[Analytical studies on thiouracils. I. Synthesis and thin-layer chromatography of thiouracils (author's transl)].
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Chromatography, Thin Layer↗
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[Analytical studies on thiouracils. II. Dissociation constants of thiouracils and their reactions with hydrogen peroxide (author's transl)].
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Chemical Phenomena↗
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↗
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↗
Differential effect of 2-thiouracil on synthesis of two plant viruses in the same host.
In cowpea leaves singly or doubly infected with cowpea chlorotic mottle virus (CCMV) and/or southern bean mosaic virus (SBMV), treatment with 2-thiouracil increased the accumulation of CCMV particles and strongly decreased the accumulation of SBMV particles. Thiouracil prevented the usual inhibition of synthesis of CCMV particles at about 6 days after inoculation, and 2-3 times as many CCMV particles accumulated as in water-treated plants. A single treatment of thiouracil 48 h before, at the time of, or 24 h after inoculation caused at least 90% decrease in the amount of SBMV particles extracted from inoculated leaves for at least 15 days. When virus particles were extracted from plants treated with thiouracil, the specific infectivity of CCMV was increased 2.3 times and SBMV was decreased 0.46 times as compared to virus from control plants.
Mosaic Viruses↗
[Sub-ppm determination of thiouraciles applicated as thyreostatics in meat by high pressure liquid chromatography (author's transl)].
The thyreostatics 2-thiouracile, 4-methyl-2-thiouracile, and 2-propyl-2-thiouracile were extracted from meat and determined by High Pressure Liquid Chromatography to a limit of about one ppb.
Animal Feed↗
Inhibition of Bacillus subtilis DNA polymerase III by arylhydrazinopyrimidines. Novel properties of 2-thiouracil derivatives.
6-(p-Tolylhydrazino)-uracil, 6-(p-tolylhydrazino)-isocytosine and 6-(p-tolylhydrazino)-2-thiouracil were synthesized and compared with respect to their chemical properties, their activity as inhibitors of DNA polymerase III of Bacillus subtilis, and their capacity to induce the formation of a complex between polymerase III and template DNA. As expected from earlier studies of analogous hydroxyphenylhydrazino compounds, the effects of the uracil derivative were reversed specifically by dGTP and those of the isocytosine derivative were reversed specifically by dATP. In contrast, reversal of the effects of the thiouracil derivative required both dGTP and dATP. The unique capacity of the 2-thiouracil analog to mimic either purine deoxyribonucleotide appears to reside in its ability to undergo tautomerism between the 2-thione and 2-thiol forms, which can pair with, respectively, template cytosine and thymine.
Bacillus subtilis↗
The effect of methionine, thiouracil, dienestrol diacetate and thyroprotein on the development and prevention of fatty liver in pullets.
The effect of two levels each of methionine (0.0 and 0.07 percent), thiouracil (0.0 and 0.05 percent), dienestrol diacetate (0.0 and 0.007 percent), and thyroactive casein (0.0 and 0.0125 percent) on the performancy, organ changes, and liver composition in 640 pullets of two strains was studied in a 24 factorial arrangement of treatments. Egg production, egg characteristics, feed conversion, organ weights, and liver composition were parameters measured. Supplemental methionine increased the phosphorus content of liver fat in strain A, but other parameters in the two strains were mot affected by the increase in dietary methionine. The thiouracil increased weight grains, gram of fat per total liver, percent of liver fat, thyroid weight, and heart weight but decreased the phosphorus content of liver fat. Nine typical cases of fatty liver syndrome with large liver hematomas occurred in the thiouracil treated birds and one case occurred in an untreated pullet. Dienestrol diacetate did not affect egg production, egg characteristics, organ weights, and liver composition in the two strains. Thyroprotein decreased weight gain, abdominal fat, liver weight. liver fat, thyroid weight, and percent red cells, but decreased percent blood sports in eggs and adjusted weights of the kidney and heart in both strains.
Adipose Tissue↗
Effects of selection on plasma thyroxine concentrations in Japanese quail under thiouracil and protein stress.
Three experiments were conducted to measure changes in plasma thyroxine (T4) concentrations occurring in male and female Japanese quail in response to treatment with dietary thiouracil (TU) and different CP levels prior to sexual maturity and to determine the influence of selection for growth under TU and protein stress on this response. Selected and unselected lines of quail were fed diets containing .2% TU or two levels of CP (20 or 28%) or both from 0 to 4 wk of age. Body weight and plasma T4 were measured at 5, 7, and 9 wk of age in Experiments 1 and 2. In Experiment 3, body weight was measured at 2, 4, 5, 7, and 9 wk and T4 at 4, 7, and 9 wk. Thiouracil inhibited growth to a greater degree than did decreased dietary CP. However, offspring from selected quail were more resistant to dietary TU when selection diets contained TU. When fed as part of a selection regimen rather than to unselected birds, low CP, TU diets inhibited body weight increase to a greater degree and longer after birds were returned to control diets. Thyroxine concentrations between 4 and 9 wk were affected by TU but not by CP level. Thiouracil significantly reduced T4 during treatment; however, T4 was elevated by 3 wk after cessation of TU treatment. Increases in T4 were greater and more immediate in selected than in unselected birds. These findings reveal the ability of quail to compensate for thyroid suppression after TU is removed from the diet and the influence of selection on this compensatory response.
Animals↗
Structure and tautomerism of the neutral and monoanionic forms of 2-thiouracil, 2,4-dithiouracil, their nucleosides, and some related derivatives.
Ultraviolet and infrared spectrophotometric techniques have been utilized to demonstrate that the monoanionic form of 2-thiouracil in aqueous medium consists of an equilibrium mixture of two tautomeric monoanions, one due to dissociation of the N1 proton, the other to dissociation of the N3 proton, in the approximate ratio 1:1. In contrast to 2,4-diketopyrimidines, and 4-thiouracil, where monoanion formation involves charge delocalization, the two tautomeric monoanions of 2-thiouracil appear to have the charge localized on the O4 position. The neutral forms of 2,4-dithiouracil and 2,4-dithiouridine are in the dithione form in both aqueous and non-aqueous media. The monoanionic form of 2,4-dithiouracil consists of a mixture of two tautomeric monoanions, the predominant one of which is that with the proton on the ring N3, and with charge delocalization on both isomeric monoanions. Such charge delocalization is also present in the monoanion of 2,4-dithiouridine. For the reference compound 2-methylthiopyrimidone-4, the dominant, virtually exclusive, form in chloroform is that with the hydrogen localized on the ring N3, whereas in aqueous medium there is a 1:1 equilibrium mixture of two neutral tautomeric forms, one with the hydrogen on N3, the other with the hydrogen on N1.
Chemical Phenomena↗
Hormonal regulation of thermogenesis in goslings. The effects of blockade with thiouracil and propranolol.
Hormonal regulation of thermogenesis in goslings. The effects of blockade with thiouracil and propranolol. Acta Physiol. Pol. 1977, 28 (1): 51-60. The experiments were carried out on 90 male goslings of White Italian breed. In goslings 5 to 7 and 18 to 21-day-old thiouracil (6 mg/100 g i.p., for 3 consecutive days) diminished the cold-induced increase in the metabolic rate. At the end of 1.5 h exposure to 5 degrees C a small but statistically significant drop of body temperature in the thiouracil-treated goslings was noted. Propranolol treatment (2 mg/kg s.c.) had no clear effect neither on body temperature of cold exposed goslings nor on the cold-induced increase in the metabolic rate. The drug caused a significant decrease in the plasma free fatty acid (FFA) levels only in the goslings kept at thermoneutrality. In those exposed to 5 degrees C the plasma FFA levels rose both in the control and propranolol-treated goslings. This suggests that the cold-induced lipolysis in the goslings may be accomplished without mediation of noradrenaline.
Age Factors↗
Thiouracil-induced myocardial fibrosis.
Rabbits were fed with thiouracil for 8 months. Subsequently their hearts were examined electron microscopically as well as biochemically for collagen and hexosamine content. Chronic treatment with thiouracil induced an increase in interstitial connective tissue collagen and hexosamine without visible necrosis. As seen by electron microscopy, the increase in collagen content might have been caused by stimulation of the fibrocytes. Furthermore, the heart muscle cells showed deep indentations and bulges of the cell membrane and an enlargement of the T-system.
Animals↗
Boron-containing thiouracil derivatives for neutron-capture therapy of melanoma.
Boron-containing derivatives of 2-thiouracil and 2,4-dithiouracil and the corresponding 6-propyl compounds, containing a dihydroxyboryl group in the 5-position, have been prepared. These compounds accumulate in B16 melanoma in mice in concentrations up to 30 micrograms of boron per gram tissue. The uptake persists. The toxicity of both 2-thiouracil derivatives is low. These compounds are therefore good candidates for boron neutron-capture therapy of malignant melanoma.
Animals↗
The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings.
A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.
Animals↗
The influence of diazepam and thiouracil upon the carcinogenic effect of diethylnitrosamine in gerbils.
N-diethylnitrosamine (DEN) was simultaneously administered with diazepam (DZP) or thiouracil (TU) once weekly for life to gerbils (Meriones unguiculatus). Additional DZP or TU treatment increased significantly average survival time and inhibited the development of cholangiocarcinomas, although cholangiomas were still observed in these groups. Tumor type and incidence in the nasal cavities were not influenced by DZP or TU. However, in comparison to DEN alone tumor latencies were prolonged.
Adenoma, Bile Duct↗
Selective uptake of 2-thiouracil into melanin-producing systems depends on chemical binding to enzymically generated dopaquinone.
2-Thiouracil (TU), an antithyroid drug, is receiving growing interest as a specific tumor marker for malignant melanoma, owing to its capability of being selectively accumulated into active melanin-producing tissues. However, up until now, the molecular mechanism of TU uptake by growing melanin has remained largely unknown. In an attempt to fill this gap, we have investigated the effect of TU on the tyrosinase catalyzed oxidation of tyrosine. At a concentration of 0.5 mM, TU was found to totally inhibit melanin formation by tyrosinase catalyzed oxidation of 0.25 mM tyrosine in phosphate buffer at pH 6.8. Polarographical monitoring of oxygen consumption under conditions of complete suppression of melanogenesis revealed a significant tyrosinase activity, with TU acting as a modest non-competitive inhibitor of the enzyme (Ki = 0.6 mM). HPLC and TLC analysis of the tyrosine-tyrosinase reaction in the presence of excess TU showed that the substrate is progressively consumed and a major hitherto unknown product (lambda max = 284 nm), positive to ninhydrin and ferric chloride, is concomitantly formed. This was isolated by repeated gel filtration chromatography of the reaction mixture on Sephadex G-10 and was formulated as the TU-dopa adduct 3,4-dihydroxy-6-(4'-hydroxypyrimidinyl-2'-thio)phenylalanine by spectral analysis. These results suggest that selective TU incorporation in pigmented melanomas and other melanin-producing systems is due to the covalent binding to dopaquinone, produced by tyrosinase catalyzed oxidation of tyrosine.
Animals↗
Synthesis and anticancer activity of 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracils.
Several 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracil have been synthesized and tested for their potential anticancer activity in vitro on KB cells and in vivo on Ehrlich carcinoma. Among the alkylating derivatives tested several showed cytotoxic activity in vitro and compound V [5-[bis(2-chloroethyl) amino] methyl-6-propyluracil hydrochloride] showed both in vitro and in vivo anticancer activity.
Alkylating Agents↗
Uptake of [131I]thiouracil in tumours of patients with disseminated malignant melanoma. A pilot study.
Previous studies on mice carrying melanoma have shown that 5-iodo-2-thiouracil (ITU) is accumulated in the tumours due to its specific incorporation into melanin during its synthesis. ITU is also selectively localized in murine melanoma metastases and in cultured human melanoma cells. Progressive formation of melanin is, however, a prerequisite for the incorporation. Four patients with disseminated melanoma were injected intravenously with 39-62 MBq [131I]TU. Blood and urine samples were gradually collected, and 3-7 days postinjection tumours were biopsied and examined by impulse counting. The patients were scanned with a gamma camera over the total body daily for 3-4 days. The radioactivity was rapidly excreted. Poor melanin pigmentation of the tumours and low proliferation rate (possibly induced by chemotherapy) decreased the uptake of radioactivity by the tumors, and no imaging was possible. One of the patients, however, had clearly progressive disease with darkly pigmented metastases which contained considerably higher levels of radioactivity than the surrounding skin. Calculations indicated that a doubling of the radioiodine dose would probably make visualization of the tumours possible.
Bone Neoplasms↗