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PubMed1996

Synthesis and Characterization of Rhenium(V) Oxo Complexes with a New Thiol-Amide-Thiourea Ligand System. X-ray Crystal Structure of [1-Phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V).

General methods for preparing Re(V)O complexes with a novel series of thiol-amide-thiourea (TATU) ligands, a new class of N(2)S(2) chelates, were developed. The TATU ligands, the first multidentate systems designed with a bidentate thiourea moiety, have been used to prepare the first high-valent transition metal complexes with bidentate thiourea coordination. Direct reaction of N-(2-aminoethyl)-2-((triphenylmethyl)thio)acetamide (1) with phenyl, 4-methoxyphenyl, 4-chlorophenyl, and methyl isothiocyanate afforded ready access to the corresponding S-protected TATU ligands in one step. A two-step preparation of the N,N-dimethylthiourea TATU ligand derived from 1 was also developed. Deprotection of thiols in trifluoroacetic acid with triethylsilane followed by a ligand exchange reaction with Re(V)O precursors yielded neutral ReO(TATU) complexes. The structure of [1-phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V) (6a) was determined by X-ray diffraction methods. Crystal data for 6a: C(11)H(12)N(3)O(2)ReS(2), fw 468.6, orthorhombic, Pca2(1); a = 22.605(5) Å, b = 13.029(3) Å, c= 9.698(2) Å; V = 2856.3(11) Å(3); Z = 8. The coordination environment of 6a was pseudo-square-pyramidal with a deprotonated thiol S, deprotonated amide N, deprotonated thiourea N, and thiocarbonyl S coordinated in the basal plane and the oxo ligand in the apical position. The thiourea function forms a four-membered chelate ring in the multidentate TATU ligands. The two N-C and the S-C bond distances within the monodeprotonated thiourea moiety were typical of bonds with multiple-bond character. Solution (1)H NMR data for all five complexes were consistent with the solid-state structure of 6a. A broad singlet attributable to the uncoordinated NH group of thiourea was observed for the monosubstituted thiourea complexes but was not present for the N,N-dimethylthiourea derivative. Instead, two singlets of equal intensity were observed for the two methyl groups, indicating that there is restricted rotation around the C-N(CH(3))(2) bond and an extended pi system in the thiourea moiety. The four-membered ring might cause difficulty because the M-S distance would be relatively long in an undistorted ligand. This may be the reason such chelate ligands have not been previously investigated. However, the N-C-S angle narrows to approximately 105 degrees, permitting a Re-S bond with a typical bond length to be formed. We conclude that such a ring represents a versatile new building block to create multidentate ligands.

Journal Article↗

PubMed1979

Effect of thiourea on microsomal oxidation of alcohols and associated microsomal functions.

Thiourea and diethylthiourea, two compounds which react with hydroxyl radicals, inhibited NADPH-dependent microsomal oxidation of ethanol and 1-butanol. Inhibition by both compounds was more effective in the presence of the catalase inhibitor, azide. Inhibition by thiourea was noncompetitive with respect to ethanol in the absence of azide but was competitive in the presence of azide. Urea, a compound which does not react with hydroxyl radicals or H2O2, was without effect. Thiourea had no effect on NADH- and NADH-cytochrome c reductase, NADPH oxidase, and NADH- and NADPH-dependent oxygen uptake. Thiourea inhibited the activities of aniline hydroxylase and aminopyrine demethylase. Thiourea, but no other hydroxyl radical scavengers, e.g., dimethyl sulfoxide, mannitol, and benzoate, reacted directly with H202 and decreased H2O2 accumulation in the presence of azide. Therefore the actions of thiourea are complex because it can react with both hydroxyl radicals and H2O2. Differences between the actions of thiourea and those previously reported for dimethyl sulfoxide, mannitol, and benzoate, e.g., effects on drug metabolism, effectiveness of inhibition in the absence of azide, or kinetics of the inhibition, probably reflect the fact that thiourea reacts directly with H2O2 whereas the other agents do not. The current results remain consistent with the concept that microsomal oxidation of alcohols involves interactions of the alcohols with hydroxyl radicals generated from microsomal electron transfer.

Aminopyrine N-Demethylase↗

PubMed1987

Antiarrhythmic agents diminish thiourea-induced pulmonary vascular protein leak in rats.

Drugs possessing membrane stabilizing activity might act to diminish the augmented microvascular permeability resulting from acute lung injury. To test this rats were pretreated with quinidine, procainamide, or lidocaine and then given the lung injury-inducing agent thiourea. Vascular permeability, assessed as the extravascular accumulation of radiolabeled protein, was increased more than threefold by thiourea. This increase was diminished by 29, 34, and 43% after pretreatment with procainamide, quinidine, and lidocaine, respectively. Lidocaine also returned the thiourea-induced increase in lung wet weight-to-dry weight ratios to control levels. This protection was not likely due to hemodynamic effects of these agents, since no differences were noted in cardiac output between pretreated rats and those receiving thiourea alone and a small increase in mean pulmonary arterial pressure in the lidocaine-pretreatment group was the only difference noted. O2 metabolites have been implicated in the pathogenesis of thiourea-induced lung injury. None of these agents scavenged O2- or H2O2 directly, but quinidine and procainamide diminished in vitro neutrophil O2- and H2O2 production, and lidocaine inhibited neutrophil H2O2 production. However, neutropenia (PMN less than 100/ml) induced with either vinblastine or cyclophosphamide (Cytoxan) failed to prevent thiourea-induced increases in pulmonary vascular protein leak. In conclusion, procainamide, quinidine, and lidocaine diminished lung injury in rats after thiourea. Although these agents diminish PMN O2 metabolite production in vitro their salutary role in thiourea-induced lung injury appears to be through an unknown mechanism that is independent of their effects on neutrophil O2 metabolite-dependent toxicity.

Animals↗

PubMed1979

Thiourea and cyanamide as inhibitors of thyroid peroxidase: the role of iodide.

Thiourea, methylmercaptoimidazole, propylthiouracil, and thiouracil are all potent inhibitors of thyroid peroxidase (TPO)-catalyzed iodination. Unlike the cyclic thioureylenes, thiourea at 5 mM has no effect on guaiacol oxidation. If iodide is added to guaiacol assays containing thiourea, enzyme activity is lost. The latter observation may be explained as follows. In the presence of iodide, the iodinating species [TPO.Ioxid], oxidizes thiourea to formamidine disulfide. This product decomposes to cyanamide at neutral pH. We have shown cyanamide to be an inhibitor of the peroxidative and iodinating functions of TPO. Studies in rats demonstrate that doses of thiourea which completely inhibit in vivo protein-bound iodine formation have no irreversible effect on TPO, as measured by guaiacol peroxidation after removal of the thyroids. The major in vivo action of cyanamide is similar to that of thiourea. The data suggest that the primary in vivo and in vitro mode of action of thiourea is the reversible Ioxid-trapping mechanism. The anomalous inhibition of guaiacol peroxidation seen in the presence of thiourea plus iodide derives from the formation of formamide disulfide, followed by its nonenzymic decomposition to cyanamide.

Animals↗

PubMed2000

Differential branchial and renal handling of urea, acetamide and thiourea in the gulf toadfish Opsanus beta: evidence for two transporters.

The possible presence of a urea transporter in the kidney of the gulf toadfish (Opsanus beta) and further characterization of the pulsatile facilitated transporter previously identified in its gills were investigated by comparing the extra-renal and renal handling of two urea analogues with the handling of urea. Toadfish were fitted with caudal artery and indwelling urinary ureteral catheters and injected with an iso-osmotic dose of (14)C-labelled urea analogue (acetamide or thiourea) calculated to bring plasma analogue concentrations close to plasma urea concentrations. Branchial permeabilities to urea, acetamide and thiourea were similar during non-pulsing periods and all increased during pulse events, although urea permeability was greater than analogue permeability during pulses. The incidence and magnitude of acetamide and urea pulses at the gills were significantly correlated, acetamide pulses being 35-50 % of the size of urea pulses. However, the thiourea and urea pulses at the gills were only weakly correlated, thiourea pulses being less than 16 % of the size of urea pulses. Thiourea inhibited branchial urea excretion by reducing the pulse frequency. The renal handling of thiourea and urea were similar in that both substances were more concentrated in the urine than in the plasma, whereas acetamide was found in equal concentrations in the urine and plasma. Urea and thiourea were secreted 2-3 times more effectively than Cl(-) and water, whereas acetamide was secreted at a similar relative rate. The differential handling of the urea analogues by the gills and kidney indicates the presence of a different, possibly unique, transporter in the kidney. The movement of thiourea and urea into the renal tubule against an apparent concentration gradient suggests the presence of an active transport mechanism.

Acetamides↗

PubMed2005

Use of a stopped-flow technique for investigation and determination of thiourea and its N-methyl derivatives as inducers of the iodine-azide reaction.

A stopped-flow technique has been used to investigate the behaviour of 2-thiourea, 1-methyl-2-thiourea, 1,3-dimethyl-2-thiourea, and 1,1,3,3-tetramethyl-2-thiourea in the induced iodine-azide reaction. This technique enables the progress of the reaction to be followed by monitoring the decrease in the absorbance of the iodine-starch complex at 595 nm. The effect of the concentration of the reagents on the rate of the reaction was investigated and a kinetic method for determination of the compounds is proposed. 2-Thiourea, 1-methyl-2-thiourea, and 1,3-dimethyl-2-thiourea can be determined in the range 3-75 micromol L(-1) and 1,1,3,3-tetramethyl-2-thiourea in the range 2-200 micromol L(-1).

Journal Article↗

PubMed1999

Thioureas differentially induce rat hepatic microsomal epoxide hydrolase and rGSTA2 irrespective of their oxygen radical scavenging effect: effects on toxicant-induced liver injury.

Thioureas have been employed as potent hydroxyl radical scavengers and also inhibit production of oxygen free radicals. The in vitro oxygen radical scavenging effect by N,N'-substituted thioureas including dimethylthiourea (DMT), diethylthiourea (DET), tetramethylthiourea (TMT) and diphenylthiourea (DPT) was assessed by the conversion of phi x-174 DNA from supercoiled DNA to the open circular form or to fragmented DNA. Addition of the N,N'-substituted thioureas to the incubation mixture significantly prevented a single strand breakage of phi x-174 DNA induced by autooxidation of benzenetriol. These thioureas were also effective in preventing degradation of phi x-174 DNA induced by autooxidation of benzenetriol in the presence of ferrous iron. In view of the in vitro radical scavenging effect by the thioureas and the role of reactive oxygen species in the induction of phase II detoxifying enzymes, expression of microsomal epoxide hydrolase (mEH) and rGSTA2 in response to these agents was investigated in the rat liver. Rats treated with each of the alkylthioureas exhibited marked increases of mEH and rGSTA2 mRNA levels with TMT being the most effective. DPT an arylthiourea, however, was minimally active in increasing the mRNAs. Time-course studies revealed that DMT, DET and TMT increased the mRNA levels to the greatest extent at 24 h after a single dose of treatment. The levels of mEH and rGSTA2 mRNA were elevated in a dose-dependent manner by the alkylthioureas. Immunoblot analysis showed that the alkylthioureas induced mEH and rGSTA2 proteins in the liver (0.6 mmol/kg per day, 3 days), which was consistent with the increases in the mRNA levels. DMT, DET or TMT enhanced CCl4-induced liver toxicity, as monitored by plasma aminotransferase activity, although each of the agents alone caused only slight increase in the alanine aminotransferase activity. In contrast to the effects of the alkylthioureas, DPT protected the liver against the toxicant-induced injury. All of the thioureas prevented decreases in the hepatic glutathione level by CCl4. Expression of cytochrome P450 2E1 and P450 2B1/2, which are implicated with metabolic activation of CCl4, was assessed after treatment with the thioureas. P450 2E1 and P450 2B1/2 were differentially induced by the alkylthioureas with the expression of P450 2E1 being inversely related with that of P450 2B1/2. These results showed that N,N'-substituted alkylthioureas were capable of inducing mEH and rGSTA2 in the liver with elevation of the mRNAs, that induction of mEH and rGSTA2 by these alkylthioureas might be mediated by production of the reactive oxygens derived from metabolic activation of the agents irrespective of their radical scavenging effect and that the agents rather enhanced toxicant-induced liver injury with the induction of P450 2E1 or P450 2B1/2.

Alanine Transaminase↗

PubMed2004

Transformation of herbicide propachlor by an agrochemical thiourea.

Propachlor and other chloroacetanilide herbicides are frequently detected contaminants of groundwater and surface water in agricultural regions. The purpose of this work was to develop a new approach to remove propachlor residues from the environment via chemical remediation by the nitrification inhibitor thiourea. The transformation processes of propachlor and thiourea mixed in aqueous solution, sand, and soil were elucidated. Analysis of transformation products and reaction kinetics indicated that an S(N)2 nucleophilic substitution reaction occurred, in which the chlorine of propachlor was replaced by thiourea, detoxifying the herbicide. It appears that propachlor undergoes a catalytic reaction in sand or soil amended with thiourea, which results in a significantly accelerated transformation rate as compared to the reaction in aqueous solution. The second-order reaction process was examined at different temperatures to investigate the role of the activation energy. The enthalpy of activation (deltaH) for the reaction of propachlor with thiourea was demonstrated to be significantly lower in sand than in aqueous solution, which provides evidence that a catalytic transformation mechanism occurs in thiourea-amended sand. The chemical reaction rate increased proportionally to the amount of thiourea added to the sand. Column experiments further suggested that the remediation strategy could be used to remove propachlor residues from sand or soil to reduce leaching and prevent contamination of surface water and groundwater.

Acetanilides↗

PubMed2006

Bioactivation of N-substituted N'-(4-imidazole-ethyl)thioureas by human FMO1 and FMO3.

Enzyme kinetic parameters of the bioactivation of thiourea-containing compounds by human flavin-containing monooxygenase enzymes (FMOs) FMO1 and FMO3 were investigated. A microtitre-based adaptation of methodology described for the thiourea-dependent oxidation of thiocholine was used to determine the turnover of thiourea-containing compounds by human FMO1 and FMO3. The results show that major differences in enzyme kinetic parameters for N-substituted N'-(4-imidazole-ethyl)thiourea exist between human FMO3 and human FMO1. Whereas Km values of N-substituted N'-(4-imidazole-ethyl)thioureas for human FMO3 are all in the millimolar range, the Km values for human FMO1 range from the low micromolar to the low millimolar range. Furthermore, among a series of N-p-phenyl-substituted N'-(4-imidazole-ethyl)thioureas an interesting structure-activity relationship is evident with both FMO1 and FMO3. Where the Km decreases with increasing electron-withdrawing capacity of the p-substituent in the case of FMO1, the opposite phenomenon may be the case with FMO3. The kcat values of the compounds were all comparable for FMO1, averaging 3.03 +/- 0.56 min-1, whereas more variation was found for FMO3 (3.71 +/- 2.01 min-1). Enzyme kinetic parameters Km and kcat/Km of human FMO1 for N-substituted N'-(4-imidazole-ethyl)thioureas show a high degree of correlation with the results obtained in rat liver microsomes, in which rat FMO1 is the most abundant form, whereas those of human FMO3 do not.

Animals↗

PubMed1997

Selective incorporation of the prototype melanoma seeker thiourea into nascent melanin: a chemical insight.

The mechanism of selective incorporation of thiourea into melanotic melanoma was investigated by model experiments in which the effect of the compound was examined at various stages of melanogenesis in vitro. Up to 50% inhibition of dopachrome formation was observed in the tyrosinase-dopa reaction in the presence of thiourea at a 2:1 molar ratio with respect to the substrate. Under these conditions, a major product was formed which was isolated and identified as a 1:1 dopa-thiourea adduct (adduct I). Subsequent stages of the oxidation were characterized by the development of a yellow chromophore (lambdamax 440-460nm), virtually identical to that obtained by separate oxidation of the adduct I. A less remarkable effect of thiourea was observed on the oxidative polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) which was apparent on spectrophotometric and high pressure liquid chromatography (HPLC) analysis. Radiolabelling experiments with 14C-thiourea showed that the label was initially incorporated into the adduct I, while in the subsequent stages of the oxidation it was associated with pigmented materials which escaped direct analysis. Incorporation of labelled thiourea into dopa-melanins was found to be significantly higher than incorporation into synthetic pigments from indole precursors. These results provide a chemical basis for the interpretation of the selective accumulation of thiourea in those melanoma areas with high rates of melanin synthesis seen in autoradiographic experiments.

Antineoplastic Agents↗

PubMed2006

The ability of thiourea to scavenge hydrogen peroxide and hydroxyl radicals during the intra-coronal bleaching of bloodstained root-filled teeth.

BACKGROUND: Hydrogen peroxide, an agent used in the intra-coronal bleaching of root-filled teeth for over a century, has been shown to diffuse from the pulp chamber to the outer root surface. Furthermore, it has been demonstrated that destructive hydroxyl radicals, the by-products of the bleaching process, have been detected on the external root surface. The control of such diffusion may be of importance in minimizing the risk of invasive cervical resorption (ICR) which has been linked to intra-coronal bleaching of discoloured root-filled teeth using hydrogen peroxide. The aims of the present in vitro study are to quantify the diffusion of hydrogen peroxide and hydroxyl radicals to the outer root surface following intra-coronal bleaching, and to evaluate the ability of thiourea incorporated into the bleaching protocol to scavenge residual hydrogen peroxide and hydroxyl radicals. METHODS: Thirty-five single rooted premolar teeth with intact cementum at the cemento-enamel junction were used in this project. Thirty teeth were stained with red blood cells and root-filled with gutta-percha and AH26. The five unstained teeth were root-filled and constituted a negative control (Group 1). The stained teeth were divided equally into the following experimental groups and subjected to various intra-coronal bleaching regimes: Group 2--'walking bleach' with 20 microl 30 per cent w/w hydrogen peroxide; Group 3--20 microl 30 per cent w/w hydrogen peroxide and thermocatalytically activated; Group 4--20 microl acidified thiourea; Group 5--20 microl acidified thiourea and 20 microl 30 per cent w/w hydrogen peroxide; Group 6--20 microl acidified thiourea and 20 microl one per cent sodium hypochlorite; Group 7--20 microl acidified thiourea, 20 microl one per cent sodium hypochlorite and 20 microl 30 per cent w/w hydrogen peroxide. The reaction products of the bleaching process were quantified at the outer root surface using high performance liquid chromatography and electrochemical detection (HPLC-ECD). RESULTS: Results showed that hydrogen peroxide used alone in Groups 2 and 3 was able to be detected at the outer root surface in 100 per cent of the samples, and that the presence of the hydroxyl radical generated in both groups was detected in equal amounts (P < 0.05). When thiourea was incorporated into the bleaching protocols in Groups 5-7, it was shown to scavenge both hydrogen peroxide and hydroxyl radicals to a significant degree (P < 0.05). CONCLUSIONS: Acidulated thiourea is an effective scavenger of residual hydrogen peroxide and hydroxyl radicals generated during the intra-coronal bleaching of bloodstained root-filled teeth.

Antioxidants↗

PubMed1979

Effect of thiourea on intracranial bone tumour formation in AkR mice.

The effect of administration of thiourea (5 g/kg in diet) alone or simultaneously with thyroxine (1 mg/l in drinking water) on the frequency of hyperplastic benign osteoma of the skull was studied in AkR mice. Animals treated with both thiourea and thyroxine were in hyperthyroidism: the thyroxine dose received was higher that that required to prevent thiourea-induced thyroid gland hypertrophy. A significant increase of the intracranial bone tumour (IBT) frequency was observed both in mice treated with thiourea alone and those which received thiourea and thyroxine simultaneously. Increase of IBT frequency was not due to the antithyroid effect of thiourea but seems due to a direct toxic action of thiourea on the pituitary.

Animals↗

PubMed2004

Grinding-induced equimolar complex formation between thiourea and ethenzamide.

We prepared and characterized a grinding-induced equimolar complex of thiourea with ethenzamide. When thiourea and ethenzamide were co-ground at a molar ratio of 3 : 1, new powder X-ray diffraction (PXRD) peaks were observed in addition to PXRD peaks of thiourea crystals. The optimum stoichiometry of the new structure was confirmed as 1 : 1 mol/mol. Effect of grinding time on the thiourea-ethenzamide equimolar complex formation was investigated by using PXRD, differential scanning calorimetry and Fourier transform infrared spectroscopy. The equimolar crystal structure was confirmed by X-ray diffraction measurements of the single crystal which was recrystallized from ethanol. It was found that the intermolecular hydrogen bond formations between thiourea and ethenzamide molecules contributed to the equimolar complex formation. The complex formation was not observed in the cases where benzamide, salicylamide or 3-ethoxybenzamide was co-ground with thiourea. 2-Alcoxyl benzamide structures should be required for the grinding-induced equimolar complex formation with thiourea.

Salicylamides↗

PubMed1976

Innate and drug-induced resistance to acute lung damage caused in rats by alpha-naphthyl thiourea (ANTU) and related compounds.

During the 3rd and 4th weeks of life rats were highly resistant to the toxic effects of alpha-naphthyl thiourea (ANTU) and of thiourea and its derivatives but toxicity developed rapidly during the following 2 weeks. Marked resistance to lung damage by toxic thioureas could be induced in older, mature rats by pretreatment with the toxic agent itself (tachyphylaxis), with other toxic and non-toxic antithyroid drugs or with iodine or iodide--even if the rats were pretreated at an early age before susceptibility to the agent developed. ANTU-tachyphylaxis was dose-dependent. Total thyroidectomy did not affect either lung damage induced by ANTU or the resistance due to tachyphylaxis or to pretreatment with iodide or the antithyroid drugs thiourea, 1-ethyl-1-phenyl thiourea or propyl thiouracil. Neither total nor medullary adrenalectomy affected ANTU toxicity. Marked resistance to ANTU-induced lung damage was induced in rats by pretreatment with either an activator (3-4 benzypyrene) or an inhibitor (SKF 525-A) of drug-metabolizine mixed-function microsomal enzyme systems; the inhibitor, sodium phenobarbitone, had no significant effect on toxicity. The sulphydryl compound, AET, induced marked resistance to ANTU; cysteine was less effective. Neither autonomic blockade with nicotine and atropine nor actinomycin D had significant effects on toxicity to ANTU. The acute pulmonary oedema induced in rats by high pressure oxygen, chemical convulsants, pressor agents and ammonium sulphate differed in many respects from that induced by toxic thioureas; it was typically haemorrhagic in nature, did not result in significant pleural effusion, did not exhibit tachyphylaxis, and was not influenced by pretreatment with iodide or derivatives of thiourea.

Age Factors↗

PubMed1990

Thioureas react with superoxide radicals to yield a sulfhydryl compound. Explanation for protective effect against paraquat.

Thiourea and superoxide dismutase were effective antidotes to paraquat toxicity in an HL60 cell culture system, whereas other hydroxyl scavengers were ineffective. The efficacy of thioureas was not due to blockage of intracellular paraquat uptake, inhibition of NADPH-P-450 reductase, or reaction with the paraquat radical. Thiourea also competitively inhibited the reduction of cytochrome c by the xanthine/xanthine oxidase superoxide-generating system, and the release of iron from ferritin by superoxide radicals. The reaction of superoxide with thiourea produced a sulfhydryl compound distinct from products formed by hydrogen peroxide or hydroxyl radicals. Spectrophotometric and chromatographic studies indicated the carbon-sulfide double bond was converted to a sulfhydryl group which reacted with Ellman's reagent. Additional confirmatory evidence for the sulfhydryl compound was obtained with carbon-13 NMR and mass spectroscopies. Thus, thioureas are direct scavengers of superoxide radicals as well as hydroxyl radicals and hydrogen peroxide. The rate constant for the reduction of thiourea by superoxide was estimated at 1.1 x 10(3) M-1 s-1. The implication of this finding on free radical studies, the mechanism of paraquat toxicity, and the metabolism of thioureas is discussed.

Acetonitriles↗

PubMed1978

[Structurally dependent effects of substituted thioureas on the concentration of potato virus X in Nicotiana tabacum L. "Samsun" (author's transl)].

A study has been made to investigate the effects of N-alkyl- and aryl-substituted thioureas as well as N,N'-alkyl-alkyl-, alkyl-aryl-, and aryl-aryl-substituted thioureas on the multiplication of PVX in Nicotiana tabacum L. "Samsun". The virus concentrations of the treated plants were serologically determined and compared with these of untreated controls. The weak antiphytoviral effect of nonsubstituted thiourea remained virtually unchanged in N,N'-dimethyl thiourea, and in N,N,N'-trimethyl thiourea. A stronger antiphytoviral effect was observed for N-phenyl, N',N'-pentamethylene thiourea, as well as N-methyl thiourea. All other substitutions, especially those by longer-chain substituents or by a larger number of substituents, were not found to have an influence on viral multiplication.

Chemical Phenomena↗

PubMed2001

Synthesis and properties of new thiourea-functionalized poly(propylene imine) dendrimers and their role as hosts for urea functionalized guests.

Five generations of poly(propylene imine) dendrimers have been modified by palmityl and adamantyl endgroups via a thiourea linkage. The synthesis of the thiourea dendrimers DAB-dendr-(NHCSNHAd)(n) and DAB-dendr-(NHCSNHC(16)H(33))(n) (n = 4, 8, 16, 32, 64) proceeds smoothly via the amino-terminated DAB dendrimer and the adamantyl and palmityl isothiocyanates, respectively. The properties of the thiourea dendrimers have been studied by IR and (1)H NMR, including relaxation (T1, T2) measurements. The thiourea dendrimers are used as multivalent hosts for a number of guest molecules containing a terminal urea-glycine unit in organic solvents. The host-guest interactions have been investigated using 1D- and NOESY-NMR. These investigations show that the guest molecules bind to the dendritic host via thiourea (host)-urea (guest) hydrogen bonding, and ionic bonding between the terminal guest carboxylate moiety and the outer shell tertiary amines of the dendrimer. The ability to bind guest molecules of the adamantyl- and palmitylthiourea dendrimers has been compared with their respective urea containing dendrimer analogues, by NMR-titration, and competition experiments. Upon complexation, the thiourea dendrimer hosts show a larger downfield NH shift than the corresponding urea dendrimer hosts, indicative of stronger hydrogen bonding in the complexed state. Furthermore, microcalorimetry has been used to determine binding constants for formation of the host-guest complexes; the binding constants are typically in the order of 10(4) M(-1). Both NMR and microcalorimetric studies show that the thiourea dendrimers bind the urea containing guests with somewhat higher affinity than the corresponding urea dendrimers.

Journal Article↗

PubMed1992

Inactivation and covalent modification of CTP synthetase by thiourea dioxide.

Thiourea dioxide was used in chemical modification studies to identify functionally important amino acids in Escherichia coli CTP synthetase. Incubation at pH 8.0 in the absence of substrates led to rapid, time dependent, and irreversible inactivation of the enzyme. The second-order rate constant for inactivation was 0.18 M-1 s-1. Inactivation also occurred in the absence of oxygen and in the presence of catalase, thereby ruling out mixed-function oxidation/reduction as the mode of amino acid modification. Saturating concentrations of the substrates ATP and UTP, and the allosteric activator GTP prevented inactivation by thiourea dioxide, whereas saturating concentrations of glutamine (a substrate) did not. The concentration dependence of nucleotide protection revealed cooperative behavior with respect to individual nucleotides and with respect to various combinations of nucleotides. Mixtures of nucleotides afforded greater protection against inactivation than single nucleotides alone, and a combination of the substrates ATP and UTP provided the most protection. The Hill coefficient for nucleotide protection was approximately 2 for ATP, UTP, and GTP. In the presence of 1:1 ratios of ATP:UTP, ATP:GTP, and UTP:GTP, the Hill coefficient was approximately 4 in each case. Fluorescence and circular dichroism measurements indicated that modification by thiourea dioxide causes detectable changes in the structure of the protein. Modification with [14C]thiourea dioxide demonstrated that complete inactivation correlates with incorporation of 3 mol of [14C]thiourea dioxide per mole of CTP synthetase monomer. The specificity of thiourea dioxide for lysine residues indicates that one or more lysines are most likely involved in CTP synthetase activity. The data further indicate that nucleotide binding prevents access to these functionally important residues.

Binding Sites↗