 10.1002/cmdc.202100177 -
The Cochrane Database of Systematic... 2000To assess the efficacy of aldose reductase inhibitors in the prevention, reversal or delay in the progression of diabetic peripheral neuropathy. (Review)
Review
OBJECTIVES
To assess the efficacy of aldose reductase inhibitors in the prevention, reversal or delay in the progression of diabetic peripheral neuropathy.
SEARCH STRATEGY
The Cochrane Diabetes Group's database was searched and the citation lists of identified trials and previous reviews checked. Investigators identified as active in the field were approached for overlooked studies.
SELECTION CRITERIA
Randomised controlled trials of aldose reductase inhibitors versus placebo, no treatment or other treatment in diabetic patients with or without clinical neuropathy.
DATA COLLECTION AND ANALYSIS
Nerve conduction velocity was the only end point measured in all trials. Treatment effect was evaluated in terms of nerve conduction velocity mean difference in median and peroneal motor and median and sural sensory nerves.
MAIN RESULTS
19 trials, testing 4 different aldose reductase inhibitors for between 4 to 208 weeks duration (median 24 weeks), met the inclusion criteria for the meta-analysis. A small but statistically significant reduction in decline of median and peroneal motor nerve conduction velocities was present in the treated group when compared to the control group (weighted mean 0.66 m/s 95% CI 0.18-1.14 m/s and 0.53 m/s 95% CI 0.02-1.04m/s respectively). No clear benefit of aldose reductase inhibitor treatment was observed in either of the sensory nerves.
REVIEWER'S CONCLUSIONS
Although aldose reductase inhibitor treatment has been demonstrated to diminsh the reduction in motor nerve conduction velocity, the clinical relevance of such a change in this outcome measure is uncertain. There was no effect in terms of this outcome measure in the smaller sensory fibres, degeneration of which is primarily responsible for the most common neuropathic syndrome associated with diabetes, that of severe pain and loss of sensation in the extremity leading in some cases to ulceration and eventual amputation.
Topics: Aldehyde Reductase; Diabetic Neuropathies; Enzyme Inhibitors; Humans
PubMed: 10796870
DOI: 10.1002/14651858.CD002182 -
Advances in Experimental Medicine and... 2018Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase that has been shown to be involved in the pathogenesis of several blinding diseases such as uveitis,... (Review)
Review
Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase that has been shown to be involved in the pathogenesis of several blinding diseases such as uveitis, diabetic retinopathy (DR) and cataract. However, possible mechanisms linking the action of AR to these diseases are not well understood. As DR and cataract are among the leading causes of blindness in the world, there is an urgent need to explore therapeutic strategies to prevent or delay their onset. Studies with AR inhibitors and gene-targeted mice have demonstrated that the action of AR is also linked to cancer onset and progression. In this review we examine possible mechanisms that relate AR to molecular signaling cascades and thus explain why AR inhibition is an effective strategy against colon cancer as well as diseases of the eye such as uveitis, cataract, and retinopathy.
Topics: Aldehyde Reductase; Animals; Cataract; Diabetic Retinopathy; Enzyme Inhibitors; Inflammation; Mice; Signal Transduction; Uveitis
PubMed: 30362099
DOI: 10.1007/978-3-319-98788-0_13 -
BioMed Research International 2019Alcoholic liver disease (ALD) is caused by heavy alcohol consumption over a long period. Acetaldehyde-mediated toxicity, oxidative stress, and imbalance of lipid... (Review)
Review
Alcoholic liver disease (ALD) is caused by heavy alcohol consumption over a long period. Acetaldehyde-mediated toxicity, oxidative stress, and imbalance of lipid metabolism are generally considered involved in the initiation of ALD. There is an increasing requirement for alternative and natural medicine to treat ALD. Recently, aldose reductase (AR) has been reported to be involved in the development of ALD by affecting inflammatory cytokines, oxidative stress, and lipid metabolism. Here, we review the effect of plant-derived AR inhibitors on ALD in rodents. And we conclude that AR inhibitors of plant origin may enhance antioxidant capacity, inhibit lipid peroxidation and inflammatory cytokines expression, and activate AMP-activated protein kinase thereby subsequently suppressing alcohol-induced lipid synthesis in liver to achieve ALD protection. This review reveals that natural AR inhibitor may be potential therapeutic agent for ALD.
Topics: Aldehyde Reductase; Antioxidants; Enzyme Inhibitors; Humans; Lipid Metabolism; Liver; Liver Diseases, Alcoholic; Oxidative Stress; Plants; Signal Transduction
PubMed: 31321234
DOI: 10.1155/2019/3808594 -
Journal of Neurochemistry Mar 2018The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy,...
The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy, whereas little is known about the functional significance of AR in the peripheral nervous system. Spontaneously immortalized Schwann cell lines established from long-term cultures of AR-deficient and normal C57BL/6 mouse dorsal root ganglia and peripheral nerves can be useful tools for studying the physiological and pathological roles of AR. These cell lines, designated as immortalized knockout AR Schwann cells 1 (IKARS1) and 1970C3, respectively, demonstrated distinctive Schwann cell phenotypes, such as spindle-shaped morphology and immunoreactivity to S100, p75 neurotrophin receptor, and vimentin, and extracellular release of neurotrophic factors. Conditioned media obtained from these cells promoted neuronal survival and neurite outgrowth of cultured adult mouse dorsal root ganglia neurons. Microarray and real-time RT-PCR analyses revealed significantly down-regulated mRNA expression of polyol pathway-related enzymes, sorbitol dehydrogenase and ketohexokinase, in IKARS1 cells compared with those in 1970C3 cells. In contrast, significantly up-regulated mRNA expression of aldo-keto reductases (AKR1B7 and AKR1B8) and aldehyde dehydrogenases (ALDH1L2, ALDH5A1, and ALDH7A1) was detected in IKARS1 cells compared with 1970C3 cells. Exposure to reactive aldehydes (3-deoxyglucosone, methylglyoxal, and 4-hydroxynonenal) significantly up-regulated the mRNA expression of AKR1B7 and AKR1B8 in IKARS1 cells, but not in 1970C3 cells. Because no significant differences in viability between these two cell lines after exposure to these aldehydes were observed, it can be assumed that the aldehyde detoxification is taken over by AKR1B7 and AKR1B8 in the absence of AR.
Topics: Aldehyde Reductase; Aldehydes; Animals; Cell Culture Techniques; Cell Line; Cell Survival; Culture Media, Conditioned; Female; Ganglia, Spinal; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peripheral Nerves; Polymers; RNA, Messenger; Schwann Cells; Signal Transduction; Up-Regulation
PubMed: 29238976
DOI: 10.1111/jnc.14277 -
Bioengineered 2018Ethylene glycol (EG) is an important chemical used as antifreeze and a raw material in polyester synthesis. The EG biosynthetic pathway from D-xylose with D-xylonate as...
Ethylene glycol (EG) is an important chemical used as antifreeze and a raw material in polyester synthesis. The EG biosynthetic pathway from D-xylose with D-xylonate as key intermediate has some advantages, but showed low EG production. Here, we reconstructed and optimized this pathway in Escherichia coli. In view of the greater intracellular prevalence of NADH, an aldehyde reductase FucO using NADH was employed to convert glycoaldehyde into EG, in replacement of NADPH-dependent reductase YqhD. To suppress the accumulation of by-products acetate and glycolate, two genes arcA and aldA were knocked out. The resultant strain Q2843 produced 72 g/L EG under fed-batch fermentation conditions, with the yield of 0.40 g/g D-xylose and EG productivity of 1.38 g/L/h. The use of NADH-dependent enzyme FucO and by-product elimination significantly improved the performance of EG producing strain, which represented the highest titer, yield and productivity of EG reported so far.
Topics: Acetic Acid; Aldehyde Reductase; Bacterial Outer Membrane Proteins; Batch Cell Culture Techniques; Biosynthetic Pathways; Cloning, Molecular; Escherichia coli; Escherichia coli Proteins; Ethylene Glycol; Fermentation; Gene Expression; Genetic Vectors; Glycolates; Kinetics; Metabolic Engineering; NAD; Recombinant Proteins; Repressor Proteins; Xylose
PubMed: 29865993
DOI: 10.1080/21655979.2018.1478489 -
The Journal of Biological Chemistry Jun 1989Aldehyde reductase [EC 1.1.1.2] and aldose reductase [EC 1.1.1.21] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl... (Comparative Study)
Comparative Study
Aldehyde reductase [EC 1.1.1.2] and aldose reductase [EC 1.1.1.21] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds. These enzymes are implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Enzyme inhibition as a direct pharmacokinetic approach to the prevention of diabetic complications resulting from the hyperglycemia of diabetes has not been effective because of nonspecificity of the inhibitors and some appreciable side effects. To understand the structural and evolutionary relationship of these enzymes, we cloned and sequenced cDNAs coding for aldose and aldehyde reductases from human liver and placental cDNA libraries. Human placental aldose reductase (open reading frame of 316 amino acids) has a 65% identity (identical plus conservative substitutions) to human liver and placental aldehyde reductase (open reading frame of 325 amino acids). The two sequences have significant identity to 2,5-diketogluconic acid reductase from corynebacterium, frog rho-crystallin, and bovine lung prostaglandin F synthase (reductase). Southern hybridization analysis of human genomic DNA indicates a multigene system for aldose reductase, suggesting the existence of additional proteins. Thus, the aldo-keto reductase superfamily of proteins may have a more significant and hitherto not fully appreciated role in general cellular metabolism.
Topics: Alcohol Oxidoreductases; Aldehyde Reductase; Amino Acid Sequence; Base Sequence; Blotting, Northern; Blotting, Southern; DNA; Humans; Liver; Molecular Sequence Data; Multigene Family; Placenta; Sequence Homology, Nucleic Acid; Sugar Alcohol Dehydrogenases
PubMed: 2498333
DOI: No ID Found -
Molecular Vision Sep 1999To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases.
PURPOSE
To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases.
METHODS
The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis.
RESULTS
Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase.
CONCLUSIONS
The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 in aldose reductase contributes to the tight binding of NADPH.
Topics: Aldehyde Reductase; Animals; Binding Sites; Coenzymes; Crystallography, X-Ray; Humans; Imidazoles; Imidazolidines; Mutagenesis, Site-Directed; NADP; Protein Conformation; Structure-Activity Relationship; Swine
PubMed: 10493777
DOI: No ID Found -
Biomolecules Jul 2020Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been...
Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. Here, we show that epigallocatechin gallate (EGCG), one of the most representative catechins present in green tea, acts as a differential inhibitor of human recombinant AKR1B1. A kinetic analysis of EGCG, and of its components, gallic acid (GA) and epigallocatechin (EGC) as inhibitors of the reduction of L-idose, 4-hydroxy2,3-nonenal (HNE), and 3-glutathionyl l-4-dihydroxynonanal (GSHNE) revealed for the compounds a different model of inhibition toward the different substrates. While EGCG preferentially inhibited L-idose and GSHNE reduction with respect to HNE, gallic acid, which was still active in inhibiting the reduction of the sugar, was less active in inhibiting HNE and GSHNE reduction. EGC was found to be less efficient as an inhibitor of AKR1B1 and devoid of any differential inhibitory action. A computational study defined different interactive modes for the three substrates on the AKR1B1 active site and suggested a rationale for the observed differential inhibition. A chromatographic fractionation of an alcoholic green tea extract revealed that, besides EGCG and GA, other components may exhibit the differential inhibition of AKR1B1.
Topics: Aldehyde Reductase; Catalytic Domain; Catechin; Enzyme Inhibitors; Gallic Acid; Glutathione; Hexoses; Humans; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Plant Extracts; Tea
PubMed: 32640594
DOI: 10.3390/biom10071003 -
Current Cancer Drug Targets May 2009Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves... (Review)
Review
Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10.
Topics: Aldehyde Reductase; Aldo-Keto Reductases; Antibiotics, Antineoplastic; Clofibric Acid; Daunorubicin; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Models, Molecular; Neoplasms; Substrate Specificity
PubMed: 19442055
DOI: 10.2174/156800909788166538