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PubMed1982

Accumulation of 125I-labelled thiouracil and propylthiouracil in murine melanotic melanomas.

We have shown that thioamides are incorporated as false precursors into melanin during its synthesis. To be clinically useful in the diagnosis or therapy of melanotic melanomas, they would have to be tagged with an appropriate isotope or possibly a cytotoxic moiety. 125I-Thiouracil (125I-TU) is here shown to be accumulated in the melanin of melanotic melanomas transplanted into mice in a similar way as is 14C-thiouracil (14C-TU). 125I-TU gives tumour/liver and tumour/muscle ratios up to 22 and 778 respectively, at 4 days after administration. 125I-TU is accumulated by melanoma cells in vitro more effectively than 14C-TU (125I-TU/14C-TU, 2.7), while the in vivo accumulation into melanomas is slightly lower for 125I-TU as compared to 14C-TU (125I-TU/14C-TU, 0.35). This appears to be due to a partial deiodination (less than 14% of the dose within 4 days) and probably a more rapid excretion of 125I-TU or its metabolite(s). The accumulation of radioactivity in the thyroid can essentially be eliminated by pretreatment with potassium iodide and/or thyroxine. 125I-Propylthiouracil is also accumulated in melanotic melanoma cells in vivo and in vitro, but at a lower level than in 125I-TU and 14C-TU.

Animals↗
PubMed1984

Depressed hypothalamic CRF immunoreactivity in 15 day old thiouracil-treated rats.

Depression of thyroid status with thiouracil has been shown to delay the response of the hypothalamus-pituitary-adrenal axis to stress in young rats. In vivo and in vitro bioassay studies have indicated that the hypothalamus is the main site of axis alteration in 15 day old animals. The present study has found a significantly depressed hypothalamic content of immunoassayable corticotropin-releasing factor (CRF) in thiouracil treated young rats.

Age Factors↗
PubMed1960

Suppressive effects of 2-thiouracil on differentiation and flowering in Cannabis sativa.

The pyrimidine, 2-thiouracil, partly annuls the effect of photoperiodic induction in the short-day plant, Cannabis sativa L., when it is supplied at the onset of the dark period in quantities of 15-30 microg per plant. This treatment also produces aberrations in cellular differentiation in the leaves. Tracer studies show that 2-thiouracil becomes bound in cellular ribonucleic acid, which suggests that the effects on morphogenesis are due to interference with nucleic acid metabolism.

Cannabis↗
PubMed1986

Scintimetric detection of choroidal malignant melanoma with [123I]-5-iodo-2-thiouracil.

[123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection in 10 patients with proven choroidal melanoma. Uptake of 123I-ITU was measured with a specially designed single eye probe collimator, 24 h after administration of 123I-ITU. Increased uptake in the tumor-bearing eye as compared to the fellow nontumor bearing eye was found in 7 out of 10 cases when the probe was located 3.5 cm in front of the eye (p less than 0.01). By using a double pinhole collimator tests were positive in 3 out of 10 123I-ITU studies only. Tests with 123I-ITU were compared with 67Ga tests in the same patients. The 67Ga tests with the single eye probe collimator were positive in 6 out 10 cases when the probe was located 6 cm in front of the eye. With the double pinhole collimator tests were positive in 7 out of 10 67Ga studies. It is concluded that 123I-labeled thiouracil is at least as useful as a radiopharmaceutical for ocular melanoma diagnosis as 67Ga-citrate, provided measurements are performed with a single eye probe.

Choroid Neoplasms↗
PubMed1978

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↗
PubMed1994

Effects of dietary thiouracil on thyroid activity, egg production, and eggshell quality in commercial layers.

The effects of thyroid suppression induced during the rearing period by providing various dietary thiouracil (TU) regimens on plasma thyroxine (T4) concentrations, growth, and subsequent egg production (EP) and eggshell quality were determined in Single Comb White Leghorn chickens. Thiouracil was provided in the feed at levels of 0, .1, and .2% from 0 to 6 wk of age in Experiment 1, and at levels of 0, .05, and .1% from 6 to 16 wk of age in Experiment 2. In both experiments, T4 concentrations were reduced during TU treatment. However, T4 later became elevated at 12 and 20 wk in both dosage level groups in Experiment 1. Additionally, BW and egg weights were suppressed by both TU treatments, and EP was reduced up to Week 23 in the .1% TU-treated birds and through Week 25 in the .2% TU-treated birds. No effects on EP were noted in Experiment 2, but feed consumption (FC) was reduced during Week 6 in birds fed .05% TU and during Weeks 6, 10, and 19 in birds fed .1% TU. Both liver and thyroid weights were increased in .1% TU-treated birds relative to controls at Week 16. Eggshell quality was affected only in Experiment 2, in which birds given .05% TU had a higher relative conductance, or maximum rate of water loss, at Week 38 than 0 and .1% TU dosage levels, and .1% TU-treated birds had a higher breaking strength than 0 and .05% TU-treated birds at Week 22.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Feed↗
PubMed1986

Synthesis, tissue distribution and cytostatic properties of two new daunorubicin derivatives of 2-thiouracil containing a guanidine bridge.

In further attempts to utilize the affinity of 2-thiouracil for melanin-producing tissues in the design of drugs active against malignant melanomas, guanidine-bridged adducts of the anthraquinone drug daunorubicin (1a) with 2-thiouracil were prepared (Scheme 3). The expected adduct (4), and a by-product in its preparation (5) (Scheme 3), were inactive against murine melanoma, in vivo, and did not show affinity for melanin-producing tissues. They were efficient DNA intercalating agents, but were much less cytostatic than daunorubicin against Cloudman melanoma, and were inactive, in vitro, against human cervical carcinoma MS 751. The coupling chemistry employed may have application in current attempts to effect binding of drugs to high molecular weight targeting antigens.

Animals↗
PubMed1982

Central nervous regulation of pituitary TSH response induced by thiouracil treatment or by thyroidectomy.

The serotoninergic neuron system of the midbrain and hypothalamus was previously shown to inhibit the basal secretion of the TRH-TSH-thyroid axis. The aim of the present study was to investigate the influence of the serotoninergic system on the TSH response of the adenohypophysis to specific loads. Serum TSH levels were determined 7 days after thyroidectomy or the beginning of thiouracil administration. Animals were simultaneously treated either by intrahypothalamic implantation of serotonin-containing needles or by intraventricular or daily subcutaneous injections of the same drug. The thiouracil-induced goitre formation and increase in serum TSH concentration were significantly diminished by serotonin treatment. Similarly, the thyroidectomy-induced rapid rise in TSH blood level was also remarkably inhibited in the serotonin-treated animals. Serotonin was proved to influence rather TRH-output than pituitary TSH secretion, since exogenous TRH, injected to serotonin-pretreated animals had the same TSH-mobilizing potency as found in the not premedicated group. It is concluded that besides the inhibition of the basal secretion of the TRH-TSH-thyroid axis by serotonin, there is an integrative role of the serotoninergic system in the mediation of the reactivity of this circuit in reply to specific influences loading pituitary-thyroid function.

Animals↗
PubMed1998

Influence of thiouracil-induced hypothyroidism on adrenal and gonadal functions in adult female rats.

The effect of hypothyroidism on adrenals and gonads in adult female rats was investigated throughout the estrous cycle. Hypothyroidism was induced by administration of 4-Methyl-2-Thiouracil (Thiouracil) in the drinking water. The weight of ovaries and adrenals, and the plasma levels of corticosterone decreased in hypothyroid rats as compared with euthyroid rats throughout the estrous cycle. Hypothyroidism resulted in decreased concentrations of plasma LH on the day of diestrus and proestrus, whereas the plasma concentrations of prolactin and progesterone increased as compared with euthyroid rats. The weight of uteri and plasma concentrations of estradiol decreased during the day of diestrus and proestrus in hypothyroid rats as compared with euthyroid rats. To further clarify the dysfunction of hypothalamo-hypophysial-adrenal axis in hypothyroid rats, animals were stressed by immobilization for 3 hr. In hypothyroid rats, a marked increase in plasma levels of ACTH in response to immobilization stress was observed compared to euthyroid control, whereas increases in plasma concentrations of corticosterone were much smaller in hypothyroid than euthyroid rats. These results clearly indicate that hypothyroidism causes both gonadal and adrenal disturbances in adult female rats. The increased concentrations of plasma progesterone may be due to hypersecretion of prolactin during the day of proestrus and estrus, which in turn result in disruption of the estrous cycle.

Adrenal Glands↗
PubMed2005

An ultrasensitive method for the determination of thiouracil and phenylthiouracil using capillary zone electrophoresis and laser-induced fluorescence detection.

This paper reports the development of a method based on capillary electrophoresis with laser-induced fluorescence detection for the simultaneous determination of thiouracil (TU) and phenylthiouracil (PhTU) with high sensitivity (nanomolar range, i.e., attomoles detected). After derivatization with 5-iodoacetamidofluorescein, the analytes were separated by capillary zone electrophoresis using 20 mM phosphate buffer (pH 10.0) and quantified by fluorescence detection. The linearity range, precision, recovery, and detection limits were determined, and the method was shown to be applicable for the determination of TU and PhTU in spiked feed samples and urine.

Animal Feed↗
PubMed1983

Potential radiopharmaceuticals for the detection of ocular melanoma. Part I. 5-iodo-2-thiouracil derivatives.

The tissue distribution of a number of 5-[131I]-iodo-2-thiouracil derivatives was measured in Syrian golden hamsters with Greene melanoma. These compounds were rapidly (in less than 1 h) distributed in all tissues, while in most tissues fast elimination (T1/2 1-3 h) was observed. Because of retention of the 131I activity in the tumour, high tumour/non-tumour tissue ratios were found (e.g. tumour/eye 2.3-10, tumour/skin 1.5-3) suggesting that some of these compounds might be used as melanoma delineating agents, when labelled with 123I.

Animals↗
PubMed1978

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↗
PubMed2002

Synthesis of new 2-thiouracil-5-sulfonamide derivatives with biological activity.

2-Thiouracil-5-sulfonylchloride 1 reacted with a series of aromatic and heterocyclic amines to give 2a-j. The same compound 1 was reacted with a series of sulphonamides giving different sulphonamides of type 3a-e. On the other hand compound 1 was allowed to react with p-aminoacetophenone givining compound 4 which in turn was allowed to react with derivatives of alkyl thiosemicarbazides to give thiosemicarbazones of type 5a-e, also compound 4 was monobrominated to give compound 6 which in turn was reacted thiosemicarbazones of some aldehydes to give the corresponding thiazole derivatives 7a-f. In the same time compound 4 was reacted with a series of aromatic and heterocyclic aldehydes givining chalcones 8a-g (Claisen-Schemidt reaction). Also compound 4 was allowed to react with a series of aromatic and heterocyclic aldehydes, ethyl cyano acetate and/or malononitrile, and ammonium acetate giving pyridine derivatives 9a-d and 10a-e respectively. The biological effects of some of the new synthesized compounds was also investigated.

Anti-Bacterial Agents↗
PubMed2005

Synthesis of new 2-thiouracil-5-sulphonamide derivatives with antibacterial and antifungal activity.

2-Thiouracil-5-sulphonic acid N-(4-acetylphenyl) Amide (1) was reacted with a series of aromatic aldehydes giving chalcones 2 (Claisen-Schemidt reaction), some of these chalcones were reacted with urea and thiourea giving pyrimidine-2-one and pyrimidine-2 thione derivatives respectively of the type 3a,b and 4a,b. In addition many chalcones were reacted with hydroxylamine hydrochloride giving isoxazoline derivatives 5a,b. They could also reacted with phenylhydrazine to give pyrazoline derivatives 6a,b, chalcones also were reacted withethylcyano acetate and/or malononitryl in pyridine giving pyran derivatives 7a,c and 8a,c. In another pathway chalcones were epoxidised by H2O2 giving epoxides 9a,c which in turn were reacted with phenylhydrazine giving 4-hydroxypyrazoline derivatives 10a,c. In another reaction chalcones were reacted with ethylcyanoacetate in presence of amm.acetate giving pyridone derivatives 11a,d which could be prepared also in exellent yield from compound 1 by its reaction with certain aromatic aldehydes and ethylcyanoacetate in presence of ammonium acetate. Finally, compound 1 was reacted with semicarbazide giving semicarbazone intermediate 12 which in turn was reacted with thionyl chloride giving thiadiazole derivative 13. The biological effects of some of the new synthesized compounds were also investigated.

Anti-Bacterial Agents↗
PubMed1990

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↗
PubMed2000

2-thiouracil is a selective inhibitor of neuronal nitric oxide synthase antagonising tetrahydrobiopterin-dependent enzyme activation and dimerisation.

2-thiouracil (TU), an established antithyroid drug and melanoma-seeker, was found to selectively inhibit neuronal nitric oxide synthase (nNOS) in a competitive manner (K(i)=20 microM), being inactive on the other NOS isoforms. The drug apparently interfered with the substrate- and tetrahydrobiopterin (BH(4))-binding to the enzyme. It caused a 60% inhibition of H(2)O(2) production in the absence of L-arginine and BH(4), and antagonised BH(4)-induced dimerisation of nNOS, but did not affect cytochrome c reduction. These results open new perspectives in the understanding of the antithyroid action of TU and provide a new lead structure for the development of selective nNOS inhibitors to elucidate the interdependence of the substrate and pteridine sites and to modulate pathologically aberrant NO formation.

Animals↗
PubMed2002

Synthesis and characterization of cobalt and nickel chelates of 5-dimethylaminomethyl-2-thiouracil and their evaluation as antimicrobial and anticancer agents.

A new antimetabolite of adenine, viz. 5-dimethylaminomethyl-2-thiouracil, was synthesized using the Mannich reaction. Owing to the biological importance of metalloelements in many biological processes, especially metabolic processes, cobalt(II) and nickel(II) complexes were also synthesized and examined for their antimicrobial and anticancer activities. These new compounds were characterized structurally by various techniques ranging from micro-elemental analyses to spectral analyses. Cobalt(II) complexes were found to be four coordinate, among which the bromo, iodo, and nitrato complexes were polymeric. The nickel(II) isothiocyanato complex exhibited four-coordinate geometry and the remaining nickel(II) complexes were six coordinate. Thermodynamic and kinetic parameters evaluated based on TG/DSC suggested that the initial stage of thermal decomposition follows a diffusion-controlled mechanism and the final stage a chemically controlled mechanism. Antibacterial, antifungal, and antitumor studies undertaken for the above compounds indicated structure-activity relationships. These metalloderivatives were more active than the parent compound. The order of activity was influenced by the chelate geometry and thermal stability. Activity increased with a decrease in coordination number and increase in thermal lability.

Animals↗
PubMed1976

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↗