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PubMedDate not supplied

[Micromethod of preparing and purifying labeled 4-methyl-5-beta-hydroxyethylthiazole].

A micromethod is developed for production and purification of small amounts (50-60 microgram) of 35S-4-methyl-5beta-hydroxyethyl thiazole(hemineurine)--a neurotropic agent, which is promising for treatment of delirium tremens. 35S-hemineurine was obtained as follows: sulfite separation of it from pyrimidine residues and other reagents py paper electrophoresis and the subsequent elution of labelled 4-methyl-5beta-hydroxyethyl thiazole from electrophoregramms. The purity of the preparation obtained was controlled by chromatographic, chemical and spectrophotometric analysis (using pure unlabelled preparation).

Asthma↗

PubMed1982

Effect of 4'-oxythiamine on thiamin transport and phosphorylation by everted jejunal sacs, and on thiamin uptake by rat isolated enterocytes.

Two preparations were used for the present investigation. Rat everted jejunal sacs were incubated at 37 degrees C for 1 h in Krebs-Henseleit buffer, pH 7.4, containing 0.2 microM [thiazole-2-14C] -thiamin, with or without 2 microM 4'-oxythiamine. Suspensions of rat isolated enterocytes were incubated at 37 degrees C for 15 min in Ringer-Krebs, pH 7.4, containing 10 mM d-glucose and 0.125 microM [thiazole-2-14C] -thiamin, with or without 1.25 or 12.50 microM 4'-oxythiamine. Radiometric methods were used for the determination of: labeled thiamin net transport, free and phosphorylated thiamin content in the sac walls, total thiamin content in the isolated enterocytes. 4'-oxythiamine, at a molecular ratio with thiamin of 10:1, did not modify labeled thiamin net transport and accumulation by everted jejunal sacs, but caused a slight, statistically insignificant, decrease of labeled phosphorylated thiamin content of the sac walls. 4'-oxythiamine, at a molecular ratio of 10:1 or 100:1, did not inhibit labeled thiamin uptake by isolated enterocytes. Therefore, 4'-oxythiamine, which is known to be unable to inhibit thiamin enzymatic phosphorylation, did not affect thiamin intestinal transport both by everted intestinal sacs and isolated enterocytes. The present results can be interpreted as a further evidence that intracellular thiamin phosphorylation is an important step in thiamin intestinal transport.

Animals↗

PubMed1996

Relative reactivity of platelets from thrombopoietin- and interleukin-6-treated dogs.

Previous reports have shown that interleukin-6 (IL-6) enhances the responsiveness of platelets to thrombin stimulation and has modest thrombocytopoietic effects in vivo. Thrombopoietin (TPO; mpl ligand) has been shown to have dramatic thrombocytopoietic effect in vivo, but little is known of its capacity to alter platelet function. In this study, a direct comparison of the effects of IL-6 and TPO on platelet function in dogs has been performed, with modest doses of TPO (1 microgram/kg/d) chosen to match or moderately exceed the platelet counts achieved with IL-6 (40 micrograms/kg/d) for 10 days. Platelet responsiveness to thrombin stimulation was assessed in TPO-treated, IL-6-treated, and control dogs by flow cytometric measurement of P-selectin expression. On day 5, the dose of thrombin promoting half maximal stimulation (EC50) of platelets was not significantly changed in TPO-treated dogs, whereas in IL-6-treated dogs the EC50 decreased to 73.1% +/- 6.1% (mean +/- 1 SD; n = 5) of control values (P < 0.01). These experiments were performed on both gel-filtered platelets and washed whole blood, indicating that the observed changes in EC50 were caused by cytokine-mediated alteration of platelets rather than plasma components. Because it has been shown that thiazole orange specifically labels a subpopulation of dog platelets that is less than 24 hours old, the thrombin responsiveness of these young, newly synthesized platelets was determined. The EC50 of thiazole orange-positive platelets from IL-6-treated dogs decreased dramatically by day 5 to 46.5% +/- 13.1% (n = 4) of control values (P < 0.001), whereas TPO-treated dogs did not significantly change. When TPO was directly incubated with platelets ex vivo, no effects on either thrombin-mediated P-selectin expression or adenosine diphosphate-induced fibrinogen binding were observed. These data show that IL-6 alters platelet function, as measured by reactivity to thrombin, whereas TPO does not. This divergence in function is observed even though TPO is equally, or more, effective at promoting platelet production under these experimental conditions.

Adenosine Diphosphate↗

PubMedDate not supplied

Development of novel high-sensitivity chemiluminescence assay for luminol using thiourea derivatives.

We have screened about 100 thiourea derivatives in order to develop a sensitive chemiluminescence detection for luminol derivatives. Among these derivatives, we found a new compound, 2-(3-methylthioureido) thiazole, that could be used to measure luminol in the presence of hydrogen peroxide (H(2)O(2)). The detection limits of luminol and N-(4-aminobutyl)-N-ethylisoluminol (ABEI) were 10 fmol and 100 fmol, respectively. The mechanism of proposed chemiluminescence reaction was studied by electron spin resonance (ESR) with and without superoxide dismutase (SOD) and the addition of ethanol. The results showed that 2-(3-methylthioureido) thiazole has the ability to generate hydroxyl radical from H(2)O(2), and produces intense chemiluminescence in the presence of luminol. The proposed novel chemiluminescence reaction for luminol and luminol derivatives was applied to a high performance liquid chromatography (HPLC) assay for amino compounds.

Amino Acids↗

PubMed1995

Reticulated platelets in uremic patients: effect of hemodialysis and continuous ambulatory peritoneal dialysis.

Platelet RNA content can be detected by flow cytometry using thiazole orange staining to identify platelets recently released into the circulation. We studied platelet RNA content and platelet function in uremic patients under different treatment regimens. Four groups were studied: (I) 15 end-stage renal disease (ESRD) patients (10M/5F) on maintenance hemodialysis (HD); (II) 11 ESRD patients (6M/5F) on continuous ambulatory peritoneal dialysis (CAPD); (III) 8 patients with chronic renal failure managed conservatively (5M/3F); and (IV) 34 controls (20M/14F). A double color labeling technique using a phycoerythrin-tagged antibody against glycoprotein Ib (CD42b) and RNA labeling by thiazole orange was performed and read by flow cytometry. Aggregation studies were made in platelet-rich plasma using ADP, epinephrine, collagen, arachidonic acid, and ristocetin. In group I, samples were also obtained after HD. Platelet counts did not differ among the groups. Aggregation studies showed a lower response to ADP and ristocetin in the HD patients, but not in the CAPD or in the chronic renal failure patients. The percentage of platelets with high RNA content in group I was significantly lower than in controls (3.72 +/- 1.72% vs. 9.05 +/- 3.53%, P < 0.01), but was also lower than in the remaining groups (I vs. II P < 0.01, and I vs. III P < 0.01). No differences were seen in platelet RNA content among groups II (8.67 +/- 2.73%), III (9.14 +/- 3.04%) and IV. In group I, the percentage of reticulated platelets decreased further after HD (2.14 +/- 1.09%, P < 0.01). Aggregation studies showed a significantly lower response to ADP and ristocetin in group I (P < 0.05), but not in groups II or III in comparison with controls. Aggregation response to ADP and ristocetin decreased after HD (P < 0.05). In conclusion, HD may decrease the percentage of RNA-rich platelets through elimination of the younger and more active platelets and worsen the thrombopathy present in uremic patients.

Adult↗

PubMed2004

Highly efficient biomimetic total synthesis and structural verification of bistratamides E and J from Lissoclinum bistratum.

The interesting biological activities of heterocycle-containing cyclic peptide-derived natural products, isolated from marine organisms over the past twenty years, have attracted the interest of many synthetic and natural products chemists. Bistratamides E-J, members of this class of natural products that were isolated very recently from Lissoclinum bistratum, exhibited cytotoxic activity against a human colon tumor (HCT-116) cell line. Here we report the first total syntheses of bistratamides E (1) and J (2) in overall yields of 19 and 34 %, respectively. The thiazole substructures have been synthesized by oxidation of their corresponding thiazoline substructures, which were obtained from cysteine containing peptides using a novel biomimetic approach wherein Val-Cys dipeptide units were converted to thiazolines by a bisphosphonium salt. The final macrocyclization was promoted efficiently using the combination of PyBOP and DMAP. This approach allows the use of readily available Fmoc-protected amino acids to make complex thiazole and oxazoline-containing natural products.

Animals↗

PubMed1994

Regulation of THI4 (MOL1), a thiamine-biosynthetic gene of Saccharomyces cerevisiae.

THI4, a Saccharomyces cerevisiae gene originally identified as a result of transient expression in molasses medium and named MOL1 is regulated by thiamine. Using a THI4 promoter-lacZ fusion on a centromeric yeast vector, we have shown that the THI4 is completely repressed throughout batch culture by thiamine at a concentration around 1 microM, but shows high level constitutive expression in thiamine-free medium. The transient expression pattern observed in molasses medium can be mimicked by the addition of 0.15 microM-thiamine to defined minimal medium. Cells grown in thiamine-free medium have an intracellular thiamine concentration of around 9 pmol/10(7) cells. A low level (1 microM) of exogenous thiamine is completely sequestered from the medium within 30 min; intracellular thiamine concentrations rise rapidly, followed by a gradual decrease as a result of dilution during growth. A saturating extracellular level of thiamine leads to a maximal intracellular concentration of around 1600 pmol/10(7) cells, at which point the transport system is shut down. After transfer from repressing to non-repressing medium, THI4 becomes induced when the intracellular concentration of thiamine falls to 20 pmol/10(7) cells. A thi4::URA3 disruption strain is auxotrophic for thiamine, but can grow in the presence of hydroxyethyl thiazole, indicating that the gene product is involved in the biosynthetic pathway leading to the formation of the thiazole precursor of thiamine.

Biological Transport↗

PubMed1998

Proteins in urine scent marks of male house mice extend the longevity of olfactory signals.

The binding of volatile semiochemicals to lipocalin proteins in many mammalian scent marks may provide a gradual release of volatile ligands, extending the life of airborne odour signals. We tested this by using menadione to displace semiochemical ligands from major urinary proteins (MUPs) in urine streaks obtained from adult male house mice, Mus domesticus, and assessed the responses of other males to these and to intact urine marks as they aged. Dominant male mice scent-mark their territories extensively with urine streaks; MUPs in these marks bind at least two semiochemically active molecules, 2-sec-butyl-4,5-dihydrothiazole (thiazole) and 2,3-dehydro-exo-brevicomin (brevicomin), associated with the males' aggressive status. Wild-caught males (N=24), housed in individual enclosures, were presented with two glass slides, behind mesh to prevent contact, on which 10 µl of both unfamiliar urine and 0.5 mg/ml menadione in ethanol had been streaked. On one slide the urine and menadione solution were mixed to displace ligands; on the other they were separate (intact urine). We carried out tests 0, 0.5, 1 or 24 h after deposition, and matched them to changes in the concentration of thiazole and brevicomin within the intact and displaced marks. Males were hesitant to approach intact urine up to 1 h old but, when ligands were displaced, or were reduced to low levels by natural evaporation from intact urine streaks aged 24 h, their approach was similar to that to water and to menadione controls. Ligands did not appear to cause any longer term avoidance and, after the first approach, investigation increased with the freshness of urine regardless of when the ligands were displaced. This is the first direct demonstration that proteins evince a slow release of olfactory signals from mammalian scent marks. The nature of their response suggests that, from a distance, mice may be unable to tell whether airborne signals emanate from scent marks or from the donor himself and we suggest that this may provide territory owners with a major advantage in defending their territories.Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1999

Unravelling the chemical basis of competitive scent marking in house mice.

Major urinary proteins (MUPs) in the urine of male house mice, Mus domesticus, bind the male signalling volatiles 2- sec -butyl-4,5-dihydrothiazole (thiazole) and 3,4-dehydro- exo -brevicomin (brevicomin) and slowly release these volatiles from urinary scent marks. To examine the role of urinary proteins and volatiles, either attached or unattached to the proteins, in competitive scent marking, we fractionated urine from isolated male BALB/c laboratory mice, Mus musculus, by size-exclusion chromatography into three pools. Pool I contained all of the urinary proteins and their bound ligands while pools II and III contained lower molecular weight components including unbound signalling volatiles. In experiment 1, pools I-III were streaked out on to absorbent paper (Benchkote) and introduced into enclosures housing single wild-caught male mice, together with a clean control surface. Each male was tested with fresh stimuli and with aged stimuli deposited 24 h previously. Only pool I stimulated significantly more countermarking and investigation than the control, attracting mice to investigate from a distance even when the rate of ligand release was considerably reduced after 24 h. Experiment 2 examined responses to pool I when this was fresh, aged by 7 days, or had been mixed with menadione to displace ligands from the proteins. Although all three protein stimuli were investigated and countermarked more than a clean control, the aged and menadione-treated pool I stimulated the strongest responses, despite containing the lowest levels of thiazole and brevicomin. Thus competitive countermarking is stimulated by proteins or by nonvolatile protein-ligand complexes in male urine, while release of volatile ligands attracts attention to a competitor's scent marks. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1975

panD, a new chromosomal locus of Salmonella typhimurium for the biosynthesis of beta-alanine.

Three mutants of Salmonella typhimurium LT2, which required either pantothenate or beta-alanine for growth, were obtained after treatment with N-methyl-N'-nitro-N-nitrosoguanidine. Their phenotype was: SM30 Pan-, SM31 Pan- Met-, SM32 Pan- Thi- (requirement for the thiazole-moiety of thiamine). Neither aspartate, dihydrouracil, nor beta-ureidopropionate replaced beta-alanine as growth factor. By conjugation it was found that the three genetic lesions (Pan-, Met-, Thi-) were located at about minute 128 of the bacterial chromosome. By transduction 63% linkage was found between the Pan and Met loci, and 84% between the Thi and Pan loci. Probably the thiazole auxotrophy was due to a lesion in the thiG locus. The new genetic locus responsible for the synthesis of beta-alanine was named panD.

Alanine↗

PubMed1993

Synthesis and fungitoxicity of some pyrimidine derivatives.

A series of 12 pyrimidine derivatives were prepared and tested in vitro against growth, sporulation and nucleic acid content of Fusarium oxysporum f. sp. lycopersici and Helminthosporium oryzae. Introduction of a thiazole ring together with two aryl groups into 2-aminopyrimidine brought about drastic toxicity for both fungi. Pyrimidine derivatives with aryl groups alone were less toxic. Nitro groups were found to enhance the toxicity of the pyrimidine derivatives especially when substituted in the ortho-position of the aryl groups. Inhibition of nucleic acid synthesis of both fungi was attributed mainly to the presence of the thiazole ring.

Antifungal Agents↗

PubMed2006

Synthesis and in vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents.

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.

Anti-HIV Agents↗

PubMed1994

Heterocyclic synthesis with nitriles: new routes for synthesis of pyridazines, pyridines and their fused derivatives.

Phenylazocyanothioacetamide 1 reacts with malononitrile to afford the pyridinethione 4 which reacts with phenacylbromide to yield the pyridine-S-phenacyl derivative 6. 1 reacts with ethyl cyanoacetate to yield the pyridazine derivative, 8, and with phenacyl bromide to afford the N-phenacyl derivative 11, instead of the thiazole 10. Compound 11 afforded the pyrazolopyridine 13 on reaction with malononitrile while 10 was obtained on coupling of the thiazole 14 with diazotised aniline. Compound 10 reacts with malononitrile to afford the thiazolyl pyridazine 15. Compound 1 reacts with malononitrile dimer to afford the pyridopyridazine derivative 17a. 1 reacts also with active methylene heterocycles to afford the pyrazolo and thiazolo-fused pyridazines 20 and 23 respectively.

Acetamides↗

PubMed2005

Role of thiamine thiol form in nitric oxide metabolism.

In alkaline media the thiamine cyclic form is converted into a thiol form (pK(a) 9.2) with an opened thiazole ring. The thiamine thiol form releases nitric oxide from S-nitrosoglutathione (GSNO). Thiamine disulfide, mixed thiamine disulfide with glutathione, and nitric oxide are produced in the reaction. Free glutathione was recorded in small amounts. The concentration of formed nitric oxide agreed well with the concentration of degraded GSNO. The concentration of released nitric oxide was determined under anaerobic conditions spectrophotometrically by production of nitrosohemoglobin. In air, the release of nitric oxide was recorded by the production of nitrite or the oxidation of oxyhemoglobin to methemoglobin. The concentration of the thiol form in the body under physiological pH values (7.2-7.4) did not exceed 1.5-2.0%. We believe that due to the exchange reactions between the thiamine thiol form and S-nitrosocysteine protein residues, nitric oxide can be released and mixed thiamine-protein disulfides are formed. The mixed thiamine disulfides (including thiamine ester disulfides) as well as the thiamine disulfide form are quite easily reduced by low molecular weight thiols to form the thiamine cyclic form with a closed thiazole ring. A possible role of the thiamine thiol form in releasing deposited nitric oxide from low-molecular-weight S-nitrosothiols and protein S-nitrosothiols and in regulation of blood flow in the vascular bed is discussed.

Anaerobiosis↗

PubMed1982

Studies on the mechanism of action of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193)--II. Relationship between dose level and biochemical effects in P388 leukemia in vivo.

Administration of the novel thiazole C-nucleoside, 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193), to BDF1 mice bearing subcutaneous implants of P388 leukemia provoked a sharp depression in the concentration of intratumoral guanine nucleotides and a correspondingly large expansion of the IMP pools. Measurements of IMP dehydrogenase in the tumors of treated mice revealed that this enzyme was inhibited in a dose-responsive way, with approximately 50% inhibition engendered by the administration of the drug at a dose of 25 mg/kg and greater than 90% inhibition by all doses greater than 100 mg/kg. The inhibition of enzyme activity, seen after a dose of 250 mg/kg, reached a maximum 120 min after treatment and had subsided substantially 8 hr after dosing; by 24 hr. enzyme activity was fully restored. These results, coupled with the observation that the antitumor activity of the drug could be prevented in large part by the simultaneous administration of guanosine, support the conclusion that 2-beta-D-ribofuranosylthiazole-4-carboxamide, after anabolism, exerts its antineoplastic effects via a state of guanine nucleotide depletion. In extracts of the tumors of mice given parenteral injections of the thiazole nucleoside, a potent dialyzable inhibitor of IMP dehydrogenase was demonstrable: its concentration fluctuated in parallel with enzyme inhibition. Although the chemical identity of the proximate inhibitory species has yet to be established, it is concluded on kinetic grounds that it is neither the native nucleoside nor its 5'-monophosphate.

Animals↗

PubMed1994

Differential expression of microsomal epoxide hydrolase gene by azole heterocycles in rats.

The effects of heterocycles including imidazole (IM), 1,2,4-triazole (TR) and thiazole (TH) on the expression of microsomal epoxide hydrolase (mEH) gene were examined in rats (200 mg/kg body weight/day, i.p.). Hepatic microsomes prepared from rats treated with IM for 3 days failed to exhibit an increase in mEH protein level whereas TR treatment resulted in an approximately 2- to 3-fold elevation in hepatic mEH levels relative to control, as assessed by both SDS-PAGE and immunoblot analyses. In contrast, thiazole-induced hepatic microsomes resulted in a substantial increase in mEH levels (i.e. approximately 5-fold). Slot and northern blot analyses, probed with an mEH cDNA, showed that the hepatic mEH mRNA levels in the animals treated with IM for 3 days were marginally increased by approximately 2-fold, as compared with untreated animals, whereas TR caused an approximately 8-fold increase in hepatic mEH mRNA levels after three consecutive daily treatments. TH treatment resulted in an approximately 22-fold increase in the mEH mRNA levels, demonstrating that TH is the most efficacious among these three azole heterocycles. Because TH was the most effective in increasing hepatic mEH protein and mRNA levels, the agent was chosen for further evaluation. Time course of mEH gene expression at early times after a single treatment with TH was determined and compared with that caused by pyrazine (PZ), a strong mEH inducer. Hepatic mEH mRNA levels were increased approximately 1-, 3-, 20- and 16-fold at 3, 6, 12 and 24 hr, respectively, following TH treatment, relative to control, whereas mEH mRNA levels were elevated approximately 1-, 1-, 22- and 18-fold, respectively, at the same time points after PZ treatment, as monitored by slot RNA hybridization analyses. Northern blot analyses using either total RNA or poly(A)+ RNA fractions exhibited comparable time courses in increasing mEH mRNA levels after TH or PZ treatment with maximal mRNA increases being noted at 12 hr post treatment. Although neither IM or TR failed to affect renal mEH gene expression to a notable extent, TH treatment caused 6- to 8-fold increases in kidney mEH mRNA levels, with a 2-fold increase in mEH protein detected. These results demonstrated that the azole heterocyclic compounds IM, TR and TH differentially induce mEH with TH as the most efficacious azole; and that the changes in mEH levels are primarily associated with increases in mRNA levels.

Animals↗

PubMed1980

Enhancement of sister-chromatid exchange in Chinese hamster ovary cells by nitrofurans.

The nitrofurans, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), 2-methyl-4-(5-nitro-2-furyl)thiazole (MNFT), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), nitrofurantoin, 5-nitro-2-furfurylidene diacetate and 5-nitro-2-furamidoxime were assayed for the enhancement of sister-chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells and for the mutagenic activity in Salmonella typhimurium strain TA100. All of the nitrofurans significantly increased the frequency of SCE in CHO cells, and they were mutagenic for Salmonella. The increases in the frequencies of SCE were well correlated with the mutagenic activities in Salmonella.

Animals↗

PubMed1977

The origin of the sulfur atom in thiamine.

The mode of biosynthesis of the thiazole moiety of thiamine, 4-methyl-5beta-hydroxyethyl thiazole (MHET) was studied using Salmonella typhimurium as test organism. It was shown by isotope incorporation experiments, that the sulfur atom, but not carbon-3, of cysteine is incorporated into MHET, indicating a separation of the sulfur atom of cysteine from the carbon chain during incorporation. Isotope competition experiments revealed that the incorporation of [35S]cysteine is not significantly diluted by the presence of methionine, homocysteine, and glutathione. No incorporation of label from [14C]glutamate and [14C]formate was observed, leaving the origin of the five-carbon unit still in doubt.

Cysteine↗