SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
[reaction: see text] Monodentate phosphoramidites, in particular PipPhos and its octahydro analogue, are excellent ligands for the rhodium-catalyzed asymmetric hydrogenation of aromatic enol acetates, enol carbamates, and 2-dienol carbamates up to 98% ee. These latter substrates were hydrogenated selectively to the carbamates of the allyl alcohol.
Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyrylcholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, Ki, Ki', kc, and ki were measured for nine different carbamates. The values were plotted according to Hammett, Taft-Kutter-Hansch, and Swan-Lupton to obtain constants that correlated the chemical nature of the substituents with inhibition potency. It was found that the negative charges of tetrahedral intermediates were more stabilized by ortho electron-withdrawing substituents of the inhibitors in butyrylcholinesterase than in acetylcholinesterase. This result confirmed formation of 3-pronged hydrogen bonds for the oxyanion hole of butyrylcholinesterase and 2-pronged hydrogen bonds for the oxyanion hole of acetylcholinesterase. Furthermore, it was found that ortho electron-donating substituents of the inhibitors accelerated inhibition of butyrylcholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyrylcholinesterase were different from those for acetylcholinesterase and cholesterol esterase; ortho substituents in the tetrahedral intermediates were located far from the negatively charged carbonyl oxygens in butyrylcholinesterase, but close to the negatively charged carbonyl oxygens in acetylcholinesterase and cholesterol esterase. In conclusion, electron-donating substituents in the ortho position were better inhibitors of butyrylcholinesterase than acetylcholinesterase, while electron-withdrawing substituents were better inhibitors of acetylcholinesterase.
Phosphoryloxymethyl carbonates and carbamates of the type R1R2X-CO-O-CH2-O-PO3(-2) (X = O or N) were evaluated as potentially novel water-soluble collapsible prodrugs for alcohols and amines. These were prepared by reaction of alpha-chloromethyl chloroformate with the starting alcohol or amine to give the corresponding alpha-chloromethyl carbonate or carbamate, respectively. Reaction with silver dibenzyl phosphate followed by debenzylation by hydrogenolysis gave the desired products. The aqueous chemical stability of the phosphoryloxymethylcarbonyl derivatives of 2-indanol (3a), beta-(3,4-dimethoxyphenyl)ethylamine (3b), and benzocaine (3c) were evaluated. The aqueous hydrolysis of 3a-3c resulted in regeneration of the parent alcohol or amines. As expected, the hydrolytic behaviors of these derivatives were found to differ from that of simple alkyl and aryl phosphomonoesters. The rates of hydrolysis were extremely rapid, with the dianionic phosphate species possessing a higher reactivity than the monoanionic species. This was attributed to the proximity of the phosphate group to the carbonyl moiety. The carbamate derivatives, 3b and 3c, displayed greater chemical stability compared to the carbonate derivative, 3a. Alkaline phosphatases-mediated hydrolysis of the phosphate ester bond in 3c led to a rapid cascade reaction resulting in regeneration of the parent amine, benzocaine. Although the alcohol derivative described here appeared to be too chemically unstable to be ideal as a prodrug, the derivatives of the amines might have some use. They are expected to be cleaved in vivo by alkaline phosphatases.
A tumour initiating dose of ethyl carbamate was administered to mice by subcutaneous injection together with a dose of one of the homologous esters or an ethyl N-alkyl derivative. The homologues used were the methyl, n-propyl and n-butyl esters, and the derivatives were the N-methyl, N-ethyl and N-n-propyl ethyl esters. The mice were then given promoting treatment with croton oil for 28 weeks.Neither the homologous esters nor the N-substituted derivatives of ethyl carbamate had any influence on the yield of tumours in the skin, lung, or liver. However, increasing the dose of ethyl carbamate increased the yields of tumours.
2,5-Dimethylphenacyl (DMP) carbamates (1a-c) released the corresponding free amines or amino acids in high chemical yields, albeit with quantum yields Phi of only 0.04-0.09, upon irradiation in either aprotic or protic solvents. The photoreaction proceeded principally from the triplet excited state via the E-photoenol. The lifetimes of the triplet enol and the E- and Z-enols in the ground state were determined by laser flash photolysis. The primary photoinitiated transformation liberated a carbamic acid derivative, which subsequently decarboxylated to the amino group-containing compound. Exhaustive irradiation of a DMP-protected aniline (1a) in acetonitrile did not provide aniline in quantitative chemical yields, because it was involved in reductive cleavage of the starting material as an electron donor, thereby decreasing the overall deprotection yield (86%). Phenylalanine methyl ester, liberated from 1c, was, however, obtained in excellent chemical yield (97%). It was also found that the carbamates, while thermally stable, released amines with higher quantum yields in acidic methanol solutions. The DMP chromophore is proposed as an excellent photoremovable protecting group for amino acids and, under specific conditions, for amines in organic synthesis and biochemistry.
1. The second-order rate constants of inhibition, k(a), of acetylcholinesterase were measured at pH values between 5.5 and 10.5 for two esters of phosphorus acids and five esters of carbamic acids. Two of the carbamates and one of the phosphates contained a quaternary nitrogen group. 2. For the three positively charged compounds the k(a)-pH plots are bell-shaped, with a pH optimum between 7.5 and 9.0. The changes in k(a) above and below the optimum pH fit theoretical curves for the dissociation of groups on the protein of pK 6.2 and 10.25. 3. For the uncharged compounds, the k(a)-pH plot on the alkaline side is identical with the one obtained for charged inhibitors. On the acid side they do not fit such a curve and the k(a) for two of the carbamates is independent of pH changes between 5.5 and 8.0. 4. The first-order rate constants, k(+3), for spontaneous reactivation were measured at pH values between 5.0 and 11.0 for N-methylcarbamoylated, NN-dimethylcarbamoylated and di-(2-chloroeth)phosphorylated cholinesterase. For all three derivatives the k(+3)-pH plots are bell-shaped, with a pH optimum between 8.0 and 8.5. The changes in k(+3) above and below the optimum fit theoretical curves for the dissociation of groups of pK 6.9 and 9.8. 5. The relevance of these results to binding, acylation and deacylation of both inhibitors and substrates is discussed.
Carbamates are a widely used class of insecticides and herbicides. They were tested for their ability to affect human blood platelet aggregation and arachidonic acid metabolism in platelets. (1) The herbicides of the carbamate type have no, or only little, influence up to a concentration of 100 microM; the carbamate insecticides, however, inhibit both aggregation and arachidonic acid metabolism in a dose- and time-dependent manner. (2) Carbaryl, the most effective compound, inhibits platelet aggregation and cyclo-oxygenase activity completely at 10 microM. The liberation of arachidonic acid from phospholipids and the lipoxygenase pathway are not affected, whereas the products of the cyclo-oxygenase pathway are drastically decreased. (3) By using [14C]carbaryl labelled in the carbamyl or in the ring moiety, it could be proved that the carbamyl residue binds covalently to platelet proteins. In contrast with acetylsalicylic acid, which acetylates only one protein, carbaryl carbamylates a multitude of platelet proteins. (4) One of the carbamylated proteins was found to be the platelet cyclo-oxygenase, indicating that carbaryl resembles in this respect acetylsalicylic acid, which is known to inhibit this enzyme specifically by acetylation.
Lipophilic amino acid methyl ester and methyl amide carbamates of 3'-azido-3'-deoxythymidine (AZT) were synthesized and their anti-HIV-1 activity in PBMCs was determined. The methyl amides were more potent (EC50s = 1.8-4.0 microM) than the methyl esters (EC50s = 2.0-20 microM). Carbamate hydrolysis by cell lysates and liberation of AZT was not observed for representative methyl ester or methyl amide AZT carbamates. No evidence of direct inhibition of HIV reverse transcriptase or integrase was observed.
Eighty-seven populations of California red scale, Aonidiella aurantii (Maskell), from the San Joaquin Valley of California were tested for insecticide resistance by using chlorpyrifos, methidathion, and/or carbaryl in a standard fruit-dip bioassay as well as for general esterase activity by using alpha-naphthyl acetate as a substrate in a colorimetric test. The percentage of individuals that survived a discriminating concentration of methidathion, chlorpyrifos, or carbaryl was significantly correlated with the percentage of individuals showing > 0.4 nmol of esterase activity per minute per microgram of protein in the colorimetric test. Scale survival of the organophosphates showed a higher correlation with esterase activity than survival of carbaryl. These results suggest that the colorimetric test of esterase activity is useful as an indicator of the frequency of organophosphate-resistant and, to a lesser extent, carbamate-resistant individuals in California red scale populations. The results of tests for activity and inhibition of acetylcholinesterase activity suggest that California red scale is using increased amounts of esterase enzymes, including acetylcholinesterase, to sequester organophosphate and carbamate insecticides, rather than modified acetylcholinesterase. Third instars collected from twigs, leaves, and fruit showed similar levels of esterase activity. The colorimetric test of esterase activity is a useful tool to detect organophosphate and carbamate resistance in San Joaquin Valley California red scale because of its speed of testing over a wide range of months, allowing for within-season decision making by citrus growers.
The distribution of organophosphate and carbamate resistance was investigated in 33 samples of Culex pipiens quinquefasciatus Say from 25 cities in Côte d'Ivoire and Burkina Faso. Organophosphate resistance levels were higher in Côte d'Ivoire than in Burkina Faso. Chlorpyrifos resistance ratios at LC95 ranged from 4 to 30 times in Côte d'Ivoire and from 3 to 6 times in Burkina Faso. For temephos, ratios ranged from 3 to 18 and from 1 to 2, respectively. Of 27 samples from Côte d'Ivoire, 25 also displayed cross resistance to carbamates as shown by a mortality plateau in bioassays with propoxur and carbosulfan (similar to chlorpyrifos). Cross resistance to organophosphates and carbamates was caused by an insensitive acetylcholinesterase allele (AceR). This gene was absent from Burkina Faso, except in Niangoloko near the Côte d'Ivoire border. Organophosphate resistance also was associated with the presence of A2-B2 overproduced esterases which had higher frequencies in Côte d'Ivoire (75-100%) than in Burkina Faso (40-50%). Two other esterases with the same electrophoretic mobility as C2 from Puerto Rico and B1 from California were identified for the 1st time in West Africa. "C2" was widespread, whereas "B1" was present in only a few mosquitoes from Côte d'Ivoire. These differences in resistance patterns should be taken into consideration in planning urban mosquito control strategies within 2 countries.
Twenty-five infants and young children intoxicated by carbamate and organophosphorus compounds are described. Presenting signs and symptoms in children differed from those described in adults and were mainly related to severe CNS depression, coma and stupor, dyspnea, and flaccidity. Other clinical signs such as miosis, excessive salivation and tearing, sweaty, cold skin, and gastrointestinal symptoms were less frequent, while fasciculations and bradycardia were quite uncommon on arrival. Only two patients presented with all typical signs of organophosphate poisoning as described in adults. Signs of carbamate poisoning were indistinguishable from those of organophosphate poisoning and included signs of myoneural and CNS cholinergic receptor involvement, in addition to parasympathetic muscarinic dysfunction. Atropine sulfate was found to have a clear beneficial CNS effect in addition to its known peripheral antimuscarinic effect. Our data suggest that the clinical presentation of carbamate and organophosphate poisoning in early childhood and its response to therapy are quite different from those of adults and older children.
Sensitization to rubber is most often due to sensitization to thiurams. Positive patch test reactions to carbamates are less frequent, and usually only diagnosed in patients with positive patch test reactions to thiurams as well. The aim of the present study was to describe the relative frequency of sensitization to thiuram mix (TH mix) and zinc diethyldithiocarbamate (ZDC) in a population where the exposure to these chemicals from rubber gloves was previously studied and considered to be of approximately the same order of magnitude. The thiuram derivatives seemed to be the most important sensitized (frequency 2.8%) compared to ZDC (frequency 0.5%), which has been the most frequently reported sensitizer among the carbamates in rubber gloves. An interesting observation was that the probability that the patient was reacting to ZDC was strongly associated with the strength of the patch test reaction to TH mix. This observation may add a new aspect to the discussion about cross-reactivity versus concomitant sensitization of thiurams and carbamates.
The objectives of the present study were to characterize the presence of selected carbamate and organophosphorous pesticides in Ten Mile Creek (Fort Pierce, FL, U.S.A.) and to evaluate the implications of sampling frequency on ecological risk estimates. Ten Mile Creek originates in a predominately agricultural watershed that is drained by an extensive network of cross-linked canals. Water samples were collected daily or every other day and were analyzed for azinphos-methyl, chlorpyrifos, diazinon, dimethoate, ethion, fenamiphos, malathion, methidathion, carbaryl, carbofuran, 3-hydroxycarbofuran, methiocarb, methomyl, oxamyl, and propoxur. A total of 457 samples were analyzed for the carbamate suite, and a total of 332 samples were analyzed for the organophosphorous suite. Carbaryl was detected in eight samples; half of these detections occurred on four consecutive days (October 26-29, 2001) at concentrations ranging from 0.33 to 0.95 microg/L. Methomyl was detected in samples collected on five consecutive days (March 30-April 3, 2002) at concentrations ranging from 1.0 to 2.2 microg/L. Oxamyl was detected in four samples, three of which occurred on three consecutive days (February 17-19, 2002) at concentrations ranging from 6.2 to 6.8 microg/L. The carbamates propoxur, 3-hydroxycarbofuran, carbofuran, and methiocarb were not detected. Diazinon and ethion were the only organophosphorous pesticides detected. Diazinon was detected at 0.9 and 0.7 microg/L on January 5, 2002, and on January 6, 2002, respectively. Ethion was detected in 18 consecutive samples (August 3-20, 2001). The mean, maximum, minimum, and median detected concentrations were 0.38, 0.61, 0.30, and 0.33 microg/L, respectively. Results indicate that frequent sampling is necessary to characterize the presence of these pesticides in this intensively drained watershed. This conclusion also may apply to similar canalized watersheds.
Two studies evaluated the effects of ammonium carbamate (AC) on preservation and digestibility of high-moisture (HM) Coastal bermudagrass (Cynodon dactylon) hay. A 3 X 7 factorial arrangement of treatments in a completely random design was used to estimate the efficacy of AC in laboratory conditions. Treatments were 25, 30, or 35% moisture (M) forage treated with levels (L) of 0, 1.14, 2.28, 3.42, 4.56, 5.70, or 6.84% AC. Nitrogen in forage increased (P less than .01) linearly due to M and L. There was a linear decrease (P less than .01) in ADF N due to M. Neutral detergent fiber decreased (P less than .01) linearly as M increased and increased (P less than .01) linearly with increased L. Acid detergent fiber decreased (P less than .01) linearly due to L. There was an M X L interaction (P less than .01) for hemicellulose (HC) concentrations and total aerobic fungal counts. The digestibility of HM hay treated with a product (ACNH) containing 57% AC was compared to that of untreated hay (UH) and UH plus urea (UHU) when fed to lambs (four lambs per treatment). Digestibility of NDF and hemicellulose (P less than .01) and ADF (P less than .05) was increased for ACNH forage compared with UH or UHU. Ammonium carbamate seems to be beneficial for preserving HM forage, and an admixture containing ammonium carbamate is effective for increasing the digestibility of Coastal bermudagrass hay.
Visual observations were made to compare the pretreatment benefits of subacute (75 micrograms/hr, sc) and acute (146 micrograms/kg, im, at 30 min) deliveries of physostigmine salicylate (Phy) against 2 or 5 LD50s (60 or 150 micrograms/kg, sc) of soman in guinea pigs; scopolamine, 80 micrograms/kg, im, was given routinely at 30 min. In a second set of studies, pretreatment with subacute carbamate [sc, Phy 36 micrograms/hr or pyridostigmine (Pyr), 50 micrograms/hr] and acute adjunct (im, scopolamine, 0.48 mg/kg, or trihexyphenidyl, 2 mg/kg) at 30 min, was used against soman (5 LD50s, sc) and VX (18.4 micrograms/kg, sc; 2 LD50s); atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) were given at 1 min post soman. In all studies, lethality, % convulsing, convulsive/subconvulsive score, and recovery time were noted. Subacute dosing for 7 days was done via 14-day osmotic minipumps (OMPs). Results of the first set of studies indicate that subacute and acute deliveries of Phy give essentially comparable protection against 2 or 5 LD50s of soman. The second set of studies show that against soman, the adjuncts scopolamine and trihexyphenidyl when compared, and the carbamates, Phy and Pyr when compared, gave similar protective benefits as indicated by all four monitored measures of toxicity. Phy with either adjunct provided excellent protection against VX induced mortality and convulsions. With both carbamates, trihexyphenidyl gave similar protective benefits against VX. Scopolamine, however, under the conditions used herein, failed to act beneficially with Pyr against VX.
Published evidence pertaining to gastrointestinal absorption and metabolism of pesticidal carbamates will be reviewed. The major body of evidence will come form investigations conducted by the author on N-methylcarbamate pesticides with rats; few investigations directly involving the gastrointestinal system have been reported by other research groups. Results derived from in vitro and isolated in vivo preparations show that pesticidal carbamates are absorbed and metabolized by gastrointestinal tissues. Numerous gastrointestinal metabolites have been separated; some have been identified and their behavior in the gut characterized; these data will be included in the review to the extent they have been published. The absorptive and metabolic capacities of the gastrointestinal system vary from one region to another. The author draws from evidence obtained from in vitro and in vivo studies and proposes the events that occur between carbamate ingestion and the appearance of the compound and/or its metabolites in the portal blood or mesenteric lymph. In this endeavor, the author acknowledges that superimposition of the metabolic precursory substrate-product sequence on the sequential physiologic steps from ingestion to defecation produces a complex situation which is difficult if not impossible to study meaningfully by investigation of one tissue component at a time (i.e., epithelial uptake, epithelial metabolism, mucosal to serosal transport, etc.).
A limited number of carbamates have been found useful for treatment of cholinergic symptoms with pyridostigmine and physostigmine being the main focus. In recent years 5-(1,3,3-trimethylindolinyl)N,N-dimethylcarbamate (I) has received considerable attention in the Chinese literature for a similar role. We report on the first synthesis of stereoisomers of an analog of (I). The isomers prepared were (R)(+)-5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate (II) and (S)(-)-5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate (III). The pKa value for each isomer was 6.8. Eel acetylcholinesterase inhibition studies were carried out at 25.0 degrees C over the pH range of 6.0 to 9.0. They reflect the first pH profiles using enantiomorphs of a cholinesterase inhibitor. The inhibition potencies for (II) and (III) over the range examined were similar. At pH 7.60 the ki for II = 7.38 x 10(3) M-1 min-1 (SD = 398) and for (III) the ki = 6.67 x 10(3) M-1 min-1 (SD = 355). In accord with the findings of Wilson and Bergmann20 on physostigmine our results indicate that the protonated form of (II) and (III) is the more potent inhibitor.
Several macromolecular inhibitors of human leukocyte elastase (HLE) were prepared by covalently bonding a low molecular weight HLE inhibitor peptidyl carbamate, p-nitrophenyl-N-[succinyl-L-alanyl-L-ananyl-L-prolylmethyl]- N-isopropyl carbamate 1, with the neutral hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide], PHEA 2. These novel polymeric compounds differed in the molecular size of their PHEA polymer backbone and the extent of loading of the peptidyl carbamate, (PC). They were shown to efficiently inhibit HLE (Ki = 97 to 12.8 nM) as intact macromolecular entities and were found to be more stable to hydrolysis than the non-polymer bound low molecular weight inhibitor 1. The inhibition of HLE by the novel macromolecular inhibitors was found to be noncompetitive and reversible, proceeding via slow formation of inhibitor-enzyme complex. The effect of loading of 1 and molecular size of the PHEA 2 polymer on enzymatic parameters Ki, kon and koff is discussed and a possible mechanism of inhibition is presented.