Thiouracil Derivatives Research Articles

Drug-associated agranulocytosis: 20 years of reporting in The Netherlands (1974-1994).

In this descriptive study, all 425 reports were included concerning drug-associated agranulocytosis as registered between 1974 and 1994 in the files of the Drug Safety Unit of the Dutch Inspectorate for Health Care. All reports were analysed as to the probability of agranulocytosis or neutropenia according to previously defined criteria. Subsequently, the causal relationship between exposure and outcome was assessed. It concerned 149 men and 271 women. One hundred and twelve reports were unclassifiable because age, gender, or total number of leukocytes at the time of reaction were unknown. In 100 reports agranulocytosis was probable, in 78 possible, in 8 reports neutropenia was probable, in 20 reports neutropenia was possible, and in 107 reports agranulocytosis or neutropenia were unlikely. In the 13 reports of probable agranulocytosis or neutropenia with a certain causal relationship, causative drugs were cimetidine, dipyrone, sulphasalazine, methyldopa, spironolactone, propylthiouracil (2), thiamazole, sulphamethoxazole with trimethoprim, gentamicin, a combination preparation containing aminophenazone, benzylpenicillin and indomethacin. The individual drugs most often reported to cause agranulocytosis or neutropenia were: dipyrone (19), mianserin (15), sulphasalazine (13), sulphamethoxazole with trimethoprim (11), the group of penicillins (9), cimetidine (8), the thiouracil derivatives (8), phenylbutazone (8), and penicillamine (8). Agranulocytosis is a serious and fairly frequently reported adverse reaction. The reporting system of the Drug Safety Unit can be used very well for signal generation concerning adverse reactions to drugs.

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.

Biotransformation of several structurally related 2B compounds to reactive metabolites in the somatic w/w+ assay of Drosophila melanogaster.

Biotransformation of several structurally related 2B compounds to reactive metabolites was evaluated in the somatic w/w+ assay of Drosophila melanogaster. Chemicals tested were the dichlorinated alkanes dichloromethane (DCM), 1,2-dichloroethane (DCE), and 1,3-dichloropropane (DCP); the thiouracil derivatives 5-methyl, 2-thiouracil (5M2TU), 6-methyl, 2-thiouracil (6M2TU), and 5-propyl, 2-thiouracil (5P2TU); and the plastic monomer styrene (STY) and its metabolite styrene 7,8-oxide (SO). The tester strains used consisted of one wild-type insecticide-susceptible (IS) laboratory strain (Leiden-S, ST), and two insecticide-resistant (IR) strains (Hikone-R, HK, and Haag-R, HG). The latter have high cytochrome P450-dependent bioactivation capacities. Drosophila larvae heterozygous for the wild-type report gene w+ were exposed chronically to at least three different exposure doses of each compound. A total of 53,694 eyes were analyzed. A positive genotoxic activity was obtained for DCM and for 6M2TU at all exposure doses and genotypes analyzed, and for SO in the IR strains HK-R and HG-R. An overall weakly recombinagenic response was shown by DCE and 5M2TU. The chemicals DCP, 5P2TU, and STY proved to be overall negative in IR as well as in IS strains, and SO was negative in the standard stock. Biotransformation mediated by cytochrome P450 monoxigenases to reactive metabolites is discussed.

Prebiotic synthesis of diaminopyrimidine and thiocytosine

The reaction of guanidine hydrochloride with cyanoacetaldehyde gives high yields (40-85%) of 2,4-diaminopyrimidine under the concentrated conditions of a drying lagoon model of prebiotic synthesis, in contrast to the low yields previously obtained under more dilute conditions. The prebiotic source of cyanoacetaldehyde, cyanoacetylene, is produced from electric discharges under reducing conditions. The effect of pH and concentration of guanidine hydrochloride on the rate of synthesis and yield of diaminopyrimidine were investigated, as well as the hydrolysis of diaminopyrimidine to cytosine, isocytosine, and uracil. Thiourea also reacts with cyanoacetaldehyde to give 2-thiocytosine, but the pyrimidine yields are much lower than with guanidine hydrochloride or urea. Thiocytosine hydrolyzes to thiouracil and cytosine and then to uracil. This synthesis would have been a significant prebiotic source of 2-thiopyrimidines and 5-substituted derivatives of thiouracil, many of which occur in tRNA. The applicability of these results to the drying lagoon model of prebiotic synthesis was tested by dry-down experiments where dilute solutions of cyanoacetaldehyde, guanidine hydrochloride, and 0.5 M NaCl were evaporated over varying periods of time. The yields of diaminopyrimidine varied from 1 to 7%. These results show that drying lagoons and beaches may have been major sites of prebiotic syntheses.

Synthesis and Antithyroid Activity of Fluorinated 2-Thiouracil Analogues

AbstractThe synthesis of four fluorinated-2 thiouracil derivatives, namely, 6-trifluoromethyl* -2-thiouracil, l-methyl-6-trifluoromethyl-2-thiouraci1, l-acetyl-6-trifluoromethyl-2-thiouracil and 6-n-heptafluoropropyl-2-thiou-racil was achieved. 6-n-Heptafluoropropyl-2-thiouracil displayed higher antithyroid activity followed by 6-trifluoromethyl derivative and 1-methyl-6-trifluoromethyl analogue when compared to 6-n-propyl-2-thiouracil. 1-Acetyl 6-trifluoromethyl-2-thiouracil exhibited no antithyroid activity. The structure-activity relationships (SAR) of this class of compounds are discussed.

Photooxidation products of merocyanine 540 formed under preactivation conditions for tumor therapy.

In order to gain insight into the preactivation of merocyanine 540 (MC540) 1 for the photodynamic therapy (Gulliya et al., 1990a, Photochem. Photobiol. 52, 831-838) its photo-oxidation was investigated. After irradiation of MC540 1 on a preparative scale three main photodegradation products were isolated with 16-20% yields. They turned out to be derivatives of benzoxazole, thiouracil and thiohydantoin with the structures 4, 5 and 6, respectively. It may be possible that they contribute to the cytostatic and antiviral activity of preactivated MC540 1.

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.

Monoorganomercury and diorganothallium derivatives of 2-thiouracil and 2- S-methylthiouracil; crystal structure of methylmercury(II)-2- S-methylthiouracilate

Monometallated derivatives of thiouracil (H 2Tu) and 2- S-methylthiouracil (HTuSMe), (R n MHTu and R n MTuSMe, R = Me or Ph, M = Hg or Tl) and dimetallated derivatives of 2-thiouracil [(RHg) 2Tu] (R = Me or Ph) have been prepared. The structure of MeHgTuSMe was determined by X-ray diffraction. The crystal was found to consist of MeHgTuSMe units, with the mercury atom bonded to nitrogen N(3) of the 2-thiouracil ring. Weak intra- and inter-molecular interactions between the metal atoms and the carbonyl group or the N(1) atom were also observed. Possible structures for the other compounds isolated are discussed on the basis of their IR, Raman and NMR ( 1H, 13C and 199Hg) spectra.

Thyreostatische Therapie in der Gravidität

Antithyroid drugs can pass the placenta, in contrast to thyroid hormones. Therefore, their application in pregnancy carries the potential risks of teratogenic effects and foetal hypothyroidism. The actual danger to the foetus, however, is controversial. The history of a hyperthyroid patient treated with carbimazole and referred for termination of pregnancy in the 8th week of gestation gave rise to review the literature in order to elucidate the foetal risks. Data of 278 pregnant women treated with imidazole derivatives (group I) and 192 women, who received thiouracil derivatives (group II) during pregnancy, were found in the literature. The rates of foetal malformations and foetal goitre in group I were 3.6% and 3.2%, respectively. In group II the corresponding rates were 3.6% for foetal malformation and 7.8% for foetal goitre. From these figures we conclude that antithyroid therapy in pregnancy does not warrant termination of pregnancy for foetal reasons if there is meticulous control of maternal thyroid metabolism.

Incorporation of thiouracil and some related compounds into growing melanin.

Several drugs, mainly polycyclic amines, are accumulated in melanin-containing tissues. They are bound to preformed melanin (both in vivo and in vitro). Thiouracil is accumulated into melanin according to another principle: It is incorporated as a false precursor during melanin formation. It is thus taken up only in growing melanin, e.g. in the eye of pigmented mouse foetuses or in melanomas. The acceptance of a foreign substance during the formation of a foetal tissue seems theoretically important. We are also interested in the practical viewpoint of using false melanin precursors as selective melanoma seekers. Some related substances are therefore compared with respect to incorporation into growing melanin. The thiouracil uptake in the ocular melanin of a 5 day old mouse was 276 times higher than that of a 3 month old mouse based on weight units of melanin. Thiourea is incorporated in growing melanin as well but also binds slightly to preformed melanin. Uracil and fluorouracil showed no specific uptake into growing melanin. It thus seems as if the sulfur is essential for the incorporation into the melanin polymer. 35S-thiouracil and 2-thio(2-14C)urcal showed the same high uptake, indicating that at least part of the uracil moiety is incorporated together with the sulfur. There seems to be a relation between the property to be incorporated into melanin and the tyrostatic activity. Both in the formation of melanin and thyroid hormones, tyrosine is the physiological precursor and both reactions are catalyzed by oxidizing enzymes. Properly labelled thiouracil derivatives seem to be promising melanoma seekers for diagnostic and radiotherapeutic purposes.

Preparation of radioiodine labelled thiouracil derivatives

2-Thiouracil and 6-propyl-2-thiouracil are radioiodinated with high yield uding the chloramine-T method at low pH to prevent oxidation of the sulfur. The radioiodine-labelled derivatives are purified by adsorption chromatography on Sephadex G-10. The identity and purity of the products obtained are demonstrated by both normal- and reversed-phase high pressure liquid chromatography. The specific activity of the tracers amounts to approximately 1750 Ci mmol −1. Conditions for storage are described as well. These radioactive compounds may be used in the investigation of the mechanism of action of thyroid peroxidase as well as of iodothyronine deiodinases.

Binding of radioiodinated propylthiouracil to rat liver microsomal fractions. Stimulation by substrates for iodothyronine 5′-deiodinase

Previous studies have shown that 2-thiouracil derivatives are uncompetitive inhibitors of iodothyronine 5'-deiodinase activity of rat liver microsomal fraction. Therefore the interaction of radioiodinated 6-propyl-2-thiouracil with rat liver microsomal fraction and the effect of substrate, cofactor and other inhibitors of 5'-deiodinase activity activity were investigated. It was found that micromolar concentrations of, in order of increasing potency, 3,5-diiodotyrosine, thyroxine, 3,3',5'-tri-iodothyronine and 3',5'-di-iodothyronine significantly enhanced binding of 5-[125I]iodo-6-propyl-2-thiouracil to the enzyme preparation. This stimulation was not seen in the presence of 1 mM dithiothreitol, 0.1 mM-6-propyl-2-thiouracil, 0.1 mM-6-propyl-2-thiouracil, 0.1 M-2-mercapto-1-methylimidazole or 1 mM-sodium sulphite. These results support the hypothesis that thiouracil derivatives inhibit 5'-deiodinase activity by forming a mixed disulphide with an intermediate enzyme complex, probably a sulphenyl iodide.

ChemInform Abstract: CARBON‐13 NUCLEAR MAGNETIC RESONANCE SPECTRA OF N‐, O‐, AND S‐METHYLATED URACIL AND THIOURACIL DERIVATIVES

Chemischer InformationsdienstVolume 9, Issue 30 Physical Organic Chemistry ChemInform Abstract: CARBON-13 NUCLEAR MAGNETIC RESONANCE SPECTRA OF N-, O-, AND S-METHYLATED URACIL AND THIOURACIL DERIVATIVES I. W. J. STILL, I. W. J. STILLSearch for more papers by this authorN. PLAVAC, N. PLAVACSearch for more papers by this authorD. M. MCKINNON, D. M. MCKINNONSearch for more papers by this authorM. S. CHAUHAN, M. S. CHAUHANSearch for more papers by this author I. W. J. STILL, I. W. J. STILLSearch for more papers by this authorN. PLAVAC, N. PLAVACSearch for more papers by this authorD. M. MCKINNON, D. M. MCKINNONSearch for more papers by this authorM. S. CHAUHAN, M. S. CHAUHANSearch for more papers by this author First published: July 25, 1978 https://doi.org/10.1002/chin.197830062AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume9, Issue30July 25, 1978 RelatedInformation

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.

Stimulation of dieldrin elimination by a thiouracil derivative and DDT in the rat: Enhancement of dieldrin oxidative metabolism?

Oral treatment of rats with either DDT or 1-benzyl-2-thio-5,6-dihydrouracil (BTDU) enhanced the elimination of intraperitoneally administered [ 14C]dieldrin. Both DDT and BTDU caused a severalfold increase in the urinary elimination of [ 14C]dieldrin. The increase in [ 14C]dieldrin elimination in the feces was less pronounced. Under similar conditions both DDT and BTDU stimulate the activity of hepatic oxidative “drug-metabolizing enzymes”. Thus the duration of hexobarbital- and progesterone-induced sleep was markedly reduced by either DDT or BTDU treatment. It is suggested that DDT and BTDU increase the elimination of dieldrin by stimulating its oxidative metabolism.

Heterocyclic studies. Part XIX. Some 6-(substituted phenyl)-uracil and -thiouracil derivatives

Ten β-(m- and p-substituted phenyl)-β-oxopropionates (I and II; X = F, Cl, Br, Me, or OMe) were synthesised and condensed with thiourea to yield the corresponding 6-(m- and p-substituted phenyl)thiouracils [(V) and (VI)], which were converted into the analogous uracils [(VII) and (VIII)] by treatment with chloroacetic acid. Nitration of 6-(p-substituted phenyl)uracil derivatives gave 5-nitro- or m,5-dinitro-compounds according to reaction conditions. 1H N.m.r. spectra of most of the compounds are recorded.

Study of placental transfer of thiouracil derivatives

Five different 14C-labeled derivates of thiouracil were prepared by condensation of 14C-thiourea with β-oxo esters. Methyl, propyl, phenyl, and benzyl radicals were substituted at positions 5 or 6 in the thiouracil ring. The placental transfer of the synthesized compounds was measured using 14-day-pregnant rats. The results indicated a rapid transfer of all five compounds, but the more complex structures displayed the slowest rate of transplacental passage. Such decrease in transfer with increasing steric hindrance suggests that the placental transfer of thiouracil derivatives involves a simple diffusion process.

Diminished biological activity of C 21-steroids in rats pretreated with a thiouracil derivative. Stimulation of steroid hydroxylation?

Treatment of male rats with 1-benzyl-2-thio-5,6-dihydrouracil (BTDU) diminished the duration of anesthesia produced by administered progesterone. BTDU treatment also decreased the induction of hepatic l-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5 (tyrosine transaminase), by triamcinolone acetonide (TrA). The diminution of the induction of tyrosine transaminase was attributed to a BTDU-mediated increased transformation of TrA into a less active derivative 6β-hydroxy-triamcinolone acetonide (6β-OH-TrA). In fact, 6β-OH-TrA was found to be markedly less active than TrA in inducing tyrosine transaminase. Furthermore, the administration of 6β-OH-TrA together with TrA did not alter the induction of tyiosine transaminase by TrA, demonstrating that the metabolite does not interfere with the action of TrA. It is suggested that BTDU treatment produces an increase in the activity of the hepatic monooxygenase system which hydroxylates steroids. Thus in BTDU-treated rats progesterone and TrA are converted at faster rates into hydroxylated derivatives which are either intrinsically less active and/or are excreted at a faster rate than the parent compounds.

CLINICAL APPLICATION OF SERUM-TOTAL-THYROXINE ESTIMATION, RESIN UPTAKE, AND FREE-THYROXINE INDEX

Resin uptake of 125I-labelled thyroxine (T 4) from serum can be used both as a primary test and also to estimate serum-total-T 4. The two procedures have been combined to give a new and more specific form of free-thyroxine index (the T 4-F.T.I.). The use of these three variables as tests of thyroid function has been studied in 376 patients and 137 controls. The two primary tests give a fair distinction between different thyroid states, but are also influenced by changes in thyroxine-binding proteins. The T 4-F.T.I. compensates for such changes in binding and seems to give an acceptable estimate of thyroid activity in a high proportion of cases of definite thyrtoxicosis or hypothyroidism. As with other tests, low values are seen in the " sick euthyroid " group. In borderline cases of thyrotoxicosis the index compares favourably with single 132I neck-uptake tests, but in partial hypothyroidism a proportion of cases gave normal results. The index is convenient for the patient and clinician as it does not involve attendance at the laboratory. It is unaffected by drugs such as iodide and thiouracil derivatives which interfere with other tests.

STIMULATION OF POLLEN TUBE GROWTH IN VITRO BY THIOURACIL AND OTHER ANTIMETABOLITES OF NUCLEIC ACID BASES

25 Purines and pyrimidines were tested for the effect on pollen tube growth and germination. 2-Thiouracil most strongly stimulates tube growth. However, 2-thiouracil decreases or does not affect metabolism of sugars. Some derivatives of thiouracil also stimulate tube growth, whereas others inhibit growth. Pollen growth response is markedly affected by the concentration of the compound tested.