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At least 19 recordsLinked to original sources
PubMed1993

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.

The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA), were examined in female Sprague-Dawley rats. All four carboxylic acids evidenced dose-dependent disposition. A dose-related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose-dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose- and compound-dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base-labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base-labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis-Menten kinetics, although the calculated Km was dose-dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.

Animals↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.

Animals↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. III. Pharmacokinetics of valproic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid in the bile-exteriorized rat.

The pharmacokinetics of valproic acid (VPA) and its structural analogs cyclohexanecarboxylic acid (CCA) and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) were examined in bile-exteriorized rats. A 0.52 mmol/kg dose (equivalent to 75 mg/kg VPA) of test compound (N = 4 rats per compound) was administered as an intravenous bolus. VPA, CCA, and MCCA concentrations in serum, bile, and urine were determined by gas chromatography before and after incubation in sodium hydroxide to hydrolyze base-labile conjugates. Concentration-time profiles of these compounds in serum displayed apparent Michaelis-Menten kinetics. Serum concentrations of base-labile conjugates were similar to parent concentrations for VPA, were an order of magnitude lower than parent concentrations for CCA, and were undetectable for MCCA. Urinary recovery of base-labile (apparently glucuronide) conjugates in the bile-exteriorized rat was 28.8%, 12.0%, and 25.2% of the administered dose for VPA, CCA, and MCCA, respectively. In contrast, more than 50% of the dose for VPA and MCCA was recovered in bile as the base-labile conjugate, with less than 5% of the CCA dose recovered via this excretory route. Bile flow was stimulated significantly by VPA and MCCA, but not by CCA; changes in bile flow correlated with the biliary excretion rate of base-labile conjugates rather than with excretion of the parent compounds themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Novel, predicted patterns of supramolecular self-assembly, afforded by tetrameric R44(12) rings of C2 symmetry in the crystal structures of 2-hydroxy-1-cyclopentanecarboxylic acid, 2-hydroxy-1-cyclohexanecarboxylic acid and 2-hydroxy-1-cycloheptanecarboxylic acid.

Determination of the crystal structures of the homologous (1R*,2R*)-trans-2-hydroxy-1-cyclopentanecarboxylic acid (5T), (1R*,2S*)-cis-2-hydroxy-1-cyclohexanecarboxylic acid (6C) and (1R*,2S*)-cis-2-hydroxy-1-cycloheptanecarboxylic acid (7C) proved a predicted pattern of supramolecular close packing. The prediction was based on the common features observed in the crystal structures of six related 2-hydroxy-1-cyclopentanecarboxylic acids and analogous carboxamides [Kálmán et al. (2001). Acta Cryst. B57, 539-550]. This pattern is characterized by tetrameric R(4)(4)(12) rings of C(2) symmetry formed from dimeric R(2)(2)(12) rings. The C(2) symmetry of such tetramers is not common in the literature, usually they have C(i) symmetry. Both types of tetramers are formed from dimers with similar or opposite orientation. The R(2)(2)(12) dimers differ in their hydrogen bonds. In 5T the monomers are joined by a pair of O1[bond]H...O2[double bond]C bonds, whereas in 7C they are joined by a pair of O3[bond]H...O1-H bonds. In 6C 60% of the disordered R(2)(2)(12) dimers are similar to those in 7C, while 40% resemble those in 5T. Apart from these hydrogen-bonding differences and the ring-size differences, the three crystals exhibit isostructurality.

Journal Article↗
PubMed1985

Intracellular localization and some properties of the system in guinea pig liver responsible for the aromatization of cyclohexanecarboxylic acid to hippuric acid.

The conversion of cyclohexanecarboxylic acid to hippuric acid in subcellular fractions from guinea pig liver was studied using a gas chromatographic-mass spectrometric method employing selected ion monitoring. Comparison of the activities of the cyclohexanecarboxylic acid to hippuric acid converting system (CHC-system) and marker enzymes in the various subcellular fractions showed that the CHC-system is localized exclusively in the mitochondria. No contribution to the total activity of the system was made by microsomal enzymes. The activity of the CHC-system in whole liver homogenate and in isolated mitochondria was similar when the latter were supplemented with ATP, alpha-ketoglutaric acid, glycine, ethylenediaminetetraacetate, PO4(3-) and Mg2+. The formation of hippuric acid in these mitochondrial preparations was linear with respect to time over a period of at least 60 min. Studies designed to optimize the incubation conditions showed that the activity of the CHC-system was reduced by PO4(3-) concentrations greater than approximately 70 mM. Conversely, both ATP and alpha-ketoglutaric acid stimulated the system. It is possible that two different types of acyl-CoA synthetases, one which is ATP-specific and one which is GTP-specific, may operate in the activation of cyclohexanecarboxylic acid.

Adenosine Triphosphate↗
PubMed1985

The aromatization of cyclohexanecarboxylic acid to hippuric acid: substrate specificity and species differences.

The ability to convert cyclohexanecarboxylic acid to hippuric acid has been studied in liver from guinea pigs, rabbits, rats and mice using a gas chromatographic - mass spectrometric method employing selected ion monitoring. Guinea pig liver showed the highest activity, giving values double of those found in rabbit liver and five times those in rat liver. Only very weak activity was found in mouse liver. (Hydroxymethyl)cyclohexane, cyclohexanealdehyde and alpha-hydroxyethylcyclohexane, which are structurally related to cyclohexanecarboxylic acid but lack the carboxyl group, were not aromatized by guinea pig liver mitochondria. This finding indicates that the carboxyl group is essential for aromatization. Absence of aromatization was also found with the homologs cyclohexaneacetic acid and cyclohexanepropionic acid and with the di-acids trans-1,2- and trans-1,4-cyclohexanedicarboxylic acid. The effect of a methyl group in cyclohexanecarboxylic acid depended on its position. 2-Methyl-1-cyclohexanecarboxylic acid was not aromatized, however the 3- and 4-methyl derivatives underwent aromatization and subsequent conjugation with glycine. The rates of formation of m-methyl- and p-methylhippuric acid were 16% and 9%, respectively, of that found for hippuric acid from cyclohexanecarboxylic acid (8.0 nmol/min/mg protein).

Animals↗
PubMed1977

The metabolism of cyclohexanecarboxylic acid in the isolated perfused rat liver.

1. Cyclohexanecarboxylic acid in isolated perfused rat livers was eliminated from the perfusion system by a first-order process. 2. After 6 h, 16% was excreted in bile as cyclohexylcarbonyl beta-D-glucuronide. The remainder was present in the perfusate as unchanged cyclohexanecarboxylic acid (10%), hippuric acid (50%), hexahydrohippuric acid (2%), 3,4,5,6-tetrahydrohippuric acid (2%), cyclohexylcarbonyl-beta-D-glucuronide (2-4%) and benzoic acid (1-2%). Six per cent of the dose was associated with the red blood cell present in the perfusion medium. 3. Unlike the whole animal, the isolated rat liver produced no detectable benzoyl glucuronide. 4. The identity and kinetics of production of the metabolites are consistent with a metabolic pathway previously proposed for cyclohexanecarboxylic acid and shikimic acid.

Animals↗
PubMed1982

The metabolism of cyclohexanecarboxylic acid and 3-cyclohexenecarboxylic acid by Pseudomonas putida.

A strain of Pseudomonas putida grew rapidly on cyclohexanecarboxylic acid as a sole source of carbon. A CoA-mediated beta-oxidation pathway was induced for the metabolism of the compound. The organism could not utilize 3-cyclohexenecarboxylic acid as a sole source of carbon for growth, but cells grown on gluconate in the presence of 3-cyclohexenecarboxylic acid were induced to metabolize cyclohexanecarboxylic acid, benzoic acid, and catechol. Evidence is presented that 3-cyclohexenecarboxylic acid was slowly metabolized by a beta-oxidation pathway and by a pathway involving benzoic acid as an intermediate. For this strain of Pseudomonas putida, 3-cyclohexenecarboxylic acid acts as an oxidizable, nongrowth substrate and induces the metabolism of cyclohexanecarboxylic acid and benzoic acid.

Cyclohexanecarboxylic Acids↗
PubMed2001

Synthesis of a broad array of highly functionalized, enantiomerically pure cyclohexanecarboxylic acid derivatives by microbial dihydroxylation of benzoic acid and subsequent oxidative and rearrangement reactions.

[reaction: see text]. We have found that the 1,2-dihydroxylation of benzoic acid with Alcaligenes eutrophus strain B9, first reported in 1971 by Reiner and Hegeman, is readily adapted for the preparation of tens to hundreds of grams of (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylic acid of >95% ee. This unique substrate undergoes many specific oxidative and rearrangement processes. Among these are transformations of unanticipated chemical novelty and many products that have not been previously described.

Benzoic Acid↗
PubMed1975

The aerobic metabolism of cyclohexanecarboxylic acid by Acinetobacter anitratum.

1. The aerobic metabolism of cyclohexanecarboxylic acid by a bacterium isolated from garden soil (Acinetobacter anitratum) was investigated. 2. Evidence for the formation of cyclohex-1-ene-1-carboxylate, 2-hydroxycyclohexanecarboxylate and pimelate when either cell suspensions or cell-free extracts were incubated in the presence of cyclohexanecarboxylic acid is presented. 3. Crude cell-free extracts required ATP, CoA, FAD and Mg2+ as cofactors for the production of pimelate from cyclohexanecarboxylic acid, suggesting the existence of an activating reaction with formation of CoA esters, in this system.

Acinetobacter↗
PubMed1978

The microbial degradation of cyclohexanecarboxylic acid by a beta-oxidation pathway with simultaneous induction to the utilization of benzoate.

The metabolism of cyclohexanecarboxylic acid by a bacterium, designated PRL W19, follows a pathway involving beta-oxidation of coenzyme A intermediates analogous to the classical oxidation of fatty acids. The organism appears to have the property for the constitutive metabolism of caproic acid, and cell extracts contain high levels of the enzymes required for the functioning of the fatty acid cycle. However, the metabolism of cyclohexanecarboxylic acid requires induction by growth or incubation with an appropriate substrate. Extracts of induced cells contain several enzyme activities which are synthesized in response to the induction process. These enzymes include cyclohexanecarboxyl-CoA synthetase, cyclohexanecarboxyl-CoA dehydrogenase, 1-cyclohexenecarboxyl-CoA hydratase, and trans-2-hydroxycyclohexanecarboxyl-CoA dehydrogenase. A characteristics feature of this organism is that it becomes induced for the metabolism of benzoate and catechol during growth on cyclohexanecarboxylic acid, but benzoate does not appear to be an obligatory intermediate in the metabolism of cyclohexanecarboxylic acid.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1982

A cyclohexanecarboxylic acid utilizing yeast: isolation, identification, and nutritional characteristics.

A yeast capable of utilizing cyclohexanecarboxylic acid as sole carbon and energy source, strain KUY-6A, was isolated from soil by enrichment cultures. Taxonomical studies indicated that strain KUY-6A was Trichosporon cutaneum. Strain KUY-6A grew on a number of carboxylic acids. Among the cyclic compounds tested, cyclohexanecarboxylic acid was the best substrate. Cyclopentanecarboxylic acid, cycloheptanecarboxylic acid, cyclopentanone, cyclohexanone, and cyclopentanol also supported growth. In addition, the organism used the monocarboxylic acids, butyric, valeric, and caproic; the dicarboxylic acids succinic, glutaric, adipic, pimelic, and suberic; and the aromatic acids, benzoic and o-, m-, and p-hydroxybenzoic. The yeast did not require any vitamins for growth, although thiamine gave slight stimulation. The cell dry weight yield was 0.75 g from 1 g cyclohexanecarboxylic acid used.

Cyclohexanecarboxylic Acids↗
PubMed1997

Excretion of benzoic acid derivatives in urine of sheep given intraruminal infusions of 3-phenylpropionic and cyclohexanecarboxylic acids.

The quantitative relationship between the urinary excretion of benzoic acid (BA) and the uptake of 3-phenylpropionic (PPA) and cyclohexanecarboxylic (CHCA) acids was assessed. PPA and CHCA are produced in the rumen by microbial fermentation of lignocellulosic feeds and metabolized, after absorption, to BA which is excreted in the urine mainly as its glycine conjugate hippuric acid (HA). Four sheep nourished by intragastric infusions of all nutrients were given continuous ruminal infusions of PPA (8, 16 or 24 mmol/d) either alone or with CHCA (8 or 16 mmol/d) in a factorial experiment. The treatments were allocated to ten consecutive 6 d periods, with a control being repeated at periods 1, 5 and 10. PPA and CHCA ruminal absorption rates, estimated using the liquid-phase marker Cr-EDTA, were 0.78 (SD 0.29)/h and 0.88 (SD 0.28)/h respectively. For the control, HA excretion was only 0.22 (SD 0.33) mmol/d and free BA was absent. For the other treatments, both HA and free BA were present and HA accounted for 0.85 (SD 0.05) of total BA: The urinary excretion of total BA showed a significant linear correlation (r = 0.997, P < 0.001) with the amounts of PPA and CHCA infused. The urinary recovery of infused PPA and CHCA as total BA was 0.79 (SE 0.01). Faecal excretion of BA and its precursors was negligible. Results of this study show that urinary total BA is a potential estimator of the absorption of PPA + CHCA produced in the rumen.

Absorption↗
PubMed1978

Stereochemistry of cis-2-hydroxy-2-phenyl-cyclohexanecarboxylic acid (cicloxilic acid).

The configuration of cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) was deduced by comparing its NMR and IR spectra with those of its diastereoisomer and of their respective analogs, the 1-hydroxy(bicyclohexyl)-2-carboxylic acids. The diastereoisomer was prepared by converting cicloxilic acid to the corresponding 2-chloro-2-phenyl-cyclohexanecarboxylic acid and subsequent hydrolysis of the latter with aqueous solvents in the presence of wet silver oxide, or by simple solvolysis. The pair of 1-hydroxy(bicyclohexyl)-2-carboxylic acid was prepared from the respective phenylic terms by catalytic hydrogenation. Comparison of the NMR spectra revealed the spatial arrangement of the -H and -COOH groups on the carbon-alpha atom and the study of the interaction between the substitutents -OH and -COOH by IR spectrography revealed the position of the -OH group with respect to the -COOH group, as a result of which the configuration and conformation of the compounds under study were established. Cicloxilic acid is thus represented by the steric formula 4.

Chemical Phenomena↗
PubMed1994

Biosynthetic studies on the origin of the cyclohexanecarboxylic acid moiety of ansatrienin A and omega-cyclohexyl fatty acids.

Feeding experiments with [2,6,10,10-2H4]chorismate in Streptomyces collinus (ansatrienin A) and Alicyclobacillus acidocaldarius (omega-cyclohexyl fatty acids), and inhibitor experiments with glyphosate in the latter organism, have shown that the biosynthesis of cyclohexanecarboxylic acid branches off from the shikimate pathway at a point prior to enolpyruvylshikimate 3-phosphate, either at shikimate or shikimate 3-phosphate.

Bacillaceae↗
PubMed1977

Metabolism and distribution of cyclohexanecarboxylic Acid, a plant growth stimulant, in bush bean.

A foliar spray of 10 mm cyclohexanecarboxylic acid (CHC), a component of the growth stimulant naphthenic acid, to primary leaves of 14-day-old plants of bush bean, Phaseolus vulgaris L., cv Top Crop, resulted in increased vegetative growth and pod production. One minute after the application of 0.5 mm CHC-7-(14)C (CHC(*)) to a primary leaf, CHC(*) was present within it. The chief conversion of the CHC(*) in the leaf during the interval 15 minutes to 4 hours after the acid had been applied appeared to be CHC(*) to its glucose conjugate (CHC(*)-G), and during 4 to 48 hours, CHC(*)-G to CHC(*)-aspartate and an unknown metabolite. Radioactivity was confined to the leaf for at least 1 hour, but by the 12th hour was detected throughout the plant. In the interval 1 to 4 weeks after CHC(*) application, the mean percentage distribution of radioactivity was: treated leaf, 65.3; roots, 18.8; stem, 7.7; trifoliate leaves, 5.9; flower buds-flowers-pods, 2.3. During this period CHC(*)-G was the most prominent metabolite in all organs; no free CHC(*) was detected. Light favored the movement of CHC(*) conjugates out of the leaf; glucose fed to dark-grown plants substituted for light to some extent but aspartate was relatively ineffective, suggesting the dependence of outward movement on ATP. The presence of the glucose and aspartate conjugates of the acid in all organs of CHC-treated plants and the absence of free CHC from them suggest that one or both conjugates, rather than the acid itself, are involved in growth stimulation.

Journal Article↗
PubMed1984

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid, a nitrosourea with latent activity against an experimental solid tumor.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid (N-Me-cis-CCCNU) was synthesized in five steps from cis-4-aminocyclohexanecarboxylic acid via an N-tosylated intermediate. N-Me-cis-CCCNU, which is incapable of the facile decomposition that characterizes the clinically useful nitrosoureas, effected a significant cure rate of both early and established murine Lewis lung carcinoma, even though its in vitro half-life was approximately 5.5 times that of the unmethylated parent compound. This is the first observation of latent activity of a nitrosourea against an experimental solid tumor.

Animals↗
PubMed1977

Cellular response to treatment with 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid, a water-soluble nitrosourea derivative.

The lethal effects of 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid (cis-acid), a water-soluble nitrosourea derivative, were investigated on a human lymphoma cell line. The survival of asynchronous cells exposed to increasing concentrations of the drug was characterized by a threshold exponential curve (Do = 20 microgram/ml; Dq = 20 microgram/ml, 1 hour) similar to that of other nitrosourea derivatives. cis-Acid exerted its main killing effect on cells in early S and in late G2 phase. Cells in mid S and early G1 phase were tenfold more resistant. Changes in survival response as a function of cell cycle stage were reflected primarily by changes in the extent of the shoulder region of the survival curve. In contrast to other nitrosoureas, the lethal effectiveness of cis-acid in solution was stable and the drug could sterilize large numbers of cells in short periods of time. Another important major difference observed for cis-acid with respect to classic nitrosourea derivatives was the capacity of treated cells to recover from sublethal and potentially lethal damage. Our studies have shown that cis-acid is as effective in killing cultured human lymphoma cells as other nitrosoureas, but possibly with a mechanism different from that of these compounds. The major shortcoming noted for cis-acid, namely the capacity of treated cells to recover from drug-induced damage, is offset by the relatively long stability of its killing effect. This, and the fact that cis-acid can be administered in an aqueous solution, make this agent an appealing compound for clinical trials.

Antineoplastic Agents↗