Phenoxyacetic Acid Derivatives Research Articles

ChemInform Abstract: Synthesis of Phenoxyacetic Acid Derivatives as Highly Potent Antagonists of Gastrin/Cholecystokinin‐B Receptors.

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Etherolytic cleavage of 4-(2,4-dichlorophenoxy)butyric acid and 4-(4-chloro-2-methylphenoxy)butyric acid by species ofRhodococcus andAureobacterium isolated from an alkaline environment

Bacterial strains were isolated from the concrete rubble of a demolished herbicide production plant. The predominant feature of these strains was the etherolytic cleavage of 4-(2,4-dichlorophenoxy)butyric acid (DCPB)1) and 4-(4-chloro-2-methylphenoxy)butyric acid (MCPB) while liberating 2,4-dichlorophenol (DCP) and 4-chloro-2-methylphenol (MCP) respectively. Some of the isolates were identified by 16S rDNA sequence analysis and shown to belong to the genera Aureobacterium sp. (strain K2-17) and Rhodococcus (Rh. erythropolis K2-12). The other strains isolated clustered into these two groups according to fatty acid analysis. Etherolytic cleavage proceeded under neutral to alkaline conditions with an optimum at around pH 8.5. With Aureobacterium sp. No. K2-17, the degradation rate was zero at a pH of 6 but as much as 60% of the maximum activity was observed at pH 10.5. With Rh. erythropolis K2-12, by contrast, pronounced activity was detected at pH 6.5 while degradation was no longer observed at pH 10.5. The maximum rates of cleavage were about 1 mmol DCPB/h.g dry mass with Aureobacterium sp. No. K2-17 and about 0.6 mmol DCPB/h.g dry mass with Rh. erythropolis K2-12. DCPB and MCPB were utilized to the same extent. Substrate cleavage and product formation (DCP) proceeded at almost equal rates with Aureobacterium sp. No. K2-17 and Rh. erythropolis K2-12, which indicates that this compound was not further metabolized. Only phenoxybutyric acid compounds served as substrates; phenoxyacetic acid and phenoxypropionic acid derivatives were not utilized by these strains.

Synthesis of phenoxyacetic acid derivatives as highly potent antagonists of gastrin/cholecystokinin-B receptors.

A novel series of phenoxyacetic acid derivatives was synthesized based on considerations of the three-dimensional structural similarity of YM022 and RP72540. The gastrin/cholecystokinin (CCK)-B and CCK-A receptor antagonist activities of these compounds were evaluated by investigation of their affinities for human gastrin/CCK-B receptors and human CCK-A receptors, respectively. It was found that N-methyl-N-phenyl-2-[2-[N-(N-methyl-N-phenyl-carbamoylmethyl)-N-[2 -[3-(3- methylphenyl)ureido]acetyl]amino]phenoxy]acetamide (20k, DZ-3514) exhibited high affinity for gastrin/CCK-B receptors and high selectivity over CCK-A receptors.

Photoelectron transfer induced decarboxylation of substituted carboxylic acids across a liquid/liquid interface

Methylene blue photocatalyzed electron transfer reactions of some phenoxyacetic acid derivatives and N-phenylglycine across a liquid/liquid interface led to their efficient decarboxylation. Nanosecond laser flash photolysis studies of this process, in a reverse micellar system of Aerosol-OT (AOT)-benzene-water indicated that the liquid/liquid interface acts as a barrier in controlling the energy wasting back electron transfer. Intramolecular CC bond forming reactions of these radicals were utilized for the synthesis of various chroman derivatives.

The fate of a thiazolidinedione antidiabetic agent in rat and dog.

1. The fate of [14C]BRL 49653C, a novel thiazolidinedione antidiabetic agent, has been studied following oral administration to the rat and dog. 2. Clearance was almost exclusively by metabolism, with only small amounts of unchanged BRL 49653 being excreted by either species. 3. Phase I metabolism resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacetic acid derivative. 4. Sulphation of phase I metabolites occurred in both species, but glucuronidation was only observed in the rat. 5. The parent compound was the major circulating component in both species at early times, but at later times sulphate conjugates of phase 1 metabolites were predominant.

Phenol and its derivatives as heterotrophic substrates for microbial growth?An energetic comparison

The growth yield coefficients of phenol as well as of chloro- and methyl-substituted derivatives and the respective phenoxyalkanoic acids have been considered in a theoretical study. The yield coefficient of phenol assimilated via theortho pathway is at a given P/O quotient 9–23% higher than that of themeta route. Chlorine, removed by a reductive mechanism, decreases the yield figure by 10% per chlorine atom; hydrolytic mechanisms are more favourable in this respect. Methylation has a positive effect on the energetics of phenol utilization. Phenoxyacetic acid derivatives have a reduced yield per carbon atom in comparison to the respective phenol derivative. This is compensated for by higher chain lengths of the alkanoic acid moiety. The yield coefficients calculated for phenol correspond to a P/O quotient of 2–3 as compared to the experimental carbon conversion. With chlorinated derivatives, e.g. 2,4-dichlorophenoxyacetic acid or pentachlorophenol, the apparent gain in energy reflects a P/O < 1, indicating uncoupling effects during growth on such compounds.

Pharmacological classification and renal actions of diuretics.

Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium.

Separation of some chlorophenoxyacetic acid congeners on a porous graphitized carbon column

The retentions of twelve phenoxyacetic acid derivatives were measured on a porous graphitized carbon (PGC) column using dioxane-water mobile phases without additives and with added sodium acetate, acetic acid and lithium chloride. Good linear correlations were found between the capacity factors and the dioxane concentration in the mobile phase. The number of substituents on the benzene ring and their hydrophilicity most strongly affected the retention behaviour of phenoxyacetic acid derivatives with dioxane-water eluents. Sodium acetate had the greatest effect on both retention and selectivity, emphasizing the considerable role of the degree of dissociation of solutes on their retention on a PGC column.

Lack of stereoselectivity in rat liver peroxisomal enzyme induction by optically active phenoxyacetic acids.

To ascertain if there is stereoselectivity in peroxisomal proliferation induced by chiral peroxisome proliferators, induction by stereoisomers of 2-methyl-4'-chlorophenoxyacetic acid and 2-methyl-2-(2'-4'-dichlorophenoxy)acetic acid were studied in rat in vivo and in vitro with isolated rat hepatocytes. No significant differences in the inducing potencies of the stereoisomers of the above two phenoxyacetic acid derivatives were found for cyanide-insensitive fatty acyl-CoA oxidizing system, fatty acyl-CoA oxidase, carnitine acetyltransferase or carnitine palmitoyltransferase. There was also no significant difference in the degree of hepatomegaly or lipid-lowering effect between the isomers. The findings with cultured rat hepatocytes agreed with those of the studies in vivo.

Characteristics of induction of peroxisomal fatty acid oxidation-related enzymes in rat liver by drugs: Relationships between structure and inducing activity

To clarify the mechanism of induction of hepatic peroxisome-associated enzymes by drugs, we examined the interrelationship between the structures of fifteen drugs of two types (phenoxyacetic acid derivatives and perfluorinated compounds) and their inducing activities. Male Wistar rats were given the drugs at 150 mg/kg body weight daily for 2 weeks, and then hepatic activities of fatty acid metabolism-related enzymes were determined. The activity of the cyanide-insensitive fatty acyl-CoA oxidizing system located in peroxisomes was increased significantly in the following order: 2,4,5-trichlorophenoxypropionic acid (12.5-fold) > 2,4-dichlorophenoxypropionic acid (6.6-fold) > clofibrate (4.5-fold) > 2-methyl-4-chlorophenoxyacetic acid (2.6-fold) > 2,4,5-trichlorophenoxyacetic acid (2.5-fold) > p-chlorophenoxypropionic acid (2.4-fold) > 2,4-dichlorophenoxyacetic acid (1.7-fold). Treatment with perfluorinated compounds, perfluorobutyric acid, perfluorooctanoic acid, perfluorodecanoic acid and perfluorooctanol, also induced the activity by 2-, 4.3-, 3.1- and 2.0-fold respectively. The profile of the induction of carnitine acetyltransferase by these compounds was quite similar to that of cyanide-insensitive fatty acyl-CoA oxidizing system. Lipophilicity of these drugs was determined by the octanol-water partition method. Among these drugs, 2,4,5-trichlorophenoxypropionic acid showed the largest octanol/water partition coefficient (log P = 0.39). These results show a strong correlation among the number of chlor-substitutions on the phenyl moiety, the methyl-group on the alpha position of the acetic acid moiety, lipophilicity and the inducibility of peroxisomal fatty acid oxidation-related enzymes.

Characteristics of Peroxisome Proliferation: Co-induction of Peroxisomal Fatty Acid Oxidation-Related Enzymes with Microsomal Laurate Hydroxylase.

The profile of the changes in the peroxisomal fatty acid oxidation activity in rat liver was compared with that in microsomal omega-oxidation under various conditions such as a 2-week administration of phenoxyacetic acid derivatives and perfluorinated compounds, short and long-term administration of clofibrate and bezafibrate, high-fat diet feeding, starvation and diabetes. The results were summarized as follows: 1) when phenoxyacetic acid derivatives and perfluorinated compounds were administered, there was a significant correlation in the increase of the activities between peroxisomal fatty acid oxidation and microsomal omega-oxidation. 2) On the long-term administration (79 weeks) of peroxisome proliferators the activities of the enzymes were significantly reduced, but the levels were still higher than the control level in a similar manner. 3) On high-fat diet feeding the patterns of the changes in the activities of peroxisomal fatty acid oxidation, carnitine acetyltransferase and microsomal omega-oxidation were similar to each other, differing from the changes in the activities of microsomal aminopyrin demethylase and mitochondrial carnitine palmitoyltransferase. 4) Under starved and diabetic conditions, co-induction of peroxisomal fatty acid oxidation and microsomal omega-oxidation was observed. From these results it is suggested that 1) the biosynthesis of these enzymes would be regulated on the gene expression of the nearby domain and 2) peroxisomal fatty acid oxidation and microsomal omega-oxidation were co-operatively regulated in order to achieve fatty acid metabolism smoothly.

Chromatographic approaches to the quality control of chiral proprionate anti-inflammatory drugs and herbicides

The chiral analysis of a range of proprionate anti-inflammatory drugs and herbicides was accomplished by gas chromatographic separation of their R-α-phenylethylamide diastereomeric derivatives. Using a packed column (3% OV-1 on Chromosorb G) good separations were obtained but analysis times were rather long. Examination of the same crystalline derivatives using a capillary column (bonded methylsilicone) resulted in good separations together with much reduced total analysis times. The technique was validated through the analysis of several derivatives prepared on a micro scale and examined directly by gas chromatography without any crystallisation step. Racemic materials all gave virtually 50:50 response ratios while the analysis of optically pure samples produced no evidence of significant racemisation. Derivatives of phenoxyacetic acid and myristic acid were also prepared and chromatographed as potential internal standards.

I. Uptake of phenylacetic acid by Penicillium chrysogenum WIS 54-1255: A critical regulatory point in benzylpenicillin biosynthesis.

The transport system of phenylacetic acid (PA) in Penicillium chrysogenum was studied. Kinetic measurements were carried out "in vivo" at 25 degrees C in 0.06 M phosphate buffer at pH 6.5. Uptake was a linear function of time over 3 minutes and the Km was 5.2 microM. PA uptake was inhibited by 2,4-dinitrophenol, 4-nitrophenol, sodium azide, potassium cyanide. N-ethylmaleimide, amino acids, xylose and fatty acids whereas lactose and ribose stimulated it. Benzylpenicillin, phenoxymethylpenicillin, penicillins DF, K and 6-aminopenicillanic acid did not modify uptake whereas phenoxyacetic acid and many phenyl derivatives strongly inhibited the incorporation of PA. PA transport is an inducible system that is strictly regulated by the carbon source used for P. chrysogenum growth. Uptake is not induced by phenoxyacetic acid and is repressed by L-lysine. The absence of the PA transport system when P. chrysogenum is grown in the presence of readily metabolized sugars and its repression by L-lysine suggests that this is a critical regulatory point in the control of benzylpenicillin biosynthesis.

Radioiodinated phenoxyacetic acid derivatives as potential brain imaging agents. I. Efficient synthesis via trimethylsilyl intermediates.

The usefulness of radioiodination via demetallation of aryltrimethylsilanes was demonstrated. The radioiodination reaction was found to be very rapid and the regiospecific incorporation of radioiodine could be carried out with high radiochemical yields and high radiospecific activity. 125I-Labeled dimethylaminoethyl iodophenoxyacetate derivatives (5a--e), dimethylaminoethyl iodophenoxyacetamide derivatives (7a--c), iodophenoxyethyl ethylenediamine derivatives (9,14) and an iodophenoxyethylpiperazine derivative (18) were efficiently synthesized from the corresponding aryltrimethylsilyl intermediates (4a--e, 6a--c, 8, 13, 17) by this method.

Radioiodinated phenoxyacetic acid derivatives as potential brain imaging agents. II. Structure-biodistribution relationship.

In developing new brain imaging agents for single photon emission computed tomography (SPECT), we synthesized eleven radioiodinated phenoxyacetic acid derivatives and investigated the relationship between the chemical structure and in vivo characteristics. Biodistribution studies in mice revealed high initial brain uptake for all the compounds. Blood radioactivity level depended markedly upon the chemical stability of the compound. The alpha, alpha-dimethylester derivative (1e), amide derivatives (2a--c) and diamine derivatives (3a, b, 4), which were stable to hydrolysis, showed low blood activity levels following i.v. administration. Disappearance of the ester and amide compounds from the brain was rapid. However, the diamine derivatives displayed improved retention in the brain. Compounds 3a and 4 possessed the best combination of high brain uptake and sufficient retention to be useful as potential brain imaging radiopharmaceuticals with SPECT devices.

Synthesis and diuretic activity of phenoxyacetic acid and anisole derivatives

It is known ethacrynic acid, or 4-(2-methylenebutyryl)-2,3-dichlorophenoxyacetic acid (I), has high diuretic activity [I]. At present, definite interest has been shown in the search for diuretics among compounds with a structure similar to that of I. As the result of investigations among the derivatives of I, very effective diuretics have been found [3-7, 12, 15, 16]. Like I, most of these contain two chlorine atoms and an OCH~COOH group in their molecule, and they differ from one another in the structure of the substituent at the 4-position of the benzene ring.

Induction of rat hepatic long-chain acyl-CoA hydrolases by various peroxisome proliferators

Induction of cytosolic long-chain acyl-CoA hydrolases was investigated in rat liver after administration of various peroxisome proliferators and related compounds. Treatment of rats with di-(2-ethylhexyl)-phthalate, di-(2-ethylhexyl)-adipate or tiadenol induced hydrolases i and II, while acetylsalicylic acid induced only hydrolase II. Among the various phenoxyacetic acid derivatives and related compounds, 2,4,5-trichlorophenoxyacetic acid, 2-(4-chlorophenoxy)-2-methylacetic acid, 2-(2-chlorophenoxy)2-methylpropionic acid and clofibric acid induced both hydrolases I and II, whereas 2, 4-dichlorophenoxyacetic acid induced only hydrolase II. All nine of the above-mentioned inducers also markedly increased the activity of peroxisomal β-oxidation. Other compounds tested (2-chlorophenoxyacetic acid, 4-chlorophenoxyacetic acid, 4-chlorophenol, phenoxyacetic acid and phenoxy-2-methylacetic acid) were ineffective as inducers. These results suggest that inducers of acyl-CoA hydrolase II also enhance peroxisomal β-oxidation activity, but do not necessarily induce acyl-CoA hydrolase I. The structure-inducing activity relationships of these compounds are discussed.

Induction of microsomal stearoyl-CoA desaturase by the administration of various phenoxyacetic acid derivatives.

The potency of seven phenoxyacetic acid derivatives to induce microsomal stearoyl-CoA desaturation activity in rat liver was compared with that of 2-(4-chlorophenoxy)-2-methyl-propionic acid (clofibric acid). These compounds were given to rats with diet. Of seven phenoxyacetic acid derivatives tested, both 2-(4-chlorophenoxy)-propionic acid and 2-(2-chlorophenoxy)-2-methyl-propionic acid increased considerably the desaturation activity as was observed with clofibric acid. Moreover, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) also increased the desaturation activity, although the inducing effect on desaturation activity was very weak compared to that of clofibric acid. These three compounds increased activity of terminal desaturase without accompanying marked changes in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase activity and cytochrome b5 content as was the case with clofibric acid. The other four phenoxyacetic acid derivatives, 2-(phenoxy)-propionic acid, 4-chlorophenoxyacetic acid, 2-chlorophenoxyacetic acid and 2, 4-dichlorophenoxyacetic acid (2,4-D) changed scarcely the desaturation activity. These compounds had no influence on NADH-cytochrome b5 reductase activity, cytochrome b5 content and terminal desaturase activity. Correlating with the changes in the desaturation activity, concentration of octadecenoic acid was increased in hepatic microsomes, whole liver and serum. Treatment with clofibric acid did not change the concentration of octadecenoic acid in brain, lung, heart, spleen, testis and adipose tissue.

Degradation of chlorinated derivatives of phenoxyacetic acid and benzoic acid byAspergillus niger

Degradation of chlorinated derivatives of phenoxyacetic acid and benzoic acid by<i>Aspergillus niger</i>

Degradation of chlorinated derivatives of phenoxyacetic acid and benzoic acid by Aspergillus niger

Degradation of chlorinated derivatives of phenoxyacetic acid and benzoic acid by Aspergillus niger