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PubMed2001

Biosynthesis of the thiazole moiety of thiamin in Escherichia coli: identification of an acyldisulfide-linked protein--protein conjugate that is functionally analogous to the ubiquitin/E1 complex.

A covalently linked protein--protein conjugate between ThiF and ThiS thiocarboxylate was found in a partially purified coexpressed ThiF/ThiS protein mixture by using Fourier transform mass spectrometry. The Cys-184 of ThiF and the C terminus of ThiS thiocarboxylate were identified to be involved in the formation of this complex by using both mutagenesis and chemical modification methods. A complementation study of Escherichia coli thiF(-) using thiF(C184S) suggests that this conjugate is an essential intermediate involved in the biosynthesis of the thiazole moiety of thiamin. This ThiF/ThiS conjugate is the first characterized example of a unique acyldisulfide intermediate in a biosynthetic system. This protein conjugate is also an example of an ubiquitin-E1 like protein-protein conjugate in prokaryotes and supports a strong evolutionary link between thiamin biosynthesis and the ubiquitin conjugating system.

Acylation↗
PubMedDate not supplied

Computer aided prediction of biological activity spectra: evaluating versus known and predicting of new activities for thiazole derivatives.

Computer aided prediction of biological activity spectra by the computer program PASS was applied to a set of 89 new thiazole derivatives. Experimentally tested activities (NSAID, local anaesthetic and antioxidant) coincide with the experiment in 70.8% cases, that exceeds significantly the random guess-work (approximately 0.1%). Therefore, computer aided prediction using the Prediction of Activity Spectra for Substances (PASS) system (http://www.ibmh.msk.su/PASS) provides a reliable basis for planning of synthesis and experimental study for new compounds. New psychotropic activities are predicted for some compounds from the series under study. In particular, 7, 44 and 55 compounds likely have anxiolytic, anticonvulsant and cognition enhancer effects, respectively. Most of these compounds have the estimated values of probability to be active (Pa) less than 60%. Therefore, if their activity will be confirmed by the experiment, they might occur to be New Chemical Entities.

Anesthetics, Local↗
PubMed2001

A flow cytometric technique using thiazole orange to detect platelet engraftment following pediatric stem-cell transplants.

BACKGROUND: Thiazole orange (TO) is a nucleic-acid-specific dye that enters cells without pretreatment. When it binds to either RNA or DNA, there is an increase in fluorescence emission. This property has been utilized to measure the amount of newly released platelets using flow cytometry. These newly released platelets differ from more mature platelets because they still contain residual amounts of RNA, and have become known as reticulated platelets. METHODS: Peripheral blood samples were collected at least 48 h following platelet infusion. For validation, manual reticulocyte counts obtained in the laboratory were compared with results obtained using TO and flow cytometry. Following validation, experiments using platelet-rich plasma were performed to evaluate the presence of reticulated platelets in the sample. RESULTS: Validation experiments comparing the manual and flow cytometric reticulocyte counts gave a strong relationship between the two values (r(2) = 0.92). Reticulated platelet studies performed on platelet-rich plasma samples yielded the following results. Patients who did not engraft within 4 days were significantly different from patients who did engraft within 4 days, idiopathic thrombocytoperic purpura (ITP) patients, and donor platelet segments (all P < 0.0008). Patients who engrafted within 4 days, ITP patients, and donor platelet segments were all statistically similar (all P > 0.08). DISCUSSION: The statistical difference between patients who did engraft within 4 days and those who did not suggests that this method could have an important clinical impact in determining those patients who are still in need of platelet support. However, great care must be taken when performing and analyzing the results.

Adolescent↗
PubMed1995

Affinities of nutty and green-smelling pyrazines and thiazoles to odorant-binding proteins, in relation with their lipophilicity.

Thirty-two green- and/or nutty-smelling compounds, most of them pyrazine and thiazole derivatives, were tested in ligand binding assays with purified 19 kDa bovine and 22 kDa porcine olfactive binding proteins (OBPs). Unlike the nutty ones, all the green odorants were found to be good ligands for both proteins. Lipophilicity appears as an interesting discriminating physicochemical parameter, predictive of the affinity for OBPs and of the related odour profile.

Animals↗
PubMed1987

Inducibility of NADPH cytochrome c (P-450) reductase in yeast: role in the bioactivation of nitroimidazo(2,1-b)thiazoles.

Nine nitroimidazo(2,1-b)thiazoles were tested for their ability to induce convertants, revertants and mitotic recombinants on growing and stationary phase cells of Saccharomyces cerevisiae D7 strain. All compounds were genetically active only on cells from the logarithmic growth phase (from a 20% glucose medium), inducing dose-related increases in conversion and reversion frequencies. The addition of S9 microsomal fraction to stationary phase cells gave positive results at levels of doses 10-100 times lower than that used with growing cells. NADPH cytochrome c (P-450) reductase activity was determined in order to compare the capability of hepatic and yeast microsomes in bioactivating the test compounds. Results showed that nitroreductive enzymes are inducible by conditions supporting growth. The greater sensitivity of the treatment with external metabolic activation could be due to the greater content (about 14-fold) of NADPH cytochrome c-reductase activity in hepatic microsomes.

Animals↗
PubMed1991

High-sensitivity two-color detection of double-stranded DNA with a confocal fluorescence gel scanner using ethidium homodimer and thiazole orange.

Ethidium homodimer (EthD; lambda Fmax 620 nm) at EthD:DNA ratios up to 1 dye:4-5 bp forms stable fluorescent complexes with double-stranded DNA (dsDNA) which can be detected with high sensitivity using a confocal fluorescence gel scanner (Glazer, A.N., Peck, K. & Mathies, R.A. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3851-3855). However, on incubation with unlabeled DNA partial migration of EthD takes place from its complex with dsDNA to the unlabeled DNA. It is shown here that this migration is dependent on the fractional occupancy of intercalating sites in the original dsDNA-EthD complex and that there is no detectable transfer from dsDNA-EthD complexes formed at 50 bp: 1 dye. The monointercalator thiazole orange (TO; lambda Fmax 530 nm) forms readily dissociable complexes with dsDNA with a large fluorescence enhancement on binding (Lee, L.G., Chen, C. & Liu, L.A. (1986) Cytometry 7, 508-517). However, a large molar excess of TO does not displace EthD from its complex with dsDNA. When TO and EthD are bound to the same dsDNA molecule, excitation of TO leads to efficient energy transfer from TO to EthD. This observation shows the practicability of 'sensitizing' EthD fluorescence with a second intercalating dye having a very high absorption coefficient and efficient energy transfer characteristics. Electrophoresis on agarose gels, with TO in the buffer, of preformed linearized M13mp18 DNA-EthD complex together with unlabeled linearized pBR322 permits sensitive fluorescence detection in the same lane of pBR322 DNA-TO complex at 530 nm and of M13mp18 DNA-EthD complex at 620 nm. These observations lay the groundwork for the use of stable DNA-dye intercalation complexes carrying hundreds of chromophores in two-color applications such as the physical mapping of chromosomes.

Benzothiazoles↗
PubMed2004

DNA sequence recognition by an isopropyl substituted thiazole polyamide.

We have used DNA footprinting and fluorescence melting experiments to study the sequence-specific binding of a novel minor groove binding ligand (thiazotropsin A), containing an isopropyl substituted thiazole polyamide, to DNA. In one fragment, which contains every tetranucleotide sequence, sub-micromolar concentrations of the ligand generate a single footprint at the sequence ACTAGT. This sequence preference is confirmed in melting experiments with fluorescently labelled oligonucleotides. Experiments with DNA fragments that contain variants of this sequence suggest that the ligand also binds, with slightly lower affinity, to sequences of the type XCYRGZ, where X is any base except C, and Z is any base except G.

Base Sequence↗
PubMed1999

Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia.

Two kynurenine hydroxylase inhibitors, (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfona mide (Ro 61-8048), have been tested as neuroprotective agents on brain lesions induced by bilateral carotid occlusion in gerbils or by middle cerebral artery occlusion in rats. The percentage of lesioned pyramidal neurones found in the hippocampal CA1 region of gerbils subjected to bilateral carotid occlusion for 5 minutes decreased from 92+/-10% in vehicle-treated animals to 7+/-6% after mNBA (400 mg/kg intraperitoneally, three times at 1, 30, and 180 minutes after occlusion) or to 10+/-11% after Ro 61-8048 (40 mg/kg intraperitoneally, three times). A significant reduction in infarct volumes also was found when the kynurenine hydroxylase inhibitors were given to rats after permanent middle cerebral artery occlusion (from 207+/-111 mm3 in vehicle-treated rats to 82+/-18 and to 62+/-57 mm3 in rats treated with mNBA, 400 mg/kg intraperitoneally, or with Ro 61-8048, 40 mg/kg intraperitoneally, respectively). The administration of mNBA (400 mg/kg intraperitoneally) or Ro 61-8048 (40 mg/kg intraperitoneally) to gerbils with a dialysis probe in their dorsal hippocampus or to rats with a dialysis probe in their parietal cortex significantly increased kynurenic acid concentration in the dialysates. The data suggest that inhibition of kynurenine hydroxylase could be a new avenue to reduce neuronal loss in brain ischemia.

Alanine↗
PubMed1991

Flow cytometric reticulocyte analysis using thiazole orange; clinical experience and technical limitations.

Flow cytometric (FCM) reticulocyte analysis using thiazole orange (TO) is becoming an increasingly popular method for routine quantification of reticulocytes. The methodology is accurate, cost-effective and shows a high correlation with manual techniques. We describe our experience with the clinical application of FCM reticulocyte analysis in a general hospital setting over a 20-month period with special emphasis on technical limitations.

Antineoplastic Agents↗
PubMed1982

Synthesis of some biologically active substituted thiazole and thiazoline-amino acid derivatives. Part I.

Synthesis of a series of N-(2-acetylaminothiazole-5-sulphonyl) amino acids (II-VI) and some of their corresponding methyl esters (VII-XI) is described. Coupling of N-tosyl-or N-phthalylamino acid with 2-amino-2-thiazoline using the DCC method furnishes 2-(N-tosyl- or N-phthalylamino acyl) amino-2-thiazoline (XII-XXI). Hydrazinolysis of 2-(N-Pht-L-Phe or N-Pht-L-Ala) amino-2-thiazoline in ethanol afforded 2-(L-Phe or L-Ala) amino-2-thiazoline (XXII and XXIII) respectively. Synthesis of the dipeptide 2-(N-Tos-L-Val-L-Leu) amino-2-thiazoline (XXIV) has been achieved employing the azide method. Sixteen thiazole- and thiazoline-amino acid derivatives were found to be active against a number of microorganisms.

Amino Acids↗
PubMed2004

Influence of a thiazole derivative on ethanol and thermally oxidized sunflower oil-induced oxidative stress.

The present work describes the protective influence of the dendrodoine analogue (DA) [4-amino-5-benzoyl-2-(4-methoxy phenylamino) thiazole] on thermally oxidized sunflower oil and ethanol-induced oxidative stress. Ethanol was fed to animals at a level of 20% [(7.9 g/kg body weight (bw)] and thermally oxidized sunflower oil at a level of 15% (15 mL/100 g feed). Hepatotoxicity was assessed by measuring the activity of plasma aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT), which were elevated in thermally oxidized oil, and ethanol fed rats when compared with normal control rats. Tissue damage was associated with increased lipid peroxidation and disruption in the antioxidant defence mechanism in thermally oxidized oil- and ethanol-fed groups when compared with normal control group. The activity of liver marker enzymes (AST, ALP and GGT) and the level of lipid peroxidation decreased when DA was administered along with ethanol and thermally oxidized oil. The antioxidant status was near normal in DA-administered groups. Thus we propose that DA exerts antioxidant properties by modulating the activity of hepatic marker enzymes, level of lipid peroxidation and antioxidant status.

Alkaline Phosphatase↗
PubMed2006

Thiazole orange, a DNA-binding photosensitizer with flexible structure, can inactivate pathogens in red blood cell suspensions while maintaining red cell storage properties.

BACKGROUND: Development of a robust pathogen reduction system for red cells (RBCs) utilizing photosensitive dyes has been constrained by hemolysis, usually mediated by reactive oxygen species emanating from dye free in solution as well as dye bound to the RBC membrane. The RBC binding properties of thiazole orange (TO), a flexible nucleic acid intercalating cyanine dye that predominantly acts as a photosensitizer only when bound, were assessed along with its virucidal, bactericidal, and light-induced hemolytic activities. STUDY DESIGN AND METHODS: Leukodepleted 20% hematocrit RBCs suspended in Erythrosol (RAS-2) were oxygenated, inoculated with test organisms, incubated with TO, and illuminated. Control and treated samples were analyzed by appropriate assay. Identically prepared, but uncontaminated samples were phototreated, concentrated to 45% hematocrit, and assayed for potassium leakage, hemolysis, and ATP during storage. RESULTS: Approximately 21 percent TO bound to RBCs. Phototreatment inactivated from 5.4 to 7.1 log(10) of 5 tested viruses and from 2.3 to greater than 7.0 log(10) of 8 tested bacteria. Phototreated RBCs exhibited only slightly increased hemolysis, moderately elevated potassium efflux, and similar levels of ATP compared to controls. CONCLUSION: TO can photoinactivate several model viruses and pathogens in RBCs under conditions that produce limited hemolysis without the addition of quenchers or competitive inhibitors.

Anti-Bacterial Agents↗
PubMed1996

Synthesis and anticonvulsant activity of some 1,2,3,3a-tetrahydropyrrolo[2,1-b]-benzothiazol-, -thiazol- or -oxazol-1-ones in rodents.

To identify more potent anticonvulsant agents and to gain insights into the structural properties determining the potency of a new class of anticonvulsants, some 3a-substituted tetrahydropyrrolo[2,1-b]benzothiazol-1-ones (1a-d) and the thiazole and oxazole analogues (2a-c and 3a-c, respectively) have been synthesized and tested for anticonvulsant activity against isoniazid-induced seizures in rodents. The most active compound, 2a, with a median effective dose (ED50, i.p.) of 24.3 mg kg-1 and 15.9 mg kg-1 in mice and in rats, respectively, was more extensively investigated and found to strengthen the effects of diazepam. No clear correlation was observed between the anticonvulsant activity and molecular lipophilicity descriptors of compounds 1-3. Structural similarity between the antiepileptic drug phenobarbital and compounds 1-3 was evidenced by molecular modelling studies and used to derive preliminary structure-activity relationships. The results demonstrate that 2a is an attractive candidate as an anticonvulsant agent worthy of further study and may help the design of other anticonvulsant drugs.

Animals↗
PubMed2002

Metabolism of a thiazole benzenesulfonamide derivative, a potent and elective agonist of the human beta3-adrenergic receptor, in rats: identification of a novel isethionic acid conjugate.

(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]- 4-[4-(4-trifluoro-methylphenyl)thiazol-2-yl]benzenesulfonamide (1) is a potent and selective agonist of the human beta3-adrenergic receptor. We report herein the data from studies of the metabolism and excretion of 1 in rats. Five metabolites were identified in the bile of male Sprague-Dawley rats administered 3H-labeled 1 by either oral gavage (10 mg/kg) or intravenous injection (3 mg/kg). These included a pyridine N-oxide derivative (M2), a primary amine resulting from N-dealkylation and loss of the pyridinyl-2-hydroxyethyl group (M4), a carboxylic acid derived from N-dealkylation and loss of the pyridyl-2-hydroxyethyl amine (M5), and the corresponding taurine and isethionic acid conjugates (M1 and M3). Metabolites M1 and M3 also were identified in rats treated with M5 and were generated in incubations of M5 with rat liver subcellular fractions in the presence of ATP and coenzyme A with supplementary taurine or isethionic acid. These results suggest that M5 is the precursor of M1 and M3 and that the formation of these conjugated metabolites follows similar mechanisms of amino acid conjugation. On the other hand, M2, M4, and M5 were produced from 1 in an NADPH-dependent manner in incubations with liver microsomes from rats, dogs, monkeys, and humans. In human liver preparations, these routes of biotransformation were shown to be catalyzed by cytochrome P450 3A4. In a bidirectional transport assay, transport of 1 across a monolayer of cells expressing P-glycoprotein (Pgp) was observed to be similar to that of vinblastine, which is an established substrate of the transporter protein. This finding, together with the observation that the parent compound was excreted in the feces of bile duct-cannulated animals following intravenous dosing, suggests that 1 is subject to Pgp-mediated excretion from intestine of rats.

Adrenergic beta-3 Receptor Agonists↗
PubMed2002

[3H]Methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine binding to metabotropic glutamate receptor subtype 5 in rodent brain: in vitro and in vivo characterization.

The binding of [3H]methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (methoxymethyl-MTEP), a potent and selective antagonist for metabotropic glutamate (mGlu)5 receptors, was characterized in rat brain both in vitro and in vivo. Nonspecific binding, as defined with 10 microM 2-methyl-6-(phenylethynyl)-pyridine (MPEP), was less than 10% of total binding in rat brain membranes. The binding of [3H]methoxymethyl-MTEP was of high affinity (K(d) = 20 +/- 2.7 nM), saturable (B(max) = 487 +/- 48 fmol/mg protein), and to a single site. The mGlu5 antagonists methoxymethyl-MTEP and MPEP displaced [3H]methoxymethyl-MTEP binding with IC50 values of 30 and 15 nM, respectively. In vivo administration of [3H]methoxymethyl-MTEP (50 microCi/kg i.v.) revealed 12-fold higher binding in hippocampus (an area enriched in mGlu5 receptors) relative to cerebellum (an area with few mGlu5 receptors) in rats. Similarly, administration of [3H]methoxymethyl-MTEP to mGlu5-deficient mice demonstrated binding at background levels in forebrain, whereas wild-type littermates exhibited 17-fold higher binding in forebrain relative to cerebellum. Systemic administration of unlabeled mGlu5 antagonists methoxymethyl-MTEP and MPEP to rats reduced the binding of [3H]methoxymethyl-MTEP with ID50 values of 0.8 and 2 mg/kg i.p., respectively, 1 h post-treatment. The mGlu5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) (0.3, 1, and 3 micromol) dose-dependently increased phosphoinositide (PI) hydrolysis in the hippocampus after i.c.v. administration in rats. CHPG-evoked increases in PI hydrolysis were blocked with MPEP at a dose (10 mg/kg i.p.) that markedly reduced [3H]methoxymethyl-MTEP binding in vivo. These results indicate that [3H]methoxymethyl-MTEP is a selective radioligand for labeling mGlu5 and is useful for studying the binding of mGlu5 receptors in rat brain in vitro and in vivo.

Animals↗
PubMed2005

The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems.

The metabotropic glutamate 5 receptor (mGlu5) receptor has been implicated as having a role in pain modulation, anxiety, and depression, as well as drug-seeking behavior. In the present study, we examined the effect of the selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat and the inbred alcohol-preferring (iP) rat. MTEP (2 mg/kg i.p.) caused a significant reduction in responding for ethanol by both strains of rats; however, in the iP rats, MTEP also induced apparent sedation at this dose, although still reduced alcohol responding at lower doses. Chronic MTEP (2 mg/kg/day) caused a significant reduction in ethanol consumption by FH rats in a two-bottle preference test; however, chronic treatment with this dose had no effect on anxiety-like behavior or depressive-like behavior in FH rats, suggesting the dose used was subthreshold for anxiolytic or antidepressive-like effects. Finally, repeated dosing with MTEP (2 mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the N-methyl-D-aspartate receptor and the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor in the cingulate cortex. A significant decrease in NR1 expression also occurred in the piriform cortex. Chronic MTEP also caused a significant decrease in mGlu5 gene expression and a significant increase in dopamine transporter and dopamine D(2)-like receptor binding within the olfactory tubercle. Collectively, these data suggest that MTEP can reduce alcohol-seeking behavior in different rodent models of alcoholism, and this effect is associated with regulation of cortical glutamate systems, particularly those in olfactory-related regions.

Alcohol Drinking↗
PubMed2002

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization.

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.

Acetylcholine↗