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PubMed1996

Stereoselective action of (R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino] propyl]-phenoxyacetic acid (BRL37344) on beta-adrenoceptors and metabolic chiral inversion.

Stereoisomers of BRL37344 ((R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2 -(3-chlorophenyl)ethylamino]propyl]-phenoxyacetic acid), a beta 3-adrenoceptor agonist, were synthesized and separated with good resolution by derivatization with 1-anthroyl cyanide prior to chiral HPLC. Agonist effects on rat right atria, guinea pig trachea, and rat brown adipocytes were due principally to the (RR) isomer, while other isomers (SS, RS, and SR) were much less potent or inactive. Since the racemate (RR +/- SS) was half as potent as the (RR) isomer in all specimens tested, the (SS) isomer does not appear to have antagonistic effects. When [14C](RR)BRL35135A ((R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propy l] -phenoxyacetate hydrobromide), the HBr salt of the methyl ester of BRL37344, was administered orally to male Wistar rats, both the (RR) and (SR) isomers of [14C]BRL37344 were detected in plasma, while only the (SS) isomer of [14C]BRL37344 was detected after [14C](SS)BRL35135A administration. These findings indicate that there is clear stereoselectivity in the effects of BRL37344 on beta-adrenoceptors, and that stereoselective chiral inversion from the RR isomer to the SR isomer occurs in rats.

Adipose Tissue, Brown↗
PubMed1996

Improvement of metabolic disorders and visceral fat obesity by the beta 3-adrenoceptor agonist (R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2 -(3-chlorophenyl)ethylamino]propyl]-phenoxyacetate hydrobromide (BRL35135A) in genetically obese rodents.

The effects of BRL35135A ((R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2 -(3-chlorophenyl)ethylamino]propyl]-phenoxyacetate hydrobromide), a beta 3-adrenoceptor agonist, on visceral and subcutaneous fat weight and metabolic disorders were studied in genetically obese C57BL/KsJ db/db mice and Zucker fa/fa rats. In db/db mice, four weeks of oral administration of BRL35135A (0.5 and 5 mg/kg/day) decreased body weight gain and reduced white fat weight. The rates of reduction of white fat weight were in the order mesenteric fat > retroperitoneal fat > subcutaneous fat. In fa/fa rats, daily administration of BRL35135A (0.05 mg/kg/day)) for 6 weeks reduced the visceral white fat weight/total energy intake ratio, particularly for mesenteric fat, without any clear effect on body weight gain. This tendency of the compound to exert effects on visceral fat was consistent with the findings that the effect of BRL37344 ((R*,R*)-(+/-) -methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl]-phenoxyacet ic acid), an active metabolite of BRL35135A, on the lipolytic activity of isolated adipocytes and the tissue concentration of [14C]BRL37344 in male Wistar rats were each greater in visceral fat than in subcutaneous fat. Moreover, BRL35135A at 0.05 mg/kg/day elevated serum insulin levels and improved hyperglycemia in db/db mice without reducing body weight gain, whereas at doses of 0.5 and 5 mg/kg/day it ameliorated hyperglycemia and hyperlipidemia, and tended to decrease serum insulin levels. In fa/fa rats, BRL35135A (0.005 mg/kg/day) was also effective in improving hyperinsulinemia, glucose intolerance, and hypertriglyceridemia without any effect on body weight gain or fat distribution. These findings suggest that the improvement of metabolic disorders by BRL35135A may be due to improvement in insulin resistance as well as reduction of visceral fat weight.

Adipose Tissue↗
PubMed2005

Radiolytic transformations of chlorinated phenols and chlorinated phenoxyacetic acids.

Hydroxyl radical reactions of selected chlorinated aromatic phenols (2,4-dichlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol) and chlorinated phenoxyacetic acids [2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-D methyl ester, 2-(2,4-dichlorophenoxy)propionic acid (2,4-DP)] were studied using the radiolysis techniques of pulse radiolysis and gamma radiolysis. Hydroxyl radical addition was the prominent reaction pathway for the chlorinated phenoxyacetic acids and also for the chlorinated phenols at pH values below the pK(a) of the compounds. A very prominent change in (*)OH reactivity was observed with the chlorinated phenoxide ions in high pH solutions. Two different reaction pathways were clearly present between the hydroxyl radical and the chlorinated phenoxide ions. One of the reaction pathways was suppressed when the concentration of chlorinated phenoxide ions was increased 10-fold. Amid a greater electron-withdrawing presence on the aromatic ring (higher chlorinated phenoxide ions), the hydroxyl radical reacted preferably by way of addition to the aromatic ring. Steady-state experiments utilizing gamma radiolysis also showed a substantial decrease in oxidation with an increase in pH of substrate.

Journal Article↗
PubMed1979

Case-control study: soft-tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols.

In 1977 a number of patients with soft-tissue sarcomas and previous exposure to phenoxyacetic acids were described. Following from these observations a matched case-control study was made. Exposure to chlorophenols was also included in this study. The results showed that exposure to phenoxyacetic acids or chlorophenols gave an approximately 6-fold increase in the risk for this type of tumour. It was not possible to determine, however, whether the carcinogenic effect was exerted by these compounds or by impurities such as chlorinated dibenzodioxins and dibenzofurans that in almost all cases were part of the commercial preparations.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1977

Fate and distribution of the herbicides 2,4-dichlor-phenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) in the dogfish shark.

1. The urinary and biliary excretion, tissue distribution and metabolism of 14C-labelled 2,4-dichloro- or 2,4,5-trichloro-phenoxyacetic acids (2,4-D or 2,4,5-T) were measured in dogfish sharks, Squalus acanthias. 2. Both herbicides are extensively metabolized (greater than 90%) to the corresponding taurine conjugates, and are excreted predominantly via the urine, where ca. 70% of the administered dose appears within 4-6 days after treatment. 3. The highest tissue levels of 2,4-D or 2,4,5-T were found in liver and kidney. Penetration of both herbicides into the CNS was restricted. 4. Plasma elimination was rapid and the 0.5 for either phenoxyacetic acid was less than 45 min. Similarly, rapid clearance as seen from renal tissue. Final t0.5 values for muscle were about 2-3 days while the major organ showing 2,4-D or 2,4,5-T retention was the liver, where t0.5 values were about 5 days for both the herbicides. 5. The overall pharmacokinetics in the dogfish shark for these herbicides resembled those seen in some mammals.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1980

[Chemistry of phenoxyacetic acid esters of oxyalkyltheophyllines and 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (etofylline clofibrate), a novel antilipaemic agent (author's transl)].

Esters of phenoxyacetic acids and oxyalkyltheophyllines were prepared as potential antihyperlipaemics. The basic idea was to ameliorate the known antilipaemic potency of phenoxyacetic acids and that of clofibric acid as the best known representative, respectively, by using alcoholic ester components with therapeutical efficacy of their own and to expand their therapeutical spectrum. Syntheses and preparative routes of these esters are presented. 1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (ML 1024; etofylline clofibrate; Duolip) was selected for further investigations. Characteristics and spectroscopic data of ML 1024 are described.

Chemical Phenomena↗
PubMed1994

Exposure to phenoxyacetic acids, chlorophenols, or organic solvents in relation to histopathology, stage, and anatomical localization of non-Hodgkin's lymphoma.

Results on 105 cases with histopathologically confirmed non-Hodgkin's lymphoma (NHL) and 335 controls from a previously published case-control study on malignant lymphoma are presented together with some extended analyses. No occupation was a risk factor for NHL. Exposure to phenoxyacetic acids yielded, in the univariate analysis, an odds ratio of 5.5 with a 95% confidence interval of 2.7-11. Most cases and controls were exposed to a commercial mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Exposure to chlorophenols gave an odds ratio of 4.8 (2.7-8.8) with pentachlorophenol being the most common type. Exposure to organic solvents yielded an odds ratio of 2.4 (1.4-3.9). These results were not significantly changed in the multivariate analysis. Dichlorodiphenyltrichloroethane, asbestos, smoking, and oral snuff were not associated with an increased risk for NHL. The results regarding increased risk for NHL following exposure to phenoxyacetic acids, chlorophenols, or organic solvents were not affected by histopathological type, disease stage, or anatomical site of disease presentation. Median survival was somewhat longer in cases exposed to organic solvents than the rest. This was explained by more prevalent exposure to organic solvents in the group of cases with good prognosis NHL histopathology.

Acetates↗
PubMed1992

Malignant lymphoproliferative diseases in occupations with potential exposure to phenoxyacetic acids or dioxins: a register-based study.

The Swedish Cancer Environment Register (CER) is a linkage of census data (e.g., on occupations) with the Swedish Cancer Register. It has been used in different studies to generate hypotheses on occupational risk factors for malignant tumors. In this study the risk for malignant lymphoma and multiple myeloma in occupations with potential exposure to phenoxyacetic acids or other related substances were investigated. An increased standardized incidence ratio (SIR) of 1.3 for multiple myeloma was verified in farmers (no. of cases = 335). This finding applied to both sexes, and the SIR increased over successive time periods. Regarding malignant lymphoma an increased SIR of 1.2 was found in farmers (no. = 227) for the latest time period studied (i.e. 1979-1984). When non-Hodgkin's lymphoma was studied separately, an increased risk (SIR = 1.2) was found only in carpenters (no. = 149), whereas for Hodgkin's disease, sawmill workers (no. = 10) had an increased SIR of 2.1. Physicians also had an elevated risk for malignant lymphoma. A major shortcoming in register studies such as CER is that no individual exposure data on different agents are available. Lack of an association between an occupation and a specific malignant disease, therefore, may not be taken as evidence that persons within that occupation are not at increased risk for that disease.

Agricultural Workers' Diseases↗
PubMed1979

Chlorinated phenoxyacetic acid derivatives and tetrachlorodibenzo-p-dioxin in foliage after application of 2,4,5-trichlorophenoxyacetic acid esters.

Six reforestation areas were sprayed with 2,4,5-T esters. Leaf samples from the areas were analyzed for the esters, tetrachlorodioxin, and dehalogenated phenoxyacetic acid esters. Tetrachlorodioxin was found in one leaf sample only, but the level found, relative to the amount of 2,4,5-T ester found, was lower than in the formulation material used in the study. The concentration of the dichlorophenoxyacetic acid esters present in several leaf samples was greater, relative to the 2,4,5-T ester, which indicated a photochemical breakdown of the 2,4,5-T in the environment.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed2000

Genotoxic effect of substituted phenoxyacetic acids.

The potential toxic and mutagenic action of 2,4-dichlorophenoxyacetic acid has been studied in different test systems, and the obtained results range from increased chromosomal damage to no effect at all. We reexamined the effect of this herbicide by simultaneous using three tests based on yeast, transformed hematopoietic, and mouse bone marrow cells. The results obtained demonstrated that 2,4-dichlorophenoxyacetic acid has cytotoxic and mutagenic effects. The positive response of yeast and transformed hematopoietic cells was verified in kinetics and dose-response experiments. The analysis of metaphase chromosomes indicated a statistically proved induction of breaks, deletions, and exchanges after the intraperitoneal administration of 2,4-dichlorophenoxyacetic acid in mice. The study of phenoxyacetic acid and its differently chlorinated derivatives showed that cytotoxicity and mutagenicity are induced by chlorine atoms at position 2 and/or 4 in the benzene ring. The mutagenic effect was abolished by introduction of a third chlorine atom at position 5. Thus 2,4,5-trichlorophenoxyacetic acid was found to have very weak, if any mutagenic effect; however, the herbicide preserved its toxic effect.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed2002

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]phenoxyacetic acid.

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.

Acetates↗
PubMed2001

A new phenoxyacetate-based linker system for the solid-phase synthesis of oligosaccharides.

[structure: see text]. A novel linker system has been designed, and its first application to solid-phase oligosaccharide synthesis is described. The use of the highly reactive o-nitro-phenoxyacetate linker allows a fast and quantitative cleavage using mild basic conditions. This method combined with the trichloroacetimidate glycosylation exhibits highly promising results as demonstrated for the synthesis of tetrasaccharide 1 (n = 3) containing glucose beta(1 --> 4) and beta(1 --> 6) linkages.

Carbohydrate Sequence↗
PubMed1992

Biodegradation of phenoxyacetic acid in soil by Pseudomonas putida PP0301(pR0103), a constitutive degrader of 2,4-dichlorophenoxyacetate.

The efficacy of using genetically engineered microbes (GEMs) to degrade recalcitrant environmental toxicants was demonstrated by the application of Pseudomonas putida PP0301(pR0103) to an Oregon agricultural soil amended with 500 micrograms/g of a model xenobiotic, phenoxyacetic acid (PAA). P. putida PP0301(pR0103) is a constitutive degrader of 2,4-dichlorophenoxyacetate (2,4-D) and is also active on the non-inducing substrate, PAA. PAA is the parental compound of 2,4-dichlorophenoxyacetic acid (2,4-D) and whilst the indigenous soil microbiota degraded 500 micrograms/g 2,4-D to less than 10 micrograms/g, PAA degradation was insignificant during a 40-day period. No significant degradation of PAA occurred in soil inoculated with the parental strain P. putida PP0301 or the inducible 2,4-D degrader P. putida PP0301(pR0101). Moreover, co-amendment of soil with 2,4-D and PAA induced the microbiota to degrade 2,4-D; PAA was not degraded. P. putida PP0301-(pR0103) mineralized 500-micrograms/g PAA to trace levels within 13 days and relieved phytotoxicity of PAA to Raphanus sativus (radish) seeds with 100% germination in the presence of the GEM and 7% germination in its absence. In unamended soil, survival of the plasmid-free parental strain P. putida PP0301 was similar to the survival of the GEM strain P. putida PP0301(pR0103). However, in PAA amended soil, survival of the parent strain was over 10,000-fold lower (< 3 colony forming units per gram of soil) than survival of the GEM strain after 39 days.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1991

Effects of phenoxyacetic acid herbicides on chicken embryo liver drug metabolizing enzymes.

Chick embryos were treated on day 0 of incubation with two phenoxy herbicides, 2-methyl-4-chlorophenoxyacetic acid (MCPA) (0.4, 2 mg/egg) and 2,4-dichlorophenoxyacetic acid (2, 4-D) (1, 2, 4 mg/egg). Both herbicides seemed to exert toxic effects mainly on the liver of 19-day-old embryos. Specific histological analysis indicated biliary stasis. Ethoxycoumarin O-deethylase was depressed by MCPA but raised by 2, 4-D. Other hepatic monooxygenase activities were unaffected by the herbicides and no significant changes were found in cytochromes. The higher dose of MCPA increased NADPH-cytochrome P450 reductase. 2,4-D treatment increased by activity of glutathione-S-transferases in the hepatic post-microsomal fraction while MCPA increased them at the lower dose and significantly reduced them at the higher. The phenoxyacetic herbicides appear thus to have some effects on hepatic drug metabolizing enzymes of the chick embryo which cannot be easily interpreted. Biliary retention, produced in particular by MCPA, could be partly responsible for these effects.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1989

Phenoxyacetic acid degradation by the 2,4-dichlorophenoxyacetic acid (TFD) pathway of plasmid pJP4: mapping and characterization of the TFD regulatory gene, tfdR.

Plasmid pJP4 enables Alcaligenes eutrophus JMP134 to degrade 3-chlorobenzoate and 2,4-dichlorophenoxyacetic acid (TFD). Plasmid pRO101 is a derivative of pJP4 obtained by insertion of Tn1721 into a nonessential region of pJP4. Plasmid pRO101 was transferred by conjugation to several Pseudomonas strains and to A. eutrophus AEO106, a cured isolate of JMP134. AEO106(pRO101) and some Pseudomonas transconjugants grew on TFD. Transconjugants with a chromosomally encoded phenol hydroxylase also degraded phenoxyacetic acid (PAA) in the presence of an inducer of the TFD pathway, namely, TFD or 3-chlorobenzoate. A mutant of one such phenol-degrading strain, Pseudomonas putida PPO300(pRO101), grew on PAA as the sole carbon source in the absence of inducer. This isolate carried a mutant plasmid, designated pRO103, derived from pRO101 through the deletion of a 3.9-kilobase DNA fragment. Plasmid pRO103 constitutively expressed the TFD pathway, and this allowed the metabolism of PAA in the absence of the inducer, TFD. Complementation of pRO103 in trans by a DNA fragment corresponding to the fragment deleted in pRO101 indicates that a negative control-regulatory gene (tfdR) is located on the BamHI E fragment of pRO101. Other subcloning experiments resulted in the cloning of the tfdA monooxygenase gene on a 3.5-kilobase fragment derived from pRO101. This subclone, in the absence of other pRO101 DNA, constitutively expressed the tfdA gene and allowed PPO300 to grow on PAA. Preliminary evidence suggests that the monooxygenase activity encoded by this DNA fragment is feedback-inhibited by phenols.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1984

Prolonged coma and delayed peripheral neuropathy after ingestion of phenoxyacetic acid weedkillers.

A case of prolonged coma and delayed peripheral neuropathy is reported following self-poisoning with a widely available domestic weedkiller containing phenoxyacetic acids. Attention is drawn to the potential toxicity of these weedkillers which may be delayed in onset, and to the possibility of spontaneous recovery from neurological abnormalities which may be severe and prolonged or late in onset.

Coma↗
PubMed1989

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.

Animals↗
PubMed1995

Structure-activity relationship study of TXA2 receptor antagonists. 4-[2-(4-substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds.

We have recently reported that 4-[2-(4-substituted phenylsulfonylamino) ethylthio]phenoxyacetic acids and related compounds showed potent thromboxane A2 (TXA2) receptor antagonist activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) was analyzed by using the Hansch-Fujita method for 36 compounds, including newly synthesized compounds. The positive coefficient for pi R and FR in the results of the QSAR study suggested that a hydrophobic an sigma electron-withdrawing substituent R at the para-position of the phenylsulfonyl moiety is required to improve the activity. Further, a substituent R which is long and moderately wide, was suggested to be preferable for the activity. The positive coefficients for pi X,Y,W-COOH and sigma Q(1)-(6) may indicate that the introduction of a hydrophobic and electron-withdrawing group on the benzene ring of the phenoxy acetic acid moiety enhances the activity. The length of the W-COOH moiety may also be important. On the other hand, the effect of the presence of methylene (n = 1) was not clear.

Animals↗