A facile synthesis of 2-(4-((4-chlorophenyl)(hydroxy)methyl) phenoxy)-2-methylpropanoic acid: Metabolite of anti-hyperlipidemic drug Fenofibrate.

Synthesis and characterization of drug metabolites has emerged as an important area of research in consideration to the significant contribution of studies on metabolites in drug research. The present work comprises synthesis of 2-(4-((4-chlorophenyl)(hydroxy)methyl) phenoxy)-2-methylpropanoic acid, a metabolite of anti-hyperlipidemic drug fenofibrate. The desired compound was prepared by two different synthetic routes.

A facile and chemoselectivity in synthesis of 4-chloro-N-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenethyl)benzamide, the alcohol derivative of Bezafibrate.

A facile method for the reduction of carboxylic acid group of Bezafibrate, an approved drug, is described. The selective reduction of carboxylic acid group to corresponding alcohol was carried out by activation of the carboxylic acid moiety via mixed anhydride followed by the addition of stoichiometric amount of NaBH and methanol to obtain the first alcohol variant of Bezafibrate. The reaction was completed in 5-10 min in excellent yield and purity.

Chemoselective Reduction of Fenofibric Acid to Alcohol in the Presence of Ketone by Mixed Anhydride and Sodium Borohydride.

A highly efficient and facile protocol for the selective reduction of carboxylic acid of Fenofibric acid to corresponding alcohol was developed. The selective reduction was carried out by activation of carboxylic acid by mixed anhydride followed by the reaction of sodium borohydride in presence of methanol. This is the first example of chemoselective reduction of carboxylic acid to alcohol in presence of a ketone without any external catalyst or ligand in a single step.

Signature of Glycylglutamic Acid Structure.

Background: Glutamate (Glu) is of great interest in biomedical research. It is considered a biomarker in diabetes, which may potentially contribute to the development of autism in genetically vulnerable human populations, and it is found in relation to advanced glycation end products (AGEs) [1]. Additionally, Glu plays an active role in the function of ligand-gated ion channel glutamate receptors, chloride channels capable of filtering glutamate, as well as Potassium (K)-channel [2].

Synthesis and Chiral Separation of Fibratol, Isopropyl 2-(4-((4-chlorophenyl)(hydroxyl) methyl)-phenoxy)-2-methylpropanoate.

Practical synthetic route for the formation of enantiomeric mixture of Isopropyl 2-(4-((4-chlorophenyl)(hydroxyl)methyl)phenoxy)-2-methylpropanoate (Fibratol 2a/b) from isopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate (Fenofibrate 1) has been developed. Method has also been established for the chiral separation of enantiomers of Fibratol 2a/b that is synthesized using the route mentioned above. The optical activity determined for enantiomerically separated Fibratol (2a) and Fibratol (2b) are -5.

Characterization of WY 14,643 and its Complex with Aldose Reductase.

The peroxisome proliferator, WY 14,643 exhibits a pure non-competitive inhibition pattern in the aldehyde reduction and in alcohol oxidation activities of human Aldose reductase (hAR). Fluorescence emission measurements of the equilibrium dissociation constants, K, of oxidized (hAR•NADP) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K values for the dissociation of WY 14,643 from the oxidized (hAR•NADP•WY 14,643) and reduced (hAR•NADPH•WY 14,643) ternary complexes are comparable to each other.

B-factor Analysis and Conformational Rearrangement of Aldose Reductase.

The NADPH-dependent reduction of glucose reaction that is catalyzed by Aldose Reductase (AR) follows a sequential ordered kinetic mechanism in which the co-factor NADPH binds to the enzyme prior to the aldehyde substrate. The kinetic/structural experiments have found a conformational change involving a hinge-like movement of a surface loop (residues 213-224) which is anticipated to take place upon the binding of the diphosphate moiety of NADPH. The reorientation of this loop, expected to permit the release of NADP, represents the rate-limiting step of the catalytic mechanism.

Biomolecular chemistry of isopropyl fibrates.

Isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and isopropyl 2-(4-chlorophenoxy)-2-methylpropanoate, also known as fenofibrate and isopropyl (iPr) clofibrate, are hypolipidemic agents of the fibrate family. In a previously reported triclinic structure of fenofibrate (polymorph I), the methyl groups of the iPr moiety are located symmetrically about the carboxylate group. We report a new monoclinic form (polymorph II) of fenofibrate and a first structural description of iPr clofibrate, and in these the methyl groups are placed asymmetrically about the carboxylate group.

The role of Cys-298 in aldose reductase function.

Diabetic tissues are enriched in an "activated" form of human aldose reductase (hAR), a NADPH-dependent oxidoreductase involved in sugar metabolism. Activated hAR has reduced sensitivity to potential anti-diabetes drugs. The C298S mutant of hAR reproduces many characteristics of activated hAR, although it differs from wild-type hAR only by the replacement of a single sulfur atom with oxygen.

Fibrates in the chemical action of daunorubicin.

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.

Cancer biomarker AKR1B10 and carbonyl metabolism.

A member of the aldo-keto reductase (AKR) protein superfamily, AKR1B10, is overexpressed in human liver cancers as well as in many adenocarcinoma cases due to smoking. AKR1B10 is also detected in instances of cervical and endometrial cancer in uterine cancer patients. In addition, AKR1B10 has been identified as a biomarker for non-small-cell lung cancer by a combined bioinformatics and clinical analysis.

Inhibiting wild-type and C299S mutant AKR1B10; a homologue of aldose reductase upregulated in cancers.

AKR1B10 is an aldose reductase (AR) homologue overexpressed in liver cancer and various forms of that enzyme in carcinomas catalyze the reduction of anticancer drugs, potential cytostatic drug, and dl-glyceraldehyde but do not catalyze the reduction of glucose. Kinetic parameters for wild-type and C299S mutant AKR1B10 indicate that substitution of serine for cysteine at position 299 reduces the affinity of this protein for dl-glyceraldehyde and enhances its catalytic activity. Fibrates suppress peroxisome proliferation and the development of liver cancer in human.

Chemistory of Fibrates.

Since the description of the synthetic chemical clofibrate in 1962, various derivatives of fibrates with a diversity of chemical structures have been developed. Several of these are used clinically to treat dyslipidemia because they are generally effective in lowering elevated plasma triglycerides and cholesterol. Studies suggest that several biochemical mechanisms underlie fibrate-mediated modulation of lipoprotein and related metabolites.

WY 14,643 inhibits human aldose reductase activity.

Aldose reductase (AR) is implicated to play a critical role in diabetes and cardiovascular complications because of the reaction it catalyzes. Our data reveal that peroxisome proliferator WY 14,643, follows a pure non-competitive inhibition pattern in the aldehyde reduction activity as well as in the alcohol oxidation activity of AR. This finding communicates for the first time a novel feature of WY 14,643 in regulating AR activity.

Crystal structure of the restriction-modification system control element C.Bcll and mapping of its binding site.

Protection from DNA invasion is afforded by restriction-modification systems in many bacteria. The efficiency of protection depends crucially on the relative expression levels of restriction versus methytransferase genes. This regulation is provided by a controller protein, named C protein.

High-resolution crystal structure of AKR11C1 from Bacillus halodurans: an NADPH-dependent 4-hydroxy-2,3-trans-nonenal reductase.

Aldo-keto reductase AKR11C1 from Bacillus halodurans, a new member of aldo-keto reductase (AKR) family 11, has been characterized structurally and biochemically. The structures of the apo and NADPH bound form of AKR11C1 have been solved to 1.25 A and 1.

Fibrates inhibit aldose reductase activity in the forward and reverse reactions.

Fibrates such as bezafibrate, gemfibrozil, clofibric acid, ciprofibrate and fenofibrate, are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha), and are used as therapeutic agents in the treatment of hyperlipidemia. Synthesis and accumulation of sorbitol in cells due to aldose reductase (AR) activity is implicated in secondary diabetic complications. In pursuit of finding a lead compound identification to design an effective AR inhibitor employing fragment-based design-like approach, we found that this class of compounds and their nearest neighbors could inhibit AR.

Fenofibric acid.

Unlike the related fenofibrate molecule [Henry, Zhang, Gao & Bruckner (2003). Acta Cryst. E59, o699-o700], fenofibric acid {systematic name: 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid}, C17H15ClO4, contains a carboxylic acid moiety instead of an ester moiety.

The role of glutathione in cancer.

Glutathione is an abundant natural tripeptide found within almost all cells. Glutathione is highly reactive and is often found conjugated to other molecules via its sulfhydryl moiety. It instils several vital roles within a cell including antioxidation, maintenance of the redox state, modulation of the immune response and detoxification of xenobiotics.