[ON A NEW METHOD OF COLORIMETRIC DETERMINATION OF 6-METHYL-2-THIOURACIL AND OF 6-PROPYL-2-THIOURACIL IN PHARMACEUTICAL TABLETS].
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Chemistry, Pharmaceutical↗
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[Changes in chlorhydric and mucinous secretions induced by synthetic antithyroid agents (4-methyl-2-thiouracil=6n propyl-2-thiouracile=4-methyl-2-aminothiazole=5,5-diethyl-2-thiobarbituric acid)].
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Antithyroid Agents↗
Synthesis and sedative-hypnotic effects of N3-allyl- and N1-allyl-5,6-substituted 2-thiouracil derivatives in mice.
Twenty four thiouracil derivatives, including N3-allyl- (19) and N1-allyl-2-thiouracil (20) were synthesized and their pharmacological effects [sedative-hypnotic activity (loss of righting reflex and spontaneous activity), convulsant activity, effect on pentobarbital (PB)-induced sleep and mortality] were evaluated in mice at doses of 320 mg/kg, i.p. and 2 mumol/mouse by intracerebroventricular (i.c.v.) injections, respectively. N3-Allyl-6-propyl-2-thiouracil (3), N3-allyl-5,6-dimethyl-2-thiouracil (10), N3-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta [d]pyrimidine (16) and N3-allyl-5-methyl-2-thiouracil (18) exhibited sedative-hypnotic activity, whereas N3-allyl-6-ethyl-5-methyl-2-thiouracil (11), N1-allyl-5-methyl-2-thiouracil (21), N1-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta[ d]pyrimidine (23) and N1-allyl-5,6-dimethyl-2-thiouracil (24) conversely displayed clonic- and/or tonic-convulsant seizures. N3-Allyl-6-propyl-2-thiouracil (3) and N3-allyl-5-methyl-2-thiouracil (18) decreased spontaneous activity. Other compounds examined were inactive, or only slightly active in the sedative-hypnotic assay even at high doses. Fifteen compounds (1-4, 7, 10, 11, 14-16, 18-21, and 23) significantly prolonged the PB-induced sleeping time. Interestingly, only N1-allyl-5,6-dimethyl-2-thiouracil (24) shortened the PB-induced sleeping time. These results showed that these thiouracils possessed many different effects such as sedative-hypnotic, anticonvulsant and/or convulsant, and that N3-allyl-5-methyl-2-thiouracil (18) and N1-allyl-5,6-dimethyl-2-thiouracil (24) had the most potent hypnotic activity and antagonistic effect against PB, respectively.
Animals↗
Effect of thiouracil in modifying folate function in severe vitamin B12 deficiency.
The effects of thiouracil in correcting defects in folic acid function produced by B12 deficiency were studied. Addition of the thyroid inhibitor, thiouracil, to a low methionine diet containing B12, increased the oxidation of [2-14C]histidine to carbon dioxide, and increased liver folate levels. Addition of 10% pectin to the diet accentuated B12 deficiency as evidenced by a greatly decreased rate of histidine oxidation (0.19%) and an increased excretion of methylmalonic acid. Addition of thiouracil to the diet restored folate function as measured by increased histidine oxidation and increased liver folate levels similar to that produced by addition of methionine to a B12-deficient diet. Thiouracil decreased methylmalonate excretion, and increased hepatic levels of B12 in animals on both B12-deficient and -supplemented diets. Hepatic methionine synthase was increased by thiouracil, which may be the result of the elevated B12 levels. S-Adenosylmethionine and the enzyme methionine adenosyltransferase were also increased by thiouracil. Thus it is possible that the effect of thiouracil in increasing folate function consists both in the effect of thiouracil in decreasing levels of methylenetetrahydrofolate reductase, and also in its action in increasing S-adenosylmethionine which exerts a feedback inhibition of this enzyme.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
UV-induced generation of rare tautomers of 2-thiouracils: a matrix isolation study.
Unimolecular photoisomerization reactions were studied for 2-thiouracil, 6-aza-2-thiothymine, 1-methyl-2-thiouracil, and 3-methyl-2-thiouracil isolated in low-temperature Ar matrixes. The IR spectra have revealed that before UV irradiation all the matrix-isolated compounds adopted exclusively the oxo-thione tautomeric form. Upon UV (lambda > 320 nm) irradiation of the matrixes, two oxo-thiol photoproducts were generated for monomeric 2-thiouracil as well as for monomeric 6-aza-2-thiothymine. Generation of these products corresponds to transfer of a proton from either the N(1)-H or N(3)-H group to the sulfur atom of the C(2)=S thiocarbonyl moiety. The first of the above reactions was photoreversible. As a consequence, after prolonged UV irradiation most of the material was transformed into the oxo-thiol-N(1)H form. The hydroxy-thiol tautomers of 2-thiouracil and 6-aza-2-thiothymine were also photogenerated as minor products. For 1-methyl-2-thiouracil and 3-methyl-2-thiouracil, thione --> thiol phototautomeric reactions yielded the oxo-thiol isomers of the compounds. Since these reactions were photoreversible, the final stages of the photoinduced processes corresponded, for both methylated 2-thiouracils, to photostationary states. All the products of the investigated photoreactions were identified by comparison of their IR spectra with the spectra calculated at the DFT(B3LYP)/6-311++G(2d,p) level.
Argon↗
Gas-phase deprotonation of uracil-Cu2+ and thiouracil-Cu2+ complexes.
The deprotonation of Cu2+ complexes with uracil, 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil has been investigated by means of B3LYP/ 6-311+G(2df,2p)//6-31G(d) calculations. The most stable [(uracil-H)Cu]+ and [(thiouracil-H)Cu]+ complexes correspond to bidentate structures in which Cu interacts with the deprotonated ring-nitrogen atom and with the oxygen or the sulfur atom of the adjacent carbonyl or thiocarbonyl group. For 2- and 4-thiouracil derivatives, the structures in which the metal cation interacts with the thiocarbonyl group are clearly favored with respect to those in which Cu interacts with the carbonyl group. This is at variance with what was found to be the most stable structure of the corresponding Cu2+ complexes, where association to the carbonyl oxygen was always preferred over the association to the thiocarbonyl group. The [(uracil-H)Cu]+ and [(thiouracil-H)Cu]+ complexes can be viewed as the result of Cu+ attachment to the uracil-H and thiouracil-H radicals formed by the deprotonation of the corresponding uracil+* and thiouracil+* radical cations. As a matter of fact their relative stability is dictated by the intrinsic stability of the corresponding uracil-H and thiouracil-H radical and by the fact that, in general, the N3-deprotonated site is a better electron donor than the N1. In all complexes, the bonding of Cu both to nitrogen and sulfur and to nitrogen and oxygen has a significantly large covalent character.
Binding Sites↗
Evidence that urinary excretion of thiouracil in adult bovine submitted to a cruciferous diet can give erroneous indications of the possible illegal use of thyrostats in meat production.
Thyrostats have been banned for use as veterinary drugs in Europe since 1981 because of their carcinogenic and teratogenic properties. Until now, the identification of thiouracil in animal biological matrices has been interpreted as the consequence of an illegal administration. The present paper studies the influence of a cruciferous-based feed on the occurrence of thiouracil as a residue in urine. Urine samples collected from two heifers fed on cabbage or rapeseed cakes were analysed for the presence of thiouracil by 3-iodobenzylbromide derivatization and liquid chromatography-electrospray ionization tandem mass spectroscopy (LC-ESI(-)-MS/MS) analysis. Urine collected after cabbage or rapeseed feeding showed thiouracil concentrations in the range 3-7 and 2-9 microg l-1, respectively, demonstrating a relationship between a diet based on cruciferous vegetables and the occurrence of thiouracil in urine. Thiouracil was excreted in urine in the hours following cruciferous intake. Complete elimination (<0.8 microg l-1) of the compound occurred within 5 days. The precursors in cruciferous vegetables responsible for the thiouracil excretion in urine were proved not to be thiouracil itself.
Animal Feed↗
A new melanoma seeker for possible clinical use: selective accumulation of radiolabelled thiouracil.
In a previous report we have shown that a few substances, especially thiouracil, are incorporated as false precursors into melanin during its synthesis. In the present investigation, we have intensified our studies on the incorporation of thiouracil into melanotic melanomas. Firstly, the distribution and retention of both 14C- and 35S-labelled thiouracil in mice with transplanted melanomas were studied. A high and selective accumulation was found in the melanotic tumours. The concentration in the rest of the body was low, with the exception of the thyroid gland. Secondly, melanoma-bearing mice were given increasing doses of thiouracil, and cultured melanoma cells were exposed to different concentrations of thiouracil, to investigate the relation between dose and uptake in melanomas and melanoma cells, respectively. A relatively linear increase in uptake with dose was found, indicating that the melanin incorporation of thiouracil is non-saturable up to subtoxic levels.
Animals↗
Selective incorporation of thiouracil into murine metastatic melanomas.
The uptake and retention of 14C-thiouracil and 125I-thiouracil in small lung metastases of B16 murine melanoma was studied in beige mice injected intravenously with melanoma cells. By impulse counting of excised tumor and organ pieces, a high concentration of radioactivity was found in the lung metastases, as compared to normal tissues. The highest tumor/organ concentration ratios appeared 24 h after injection of the radiolabeled thiouracil. A separate autoradiographic study on the disposition of 14C-thiouracil in mice with melanoma metastases confirmed the impulse counting results and also showed the absence of any other site of retention of radioactivity except for hair follicles and to some extent the thyroid. The selective uptake of 14C- and 125I-thiouracil in melanomas depends on their acceptance as false melanin precursors, making them specific markers for growing melanin. The results indicate that radiolabeled thiouracil may be useful for clinical diagnosis and, possibly, therapy of malignant melanotic melanomas.
Animals↗
Response of adrenal 3beta-hydroxy-delta5-steroid dehydrogenase to adrenocorticotropin treatment in thiouracil-fed male mice.
A number of parallels can be drawn between the reported endocrine status of thiouracil-fed young rodents and that of aged animals, particularly with regard to the hypothalamus-pituitary-adrenal axis. Since the activity of the adrenal steroidogenic enzyme 3beta-hydroxy-delta5-steroid dehydrogenase (3beta-HSD) has been shown to be depressed in aged rats and mice, the present study was done to determine whether exposure of young mice to thiouracil had a similar effect on adrenal 3beta-HSD activity. Feeding the goitrogen thiouracil at 0.25% (w/w) of the maternal diet from conception, and keeping it 0.25% of the offsprings' diet after weaning, significantly elevated activity of 3beta-HSD per gram of adrenal gland above control levels in 4-month-old mice, perhaps to compensate for depressed adrenal mass. Daily subcutaneous injections of physiological saline (0.9%) for 4 days was sufficient to increase 3beta-HSD activity per gram of adrenal tissue in euthyroid (P less than 0.05) but not in thiouracil-fed mice. Subcutaneous administration of ACTH (2 IU daily for 4 days) significantly increased adrenal 3beta-HSD activity to comparable levels in thiouracil-fed and euthyroid animals. Thus, thiouracil enhances the activity of 3beta-HSD per gram of adrenal tissue and does not prevent response of enzyme activity to exogenous ACTH.
3-Hydroxysteroid Dehydrogenases↗
X-ray photoelectron spectrometry of copper-thiouracil complexes.
X-ray photoelectron spectrometry was applied to evaluate the correct oxidation number of copper in complexes with 2-thiouracil, 6-amino-2-thiouracil and 6-methyl-2-thiouracil. Regardless of the mode of preparation exclusively Cu(I) was bound to the different thiouracil compounds, producing one homogeneous signal of the Cu2p3/2 electrons at 932.5 eV. Upon oxidation with H2O2, a typical Cu(II) satellite appeared in the main signal of the Cu2p3/2 level was shifted to higher binding energy values. The reaction of Cu(II) with thioracil yielded identical complexes as above, in which Cu had the formal oxidation state +I. During this reaction portions of the thiouracil were oxidized to 2,2'-dithiobis(4-pyrimidinol) [bis(4-hydroxy-2-pyrimidinyl)disulphide], as seen by the shifted sulphur 2p signals to 163.5 eV. After treating the Cu-thiouracil complexes with H2O2, the simultaneous presence of sulphur species having the oxidation states RStheta (161 eV), RSSR (163.5 eV) and RSOtheta3 (168.5 eV) is indicated by the ESCA signals monitored.
Copper↗
Horseradish peroxidase inhibition by thiouracils.
In this paper, the activity of horseradish peroxidase was further determined in the presence of several uracil derivatives. The rate of guaiacol peroxidation decreases in presence of 2-thiouracil and of 6-n-propyl-2-thiouracil, but is not changed by 6-n-propyluracil nor uracil. Thus, thiouracils inhibit horseradish peroxidase in a noncompetitive form. The binding of 6-n-propyl-2-thiouracil, 2-thiouracil, 6-n-propyluracil and uracil with horseradish peroxidase shows difference spectra due to changes in the environment of heme group in peroxidase. Then, the binding sites for these uracil derivatives are in an hydrophobic pocket at the heme periphery of peroxidase. The lesser binding rates were for uracil and propyluracil, which did not inhibit the peroxidase activity. These results point to the thiol group in uracils as responsible for the inhibition of peroxidase activity through interaction with an allosteric binding site, in peroxidase heme environment.
Antithyroid Agents↗
Effect of thiouracil upon canine arterial elastic tissue.
Unlike some other mammalian species, the dog is relatively resistant to the development of elevated levels of serum cholesterol after prolonged cholesterol feeding. This may be overcome by suppressing thyroid activity with thiouracil. Information regarding possible activity of thiouracil itself upon the arterial tissues is almost nonexistent. The present investigation was undertaken to test whether this drug has any such action, especially upon the arterial elastic tissues. Destructive changes were observed in arterial elastic tissues in dogs given thiouracil for three and six months. The changes consisted of accentuation of the elastic fibrillar components, formation and subsequent coalescence of clefts, and fragmentation and ultimate "dissolution" of the elastic elements. The results suggest that thiouracil may exert a damaging effect upon the arterial elastic fibers; thus, it is possible that one of the mechanisms by which thiouracil and cholesterol administration induces experimental atherosclerosis in the dog is by elastic tissue destruction, possibly promoting the subsequent lipid accumulation in the arterial wall.
Animals↗
Synthetic approaches to a carboranyl thiouracil.
Thiouracil is selectively incorporated into melanotic murine melanomas during melanin synthesis. This selectivity makes thiouracil a likely vehicle for boron in the diagnosis and therapy of melanoma. Several synthetic routes to thiouracils bearing an alkyl decacarboranyl group attached to various positions on the ring have been investigated. The successful syntheses of three new alkynyl thiouracils and the conversion of one of them into a carboranyl thiouracil are described.
Animals↗
Unimolecular photochemistry of 4-thiouracils.
Unimolecular phototautomeric reactions in 4-thiouracil, 1-methyl-4-thiouracil and 6-aza-4-thiouracil were studied using the matrix-isolation technique combined with infrared absorption spectroscopy. For monomers of these compounds, isolated in solid argon at 10 K, an intramolecular proton-transfer photoreaction was observed. Upon UV (lambda > 345 nm) irradiation, the initial oxo-thione forms of 4-thiouracils were converted into the corresponding oxo-thiol tautomers. The photogenerated oxo-thiol isomers were identified by comparing their experimental IR spectra with the spectra theoretically calculated at the DFT(B3LYP)/6-311++G(2d,p) level. Good agreement between the observed and predicted pattern of spectral bands allowed a reliable identification. This is the first report on experimental observation of isomeric forms of 4-thiouracils other than the canonical oxo-thione tautomers.
Aza Compounds↗
Consequences of sequential induction of diabetes mellitus by streptozotocin and hypothyroidism by thiouracil in mice.
Both clinical diabetes and chemically-induced diabetes have been reported to alter control processes of the hypothalamic-pituitary-thyroid axis. One of the sites of alteration appears to be depression of thyrotrophin releasing hormone (TRH) stimulated thyrotrophin (TSH) release. The present study examined the influence of sequential administration of streptozotocin and the goitrogen thiouracil to male mice for 4 weeks in view of their possibly opposing effects on TSH release. The drugs produced the expected results when administered singly, with streptozotocin producing hyperglycemia and thiouracil causing hypothyroxinemia and goitrogenesis. Additionally, thiouracil administration produced hyperinsulinemia. Sequential administration of the drugs appeared to ameliorate the thyroid status and glycemic condition caused by individual exposure. Streptozotocin reduced the goitrogenic influence of thiouracil and thiouracil reduced the hyperglycemia of streptozotocin, but not to control levels. Thus, sequential administration resulted in mice with simultaneously elevated circulating glucose and insulin levels, and depressed thyroxine levels. Similar effects on glucose, insulin, and the thyroxine levels have been reported clinically in patients with non-insulin-dependent diabetes mellitus.
Animals↗
Flow injection analysis system equipped with a newly designed electrochemiluminescent detector and its application for detection of 2-thiouracil.
A new flow injection analysis (FIA) system equipped with an electrochemiluminescent (ECL) detector has been developed and applied for the ECL detection of 2-thiouracil. The FIA-ECL system used a specially designed flow-through ECL thin-layer cell to reduce the dead volume, the IR drop across the cell, and the probability of accumulation of gas bubbles in the cell. It was thus envisioned to improve the detection limit of the FIA-ECL method. After being established, the new FIA-ECL system was used to investigate the ECL response of 2-thiouracil in the presence of the ECL of Ru(bpy)3(2+). It was found that 2-thiouracil could enhance the ECL of Ru(bpy)3(2+) over a wide pH range (pH 4.0-12.0). A highly sensitive method for detection of 2-thiouracil in biological samples was developed by the new FIA-ECL system after optimizing several experimental conditions, such as the applied potential of the working electrode, the pH value of the aqueous solution, the flow rate of carrier solution, and the concentration of Ru(bpy)3(2+).
Electrochemistry↗
Synthesis of 6-anilino-2-thiouracils and their inhibition of human placenta iodothyronine deiodinase.
Several 6-anilino-2-thiouracils were synthesized and tested for their ability to inhibit the inner-ring iodothyronine deiodinase from human placenta. The p-ethyl and p-n-butyl analogues were strongly inhibitory to the enzyme and were much more effective than the standard deiodinase inhibitor, 6-propyl-2-thiouracil. The degree of inhibition caused by 6-(p-n-butylanilino)-2-thiouracil was, moreover, unaffected by high concentrations of reducing agent in the enzyme assay. Attempts to prepare 3-alkyl derivatives via S-debenzylation of 2-benzylthio intermediates led to rearrangement to, for example, 3-methyl-5-benzyl-6-amino-2-thiouracil. This compound also strongly inhibited the deiodinase reaction. Preliminary results suggest that these compounds are useful to study in vitro and in vivo metabolism of thyroid hormones and may be clinically useful to enhance the availability of active thyroid hormones to certain organs.
Chemical Phenomena↗