Hydrolysis of thiocarbamates and trapping of a reactive intermediate in the hydrolysis of N-monosubstituted arylcarbamates and -thiocarbamates.
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Carbamates↗
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The first bipodal thiocarbamic acid ester, O,O'-diethyl N,N'-(p-phenylenedicarbonyl)bis(thiocarbamate).
The title compound, C(14)H(16)N(2)O(4)S(2), is the first reported X-ray crystallographic structure determination of a bipodal O-alkyl N-benzoylthiocarbamate. This compound crystallizes in a cis-S,O orientation (Z,Z' configuration), with the two S/O moieties anti relative to one another, as indicated by the twofold rotation axis located at the center of the benzene ring.
Journal Article↗
Synthesis and in-vitro evaluation of novel low molecular weight thiocarbamates as inhibitors of human leukocyte elastase.
A series of novel low molecular weight thiocarbamate esters (1e-6e) were synthesized and evaluated as inhibitors of human leukocyte elastase (HLE). The thiocarbamate esters studied consist of a substituted primary or secondary aliphatic or aromatic amine and a 1-phenyl-1H-tetrazole-5-thiol (Table I). The HLE catalyzed hydrolysis of N-methoxysuccinyl- L-Ala-L-Ala-L-Pro-L-Val-p-nitroanilide substrate was utilized as the measure of inhibition. N-n-butyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (1e) exhibited the highest inhibitory activity (k(obs) /[I] = 2.1 x 10(5) M(-1). min(-1) ) and N-allyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (2e) (K(obs) /[I] = 6.1 x 10(4) M(-1). min(-1) ) exhibited the second highest inhibitory activity of all the thiocarbamates. The aromatic N-phenyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (4e) showed the lowest inhibitory activity (K(obs) /[I] = 1.9 x 10(2) M(-1). min(-1) ) among the N-monosubstituted derivatives, similar to that of N-ethyl-N-n-butyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (5e) (K(obs) /[I] = 1.8 x 10(2) M(-1).min(-1) ). The N-isopropyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (3e) (K(obs) /[I] = 3.3 x 10(3) M(-1).min(-1) ) was about 10 fold more active than (4e) and N, N-diisopropyl, 1-phenyl-1H-tetrazole- 5-thiocarbamate (6e) showed no inhibitory activity against HLE. In the present work less than 3% of HLE specific activity was regained after 24 hours incubation with each of the tested N-monosubstituted thiocarbamates (1e-4e). The time-dependent inhibition of HLE by the thiocarbamate compounds (1e-5e) seems to involve the interaction and possible chemical modification of one enzyme residue. Straight chain nonpolar aliphatic substituents on the nitrogen of the thiocarbamate functionality may be essential for high inhibitory activity. As the degree of substitution (branching) on the nitrogen of the thiocarbamate functionality increases the inhibitory activity of the compounds decreases. The time-dependent inhibition of HLE and the slow deacylation rates by the N-monosubstituted thiocarbamates are consistent with irreversible inhibition.
Drug Design↗
Palladium(0)-catalyzed enantioselective O,S-rearrangement of racemic O-allylic thiocarbamates: a new entry to enantioenriched allylic sulfur compounds.
Reaction of (+/-)-(E)-pent-3-en-2-ol, (+/-)-(E)-hept-4-en-3-ol, (+/-)-(E)-2,6-dimethylhept-4-en-3-ol, (+/-)-cyclohex-2-en-1-ol, and (+/-)-cyclohept-2-en-1-ol with methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and benzyl isothiocyanate gave the corresponding racemic O-allylic thiocarbamates of medium to good thermal stability in good yields. The palladium(0)-catalyzed rearrangement of the (+/-)-(E)-pent-3-en-2-ol-, (+/-)-(E)-hept-4-en-3-ol-, (+/-)-cyclohex-2-en-1-ol-, and (+/-)-cyclohept-2-en-1-ol-derived O-allylic thiocarbamates at room temperature in methylene chloride by using Pd2(dba)3*CHCl3 (dba = dibenzylideneacetone) as precatalyst and (+)-(1R,2R)-1,2-bis-N-((2-(diphenylphosphino)benzoyl)-1,2-diaminocyclohexane as ligand for the palladium atom proceeded quantitatively and gave the corresponding acyclic (R)-configured S-allylic thiocarbamates and the cyclic (S)-configured S-allylic thiocarbamates with ee values ranging from 85% to > or = 99% in yields of 76-94%. Rearrangement of the O-allylic thiocarbamates carrying a methyl group at the N atom not only was the fastest but also proceeded with the highest enantioselectivity. No rearrangement was observed under these conditions in the case of the racemic N-methyl O-allylic thiocarbamate derived from (+/-)-2,6-dimethylhept-4-en-3-ol, which has a branched carbon skeleton. (S)-cyclohex-2-enethiol of 97% ee was obtained through hydrolysis of the corresponding N-methyl S-allylic thiocarbamate. 2-((R)-(E)-1-methylbut-2-enylsulfanyl)pyrimidine of 91% ee and 2-((S)-cyclohex-2-enylsulfanyl)pyrimidine of 97% ee were synthesized in one synthetic operation from the corresponding N-methyl S-allylic thiocarbamates and 2-chloropyrimidine. Similarly, (S)-cyclohex-2-enylsulfanyl)benzene of 97% ee was obtained in one synthetic operation from the corresponding N-methyl S-allylic thiocarbamate through a palladium(0)-catalyzed substitution of iodobenzene in the presence of a base. The palladium(0)-catalyzed enantioselective rearrangement of O-allylic carbamates to S-allylic carbamates has been extended from the solution phase to the solid phase by using a methyl thioisocyanate polystyrene resin. In the case investigated the enantioselectivity of the rearrangement on the solid phase was considerably lower than that in solution.
Journal Article↗
Inhibition of rat liver low Km aldehyde dehydrogenase by thiocarbamate herbicides. Occupational implications.
S-Methyl N,N-diethylthiolcarbamate (DETC-Me) is a metabolite formed during the bioactivation of disulfiram. The formation of its corresponding sulfoxide, S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), from DETC-Me is required for low Km mitochondrial aldehyde dehydrogenase (ALDH2, EC 1.2.1.3) inhibition. DETC-Me is similar in structure to thiocarbamate herbicides with the general structure R1R2NC(O)SR3. Representative herbicides studied were n-propyl, n-propylthiocarbamate ethyl ester (EPTC), molinate, vernolate, ethiolate and butylate. All of these thiocarbamate herbicides inhibited rat liver ALDH2 in vivo. The dose of these thiocarbamates that inhibited rat liver ALDH2 by 50% (ID50) when administered 8 hr before determination of ALDH2, was found to be 5.2, 3.1, 1.6, 12, and 174 mg/kg, respectively. These thiocarbamates were ineffective rat liver ALDH2 inhibitors in vitro, unless rat liver microsomes and an NADPH-generating system were added to the incubation. The respective thiocarbamate sulfoxides were formed when the thiocarbamates were incubated with liver microsomes and an NADPH-generating system. The thiocarbamate sulfoxides all inhibited rat liver ALDH2 in vitro. An equimolar dose of molinate and molinate sulfoxide inhibited rat liver ALDH2 in vivo to the same degree. Molinate-treated rats challenged with ethanol exhibited a disulfiram-like ethanol reaction. In conclusion, thiocarbamate herbicides inhibit ALDH2, probably due to the formation of their sulfoxide, and therefore have the potential to produce a disulfiram-like ethanol reaction in an unsuspecting population.
Aldehyde Dehydrogenase↗
Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat.
Thiocarbamates are a major class of herbicides used extensively in the agricultural industry. It has been shown that thiocarbamates can form reactive sulfoxide and sulfone intermediates, which may be involved in the toxicity of thiocarbamates through covalent modification of cysteine and serine active sites of enzymes. Molinate has been shown to generate an S-hexahydro-1H-azepine-1-carbonyl adduct on the Cys-125 residue of the beta2- and beta3-chains of rat globin analogous to that reported for disulfiram and to inhibit aldehyde dehydrogenase and nonspecific esterase activity. The present study examined whether other thiocarbamate herbicides produce similar covalent protein modifications and enzyme inhibition to that reported for molinate and whether S-(N,N-dialkylaminocarbonyl)cysteine adduct levels are correlated to enzyme inhibition or the structure of thiocarbamate herbicides. Additionally, the potential of molinate to act as a peripheral demyelinating agent similar to disulfiram was evaluated. To address these aims, rats were exposed ip to molinate, vernolate, ethiolate, EPTC, or butylate for 5 days after which hemogloblin was isolated and analyzed for protein adducts using HPLC and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In addition, brain, liver, and testes mitochondrial and microsomal fractions were assayed for nonspecific esterase, low Km ALDH, or total ALDH activities, and S-(N,N-dialkylaminocarbonyl)cysteine adducts were measured by LC/MS/MS. For the neurotoxicity assessments, rats were administered molinate parenterally for subchronic periods and morphological evaluations performed on peripheral nerves. All of the thiocarbamates except butylate produced S-(N,N-dialkylaminocarbonyl)cysteine adducts on globin and the quantity of adducts detected decreased with increasing size of the nitrogen substituents. In contrast, a clear relationship between cysteine modification in mitochondrial and microsomal samples to nitrogen substituents was not evident, and although molinate produced relatively high levels of adducts and esterase inhibition and butylate low levels of adducts and esterase inhibition for most samples, in general, the level of S-(N,N-dialkylaminocarbonyl)cysteine adducts did not appear to be related to enzyme inhibition. Molinate did not produce segmental demyelination in peripheral nerve, suggesting that molinate and possibly other thiocarbamates do not share the neurotoxic potential of dithiocarbamates.
Animals↗
Aldehyde dehydrogenase of mice inhibited by thiocarbamate herbicides.
The herbicide S-ethyl N,N-dipropylthiocarbamate (EPTC) and three of its candidate metabolites (the sulfoxide, N-depropyl and S-methyl derivatives) inhibit mitochondrial low-Km aldehyde dehydrogenase (ALDH) in liver by 56 to 82% 2 hr after these thiocarbamates are administered intraperitoneally (ip) to mice at 8 mg/kg. They also greatly elevate the acetaldehyde level (determined as the O-benzyloxime ether) in blood (up to 500 microM) and brain (up to 3 ppm) 30 min after two ip treatments, the first with the thiocarbamate at 40 mg/kg and 2 hr later with ethanol at 1000 mg/kg. EPTC at 4 mg/kg inhibits liver ALDH activity by 50% and at 8 and 18 mg/kg gives half of the maximum ethanol-dependent elevation of acetaldehyde levels in blood and brain, respectively. The in vivo effects of other thiocarbamate herbicides at 8 mg/kg on ALDH activity and 40 mg/kg on acetaldehyde levels decrease in the order of thiobencarb, pebulate, vernolate and molinate > butylate and triallate >> cycloate. The percentage inhibition of liver ALDH activity generally correlates with the elevation in blood and brain acetaldehyde under these treatment protocols. B.W. Hart and M.D. Faiman (Biochem. Pharmacol. 43 403-406, 1992) have shown that the alcohol-aversion drug disulfiram is metabolized to S-methyl N,N-diethylthiocarbamate and its sulfoxide as the penultimate and ultimate metabolites inhibiting ALDH. Thus, the thiocarbamate herbicides and their metabolites are similar to the disulfiram metabolites not only in homologous structure but also in their potency range as ALDH inhibitors in vivo. On this basis some of the thiocarbamate herbicides may sensitize agricultural workers to ethanol intoxication.
Acetaldehyde↗
Inhibition of Cuticular Lipid Biosynthesis in Pisum sativum by Thiocarbamates.
Treatment of slices of young pea leaves (Pisum sativum) with muM solutions of alpha-chlorallyl diethyldithiocarbamate, dichloroallyl diisopropylthiocarbamate, or S-ethyldipropylthiocarbamate resulted in inhibition of incorporation of [1-(14)C]acetate into C(31) alkane and C(31) secondary alcohol, very little effect on the synthesis of C(26) and C(28) fatty alcohols, and an accumulation of (14)C in shorter chain cuticular lipids, particularly C(22) acid. Higher concentrations of the thiocarbamates caused inhibition of synthesis of C(26) and C(28) fatty alcohols and an accumulation of label in C(22) acid. Further increase in thiocarbamate concentration resulted in inhibition of C(22) acid synthesis also. The three thiocarbamates at muM concentration also inhibited incorporation of [1-(14)C]stearic acid specifically into C(31) alkane and C(31) secondary alcohol. These results suggest that thiocarbamates reduce cuticular lipid formation by a concentration-dependent inhibition of the various chain-elongating enzyme systems.
Journal Article↗
Computer-assisted structure--anticancer activity correlations of carbamates and thiocarbamates.
With the aid of the computer, approximately 8000 compounds that incorporate a carbamate or thiocarbamate moiety, which have been tested as potential anticancer agents at the National Cancer Institute (NCI), were classified and their structure-activity correlations against the in vivo P-388 and L-1210 leukemias were evaluated. Aromatic carbamates and thiocarbamates have shown good activity against P-388 and poor activity against L-1210. The majority of active compounds in this series of aromatic carbamates possess a 2- or 4-heteroatom-substituted phenyl attached to the carbamate oxygen atom or the thiocarbamate sulfur atom with the carbamate nitrogen atom as NHMe. The N-phenyl carbamates were much less active against P-388 than the phenyl carbamates; only bis-N-phenyl carbamates with a methylene bridge between the two phenyl groups showed good activity against both P-388 and L-1210 leukemias. Except for the mycophenolic acid carbamates, the fused phenyl carbamates showed poor activity against both P-388 and L-1210 leukemias. Certain nitrogen-heterocyclic carbamates and carbamates with heteroatom substituents have been selected by the NCI for development toward clinical trials. The nature of the heterocyclic carrier and the position of attachment to the carbamate moiety have a major role on the mode of action of the antitumor activity of these compounds.
Animals↗
The thiocarbamate-inducible Rhodococcus enzyme ThcF as a member of the family of alpha/beta hydrolases with haloperoxidative side activity.
Purified thiocarbamate-inducible ThcF of Rhodococcus erythropolis NI86/21, overexpressed in Escherichia coli, displayed several characteristics of the HASH family of enzymes that groups prokaryotic proteins of the alpha/beta hydrolase superfamily possessing serine-dependent hydrolase and/or haloperoxidase activity. Kinetic analysis of bromination and ester hydrolysis revealed a low affinity of ThcF for model substrates. Sulfoxidation of thiocarbamates was demonstrated but probably represents a side activity due to peroxoacid generation by the enzyme. The thcF-linked thcG gene, encoding a LAL-type regulator, triggers expression of thcF in Rhodococcus. The tandem gene organization thcG-thcF is conserved in the thiocarbamate-degrading strain Rhodococcus sp. B30. It is proposed that HASH enzymes may be involved in the metabolism of plant-derived compounds.
Esterases↗
Kinetics and mechanistic studies of the hydrolysis of diisocyanate-derived bis-thiocarbamates of cysteine methyl ester.
Diisocyanates (dNCOs) are the most commonly reported cause of chemically induced occupational asthma, but the ultimate antigenic form is unknown. Reactions of the three most common monomeric dNCOs, hexamethylene dNCO (HDI), methylene diphenylisocyanate (MDI), and toluene dNCO (TDI), with cysteine methyl ester (CME) gave the corresponding bis-dithiocarbamates (HDI-CME, TDI-CME, and MDI-CME). The dissociation kinetics of these bis-thiocarbamates, in aqueous conditions, was followed spectrophotometrically under varying pH and temperature conditions. Reaction of the adducts with methylamine or human serum albumin (HSA) produced diurea, monourea, and diamine products, and this was consistent with the base-catalyzed elimination reaction (E1cB) pathway being the dominant, but not exclusive, dissociation mechanism. The hydrolysis of the adducts was first-order with respect to OH(-) concentration and overall second-order (HDI-CME, k = 3.36 x 10(2) M(-)(1) min(-)(1); TDI-CME, k = 2.49 x 10(4) M(-)(1) min(-)(1); and MDI-CME, k = 5.78 x 10(4) M(-)(1) min(-)(1) at pH 7.4) with deviation from second-order when the dNCO had an aromatic functional group. Arrhenius plots gave activation energies (HDI-CME, E(a) = 70.6 kJ/mol; TDI-CME, E(a) = 46.1 kJ/mol; and MDI-CME, E(a) = 44.5 kJ/mol) that were consistent with the following order of stability: HDI-CME > TDI-CME > MDI-CME. Therefore, the stability of different dNCO-derived thiocarbamates in aqueous environments can vary greatly. Thiocarbamate dissociation rates and type of products formed may potentially influence antigenicity and subsequent hypersensitivity/toxic reactions following dNCO exposures.
Algorithms↗
Feasibility of thiocarbamate pesticide analysis in apples by supercritical fluid extraction and high-performance liquid chromatography.
Supercritical fluid extraction produced comparable results with liquid-solid extraction for the analysis of several thiocarbamate pesticides from apples at the 2 ppm spike level. These results were achieved with a simple one-step extraction procedure. The use of diatomaceous earth (Celite, Supelco, Inc.; Bellefonte, PA) served to increase thiocarbamate recoveries by aiding in the immobilization of the aqueous component of the apple matrix. High-performance liquid chromatography coupled with ultraviolet absorbance detection (HPLC-UV) had the most viable means of quantitation when compared with micro-HPLC-sulfur chemiluminescence detection (SCD) and gas chromatography-flame-ionization detection (GC-FID). The small injection volumes used with the micro-HPLC-SCD system made thiocarbamate detection at a spiking level of 2 ppm impossible. SCD did provide, however, valuable qualitative information about the nature of the apple coextractants.
Chromatography, High Pressure Liquid↗
Fatty acid elongation is important in the activity of thiocarbamate herbicides and in safening by dichlormid.
The thiocarbamates, such as pebulate (S-propyl butyl (ethyl) thiocarbamate) are a well-established class of herbicides. They inhibit fatty acid elongation, which is necessary for the biosynthesis of constituents of surface waxes and suberin and this has been proposed to be important for their toxicity. In this study lipid metabolism was investigated in herbicide-treated barley (Hordeum vulgare) and a pernicious weed, wild oats (Avena ludoviciana), to test the hypothesis that inhibitory effects on fatty acid elongation could be counteracted by the safer, dichlormid. Pebulate and its sulphoxide derivative (thought to be the active metabolite in vivo) were tested against lipid metabolism in barley or wild oat shoots. In both plants there was a significant inhibition of very long chain fatty acid (VLCFA) synthesis at herbicide concentrations > or =25 micro M. The extent to which safener dichlormid could prevent the inhibition of VLCFA synthesis was different in the two species. Previous treatment of barley with dichlormid (N,N-diallyl-2,2-dichloroacetamide) enabled fatty acid elongation in the presence of pebulate or pebulate sulphoxide, but had no effect on wild oats. The effects on fatty acid elongation mimicked the differential safening action of dichlormid observed on shoot elongation and growth in the two species. These data provide further evidence that inhibition of VLCFA formation is important for the mechanism of action of thiocarbamates.
Acetamides↗
Thiocarbamate herbicide-inducible nonheme haloperoxidase of Rhodococcus erythropolis NI86/21.
During biodegradation of thiocarbamate herbicides by Rhodococcus erythropolis NI86/21, a protein with an M(r) of 30,000 is induced (I. Nagy, G. Schoofs, F. Compernolle, P. Proost, J. Vanderleyden, and R.De Mot, J. Bacteriol. 177:676-687, 1995). Based on N-terminal sequence data for the protein purified by two-dimensional electrophoresis, the corresponding structural gene, thcF, was cloned and sequenced. The deduced protein sequence of ThcF is homologous to those of nonheme haloperoxidases. A particularly high level of sequence identity (72.6%) was observed for the chloroperoxidase from Pseudomonas pyrrocinia. A polyclonal antibody against the latter enzyme cross-reacted with ThcF either produced by the original Rhodococcus cells or overexpressed heterologously in Escherichia coli. In both thiocarbamate-grown Rhodococcus cells and E. coli cells expressing thcF, the haloperoxidase activity of ThcF was demonstrated. The thiocarbamate-inducible R. erythropolis ThcF protein represents the first (nonheme) haloperoxidase to be identified in a nocardioform actinomycete.
Amino Acid Sequence↗
[Preparation and antifungal activity of carbamic and thiocarbamic esters of thiophenols].
A series of N-substituted carbamic and thiocarbamic esters of thiophenols [substances (I leads to XLII)] was prepared and tested for in vitro antifungal activity. The substances were obtained by condensation of thiophenols with suitable isocyanates and isothiocyanates. The antifungal activity of the products was tested in vitro against the following strains: Candida albicans, Candida tropicalis, Saccharomyces cerevisiae and Trichophyton mentagrophytes. The results obtained, given in the Table I, show that the carbamic and thiocarbamic esters of the thiophenols examined have marked antifungal activity. The results give some information on structure-activity relationships and also show that in general the derivatives of dithiocarbamic acid are more active than the bioisosteric derivatives of thiocarbamic acid. Of the compounds examined the most active were esters of N-benzyl and N-allyldithiocarbamic acid.
Antifungal Agents↗
Thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of demethylpenclomedine as novel anticancer agents.
PURPOSE: The purpose of this investigation was to synthesize a series of thiolo-, thiono- and dithiocarbonate and thiocarbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) in patients observed subsequently to be an active antitumor agent and non-neurotoxic in a rat model, in order to compare their antitumor activity with that of DM-PEN. METHODS: Derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted in the mammary fat pad, several of which were also evaluated against human brain tumor xenografts. RESULTS: Thiolocarbonate and thiocarbamate derivatives were found to be superior to DM-PEN against MX-1 tumor and modestly active against glioblastoma. CONCLUSION: The activity of the thiolocarbonates and thiocarbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.
Animals↗
A facile method for the synthesis of thiocarbamates: palladium-catalyzed reaction of disulfide, amine, and carbon monoxide.
[reaction: see text] A new method for the synthesis of thiocarbamates has been developed. When dialkyl or diaryl disulfides were allowed to react with secondary amines and carbon monoxide in the presence of a catalytic amount of a palladium complex, the thiocarbamates were obtained in moderate to good yields. In contrast to that of secondary amines, in the reaction of a primary amine, no formation of thiocarbamate was confirmed, but urea was formed in good yield.
Journal Article↗
Dichloroacetamide antidotes for thiocarbamate herbicides: mode of action.
Thiocarbamate sulfoxides formed on metabolic sulfoxidation of thicoarbamate herbicides in plants and mammals are effective carbamoylating agents for glutathione and other tissue thiols. Dichloracetamides that protect corn from thiocarbamate herbicide injury more rapid detoxification of the thiocarbamate sulfoxides by increasing their rate of carbamoylation of glutathione through elevation of the root glutathione level and glutathione s-transferase activity.
Acetamides↗