Glutathione-Hemin/Hematin Adduct Formation to Disintegrate Cytotoxic Oxidant Hemin/Hematin in Human K562 Cells and Red Blood Cells' Hemolysates: Impact of Glutathione on the Hemolytic Disorders and Homeostasis.

Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and proposed to scavenge cytotoxic free heme, which is released from hemoglobin of damaged red blood cells (RBCs) during different hemolytic disorders. In the present study, we aimed to uncover the molecular mechanism by which GSH inhibits hemin-induced cytotoxicity (HIC) by affecting hemin's structural integrity in K562 cells and in RBC hemolysates.

Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log and log in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log /log assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs.

Formation of novel N-acetylcysteine-hemin adducts abrogates hemin-induced cytotoxicity and suppresses the NRF2-driven stress response in human pro-erythroid K562 cells.

Heme (iron protoporphyrin IX), as the prosthetic group in hemoproteins, regulates vital cellular functions in human tissues. However, free heme released during hemolysis events promotes severe complications to millions of people worldwide. Over the years, thiols like glutathione (GSH) were known to antagonize heme toxicity.

Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H-pyrrol-1-yl)phenol as a scaffold for improved membrane permeation.

Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa≥7.4, were synthesized and evaluated for aldose reductase inhibitory activity.

Development of aldose reductase inhibitors for the treatment of inflammatory disorders.

Introduction: Accumulating evidence attributes a significant role to aldose reductase (ALR2) in the pathogenesis of several inflammatory pathologies. Aldose reductase inhibitors (ARIs) were found to attenuate reactive oxygen species (ROS) production both in vitro and in vivo. Thus, they disrupt signaling cascades that lead to the production of cytokines/chemokines, which induce and exacerbate inflammation.

Synthesis of derivatives of the keto-pyrrolyl-difluorophenol scaffold: some structural aspects for aldose reductase inhibitory activity and selectivity.

Seven novel ARIs (3a-c, 4a-c and 5) were synthesized with the implementation of an optimized and, partially, selective synthetic procedure, via a Friedel-Crafts acylation reaction. The synthesized ARIs have values of IC(50)(ALR2) ranging from 0.19μM (in case of compound 3b) to 2.

Novel aldose reductase inhibitors: a patent survey (2006--present).

Introduction: Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors.

Areas Covered: Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest.

Bis-pyrrolyl-tetrazolyl derivatives as hybrid polar compounds: A case of lipophilic functional bioisosterism with bis-acetamides.

Based on previous studies on bis-acetamides that act as hybrid polar compounds to induce leukemia cell differentiation, an attempt was made to bioisosterically replace the amide moiety with the lipophilic non-classical bioisostere tetrazole. A pyrrole group was also included in the molecule in order to retain the hydrogen bond donor capability. Thus, by linking the two polar ring systems with a highly lipophilic methylene chain compounds 2-4 were synthesized and assessed for their anti-proliferative activity in combination with their ability to induce murine erythroleukemia (MEL) cell differentiation.

Structure-activity relations on [1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone. The effect of methoxy substitution on aldose reductase inhibitory activity and selectivity.

Based on our previous work, we studied the effect of methoxy-substitution as well as the regioposition of the benzoyl-moiety of 4a [(1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone]. On this basis, compounds 4b-c and 5a-c were synthesized and assayed for aldose and aldehyde reductase inhibitory activity. Furthermore, a 4,6-difluoro-5-hydroxyphenyl pattern (9) was studied, in order to verify the optimum position of the phenol-moiety.

A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity.

We have previously reported the successful replacement of a carboxylic acid functionality with that of a difluorophenolic group on the known aldose reductase inhibitors (ARIs) of 2-(phenylsulfonamido)acetic acid chemotype. In the present work, based on bioisosteric principles, additional 2,6-difluorophenol and tetrazole, methylsulfonylamide, and isoxazolidin-3-one phenylsulfonamide derivatives were synthesized and tested in vitro in protocols primarily related to the long-term diabetic complications. Most of the compounds were found as ARIs at IC(50) < 100 μM, while the introduction of the 4-bromo-2-fluorobenzyl group in a phenylsulfonamidodifluorophenol structure resulted in a compound (4c) presenting a submicromolar inhibitory profile.

Nutritional overview on the management of type 2 diabetes and the prevention of its complications.

Diabetes mellitus is an increasing world health problem; particularly the prevalence of type 2 diabetes has assumed epidemic dimensions in Western industrialized societies. It is mainly the environmental, dietary and lifestyle behavioral factors that are the control keys in the progress of this disease. Several epidemiological studies have linked over nutrition and lack of physical activity with type 2 diabetes.

Evaluation of aldose reductase inhibition and docking studies of 6'-nitro and 6',6''-dinitrorosmarinic acids.

Aldose reductase (ALR2) of the polyol metabolic pathway is a target enzyme for the treatment of diabetic complications. A variety of synthetic and natural compounds have been observed to inhibit aldose reductase. Among them, rosmarinic acid has been shown to be in vitro an aldose reductase inhibitor in a micromolar range.

HPLC-based lipophilicity of pyrrolyl-acetic acid ARIs: Relationships with biological activity.

Reversed phase HPLC was used to assess the lipophilicity of a series pyrrolyl-acetic acid derivatives with aldose reductase inhibitory activity. The pH conditions were adjusted at 3.0 to investigate the behavior of the neutral species and at pH 7.

Aldose reductase enzyme and its implication to major health problems of the 21(st) century.

Aldose reductase enzyme (ALR2) of the polyol metabolic pathway, apart from its role as detoxifying enzyme towards toxic aldehydes, osmoregulator in the kidney and regulator of sperm maturation, was first found to be implicated in the etiology of the long term diabetic complications. However, to date, emerging reports have suggested that under normal glucose concentration, ALR2 may be up-regulated by factors other than hyperglycemia and therefore be involved also in other pathological processes that have become major threats to human health in the 21(st) century. Such pathologies are a number of cardiac disorders, inflammation, mood disorders, renal insufficiency and ovarian abnormalities.

Design and synthesis of N-(3,5-difluoro-4-hydroxyphenyl)benzenesulfonamides as aldose reductase inhibitors.

N-(3,5-Difluoro-4-hydroxyphenyl)benzenesulfonamide (4) and its derivatives 5-7 were prepared as putative bioisosteres of the previously reported aldose reductase inhibitors, which are the N-benzenesulfonylglycine derivatives I-IV. The in vitro aldose reductase inhibitory activity of the prepared compounds is higher than that of the respective glycine derivatives. Furthermore, the parent compound 4 reveals high antioxidant potential.

Inhibitory effect of polar oregano extracts on aldose reductase and soybean lipoxygenase in vitro.

The effect of methanol and aqueous methanol extract of Origanum vulgare L. ssp. hirtum on aldose reductase and soybean lipoxygenase was investigated.

Permeability characteristics of novel aldose reductase inhibitors using rat jejunum in vitro.

The aim of this study was to estimate in vivo permeability and bioavailability of epalrestat and newly synthesized compounds with possible therapeutic activity as aldose enzyme inhibitors (ARIs). For this purpose permeability in vitro using rat jejunum mounted in side-by-side diffusion cells was determined. Tested substances were found to be low and moderately permeable and some of them were also substrates for efflux transporters.

Evaluation of aldose reductase inhibition and docking studies of some secondary metabolites, isolated from Origanum vulgare L. ssp. hirtum.

Five polar constituents of Origanum vulgare L. ssp. hirtum were investigated for their ability to inhibit aldose reductase (ALR2), the first enzyme of the polyol pathway implicated in the secondary complications of diabetes.

[1-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a bioisostere of a carboxylic acid aldose reductase inhibitor.

[1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone (6) was synthesized as a putative bioisostere of the known aldose reductase (AR) inhibitor (3-benzoylpyrrol-1-yl)acetic acid (I). It was found that 6 is approximately 5 times more potent as an in vitro inhibitor of AR than I, with an IC(50) value in the submicromolar range. Furthermore, 6 showed considerable activity in an in vitro experimental glycation model of diabetes mellitus.

Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent.

BACKGROUND: Tardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D2 and serotonin 5-HT1A receptors in in vitro competition binding assays.

Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.

Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and (2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75) were synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. It was found that a number of the tested compounds exhibited considerable activity in the micromolar range. Important structural features for the potent compounds is the presence of substituents with relatively low Hammett sigma values and/or moieties which increase their overall aromatic area.

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.