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PubMed1994

[Synthesis of tert-butylcyclopentane-fused 1,3-oxazines and 1,3-thiazines].

Chlorosulphonyl isocyanate (CSI) addition to 4-tert-butylcyclopentene furnished the azetidinone (3) in a stereospecific reaction. Azetidinone 3 was transformed by ring opening esterification and lithium aluminium hydride (LAH) reduction to the 2-hydroxy-methyl-4-tert-butyl-1-cyclopentylamine (6). The N-methyl-aminoalcohol (8) was prepared from amino esters (5) with ethyl chloroformate and subsequent LAH reduction. By different ring-closure methods, a number of tert-butyl-cyclopentante-fused 1,3-oxazines and 1,3-thiazines were synthesized. A comparative study of the prepared compounds was performed by IR, 1H- and 13C-NMR, DEPT and DNOE measurements.

Indicators and Reagents↗
PubMed1994

Studies on synthesis and biological properties of pyrazolo[4,3-c]-pyrido[3,2-e]-1,2-thiazine-5,5-dioxide bearing 4-substituted-1-piperazinylpropyl moiety.

Derivatives of the pyrazolopyridothiazine-5,5-dioxide 6 and the pyridothiazine-1,1-dioxide 2 bearing 4-phenyl-(heteroaryl)-1-piperazinylpropyl substituent at the nitrogen of the thiazine ring were synthesized. The acute toxicity and preliminary results of the CNS activity of some derivatives 2 and 6 are described. A structure-activity relationship is discussed.

Animals↗
PubMed1993

Uptake and photoeffectiveness of two thiazines in HeLa cells.

A comparative study of the uptake and photoinactivation of HeLa cells treated with methylene blue (MB) and toluidine blue (TB) has been performed. Cell toxicity induced by different concentrations of either MB or TB showed that 10(-5) M was the concentration at which dark damage was not observed, while an elevated photoinactivation could be detected with both thiazines. The uptake studies showed that the penetration kinetics of 10(-5) M MB into HeLa cells is faster than that of TB, used at the same concentration, reaching saturation (approximately 1.8 micrograms/10(6) cells) after 6 or 12 h of incubation, respectively. For both sensitizers, the survival of HeLa cells was dependent on the incubation time, as well as the light dose, for a given concentration (10(-5) M). Moreover, cell photoinactivation produced by MB was higher than that produced by TB. The differences between MB and TB obtained under our experimental conditions are discussed.

Carcinoma↗
PubMed1996

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. X--Synthesis and inhibition of benzodiazepine receptor binding of new 1,4-thiazine and 1,5-thiazepine polycondensed heterocycles with steroidal structure.

Some naphtho[1,2,-b]-s-triazolo[4,3-d]-1,4-thiazine and 1,5-thiazepine and s-triazolo[4', 3'-4,5]-1,4-thiazino[3,2-c]quinoline derivatives have been synthesized and tested for their ability to displace [3H]RO 15-1788 binding from bovine brain membranes. Several compounds showed moderate binding affinity for the benzodiazepine receptor.

Animals↗
PubMed1981

Preliminary evaluation of mesoionic 6-substituted 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones as potential novel prodrugs of methimazole.

A series of five 6-alkyl- and 6-aryl-mesoionic 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones was synthesized and found to produce 1-methyl-3H-imidazole-2-thione (methimazole) upon alkaline hydrolysis or treatment with amine or thiol reagents. The alkaline hydrolysis followed a second-order rate expression, being dependent on both substrate and hydroxide-ion concentrations. The rate constants for the five derivatives fell within 6-15 x 10(-2) liter/mole min at 40 degrees. These compounds were stable in aqueous acidic solutions and in human serum or rat liver homogenate under conditions producing rapid hydrolysis of the methimazole prodrug 1-carbethoxy-2-methylimidazole-2-thione (carbimazole).

Animals↗
PubMed2002

Heterogeneity of nigral and cortical Lewy bodies differentiated by amplified triple-labeling for alpha-synuclein, ubiquitin, and thiazin red.

Alpha-synuclein(alpha-S) and ubiquitin(Ub) are constituents of the Lewy bodies (LBs), composed of fibrillary structures. To clarify morphological heterogeneity of LBs, we looked for localization of these epitopes in relation to fibrillary structure possibly detectable by a fluorochrome, thiazin red (TR). On the sections of the substantia nigra (SN) and the cingulate gyrus (CG) obtained from Parkinson's disease brains, double amplification by CARD fluorescent immunohistochemistry with anti-alpha-S monoclonal (LB509) and anti-Ub polyclonal antibodies was performed, followed by staining with TR. These triple-labeled images were captured by a confocal laser microscope and subsequently stained with Campbell-Switzer method, a silver staining specific for LBs. Staining profiles of LBs were different between those in the SN and in the CG. Immunolabeling either with the anti-alpha-S or anti-Ub antibody was diffuse without halo structure in LBs of CG. In addition to this diffuse staining, a lot of LBs of SN exhibited a halo structure immunopositive for alpha-S and Ub, probably representing later stages of LB evolution. Irrespective of the presence of this halo structure, the TR signal was always concentrated in the center of LBs, as the silver-stained material was, suggesting that fibrillary components in the central portion of LBs undergo some conformational changes detectable by TR and the silver-staining. This technique reveals different epitopes in relation to LB evolution in vivo. Heterogeneity in staining profile of LBs, as clarified by this method, may represent evolutional changes of LBs, related to conformational states of their constituents.

Aged↗
PubMed1985

On the nature of Romanowsky-Giemsa staining and the Romanowsky-Giemsa effect. I. Model experiments on the specificity of azure B-eosin Y stain as compared with other thiazine dye-eosin Y combinations.

After incorporation into a polyacrylamide matrix, the biopolymers DNA, RNA, heparin, hyaluronic acid, collagen and the synthetic polymers poly(U) and poly(A, U) were stained with the pure thiazine dyes, Methylene Blue, the Azures and Thionin alone and combined with Eosin Y. Satisfactory spectrophotometric agreement was obtained between the staining reactions of the biopolymers in the artificial matrix and those in their natural surroundings. This was especially true with respect to the specificity of the Azure B-Eosin Y dye-pair, which is based on the generation, on suitable substrates, of a purple colour, the Romanowsky-Giemsa effect (RGE), with an absorbance maximum near 550 nm. In the model experiments, DNA, heparin, hyaluronic acid and collagen were found to be RGE-positive and poly(U), poly(A, U) and RNA RGE-negative. A theory of RGE is proposed which complies with the new and earlier observations: after saturation of available anionic binding sites and aggregate formation by Azure B, electron donor acceptor complexes are formed between Eosin Y and Azure B via hydrogen-bridge formation of the aminosubstituent proton of Azure B and between Eosin Y and the biopolymer surface. Charge-transfer complex formation may also account for the qualitative identity of Azure B-Eosin Y and Azure A-Eosin Y spectra of substrates, which are coloured purple. Quantitatively, Azure A-Eosin Y is less efficient in giving RGE. The generation of RGE is time-dependent. Equilibrium staining is attained after about 120 h. The implications of the results for the biological application of Romanowsky-Giemsa staining are discussed briefly.

Azure Stains↗
PubMed2000

Tau-positive neurons in corticobasal degeneration and Alzheimer's disease--distinction by thiazin red and silver impregnations.

Thiazin red (TR), a fluorochrome that has an affinity to fibrillary structures such as neurofibrillary tangles (NFTs) or senile plaques, was utilized to investigate assembly of tau protein into fibrils in tau-immunopositive neocortical neurons of corticobasal degeneration (CBD) and of Alzheimer's disease (AD). Double fluorescence with anti-paired helical filament monoclonal antibody (AT8) and TR was followed by either the Gallyas or Bodian silver impregnation method, which enabled a comparison of the staining features by three different methods on the same neuron. NFTs of AD were uniformly stained by TR and Gallyas method. Most of tau-immunopositive neurons of CBD were similarly stained by Gallyas method but barely or only weakly by TR or Bodian method, suggesting that tau in neocortical neurons of CBD is less liable to form fibrillary structures than in those of AD, easily distinguishable by TR staining. Clarifying the process of tau assembly using this fluorochrome will give a clue to understanding mechanisms of tau deposition, which may be different in various neurological disorders.

Aged↗
PubMed2001

Evolution from pretangle neurons to neurofibrillary tangles monitored by thiazin red combined with Gallyas method and double immunofluorescence.

Double immunofluorescence for paired helical filament (PHF)-tau (AT8) and ubiquitin, enhanced by catalyzed reporter deposition amplification, was combined with thiazin red (TR), a fluorochrome, which has an affinity to fibrillary structures such as neurofibrillary tangles (NFTs). After recording these triple-fluorescent images, sections were subjected to the Gallyas silver impregnation method, so that four different staining properties could be compared on the same structure. Among pyramidal neurons quantified in the hippocampus from six cases of Alzheimer's disease, 60.3% were positive for ubiquitin, and were consistently positive for TR. TR-positive neurons (77.1%) harbored fibrillary structures in the cytoplasm and were always positive for the Gallyas stain, which stained the largest number of legions (94.5%). AT8-positive neurons without fibrillary structure were negative for TR (11.6%, pretangle neurons). Some of the pretangle neurons were positive for the Gallyas stain even without fibrillary structures. Appearance of TR stain and ubiquitin in NFTs, but not in pretangle neurons, suggests that ubiquitin is integrated into tau-positive neurons after their transformation into NFTs. Because TR-positive NFTs sometimes lacked ubiquitin-like immunoreactivity, involvement of ubiquitin may not be an early event during NFT formation. This combined method is now found useful in determining how molecules other than tau are involved during the evolution from tau-positive neurons to NFTs in various neurological disorders characterized by the deposition of tau.

Aged↗
PubMed2001

Different conformation of neuronal tau deposits distinguished by double immunofluorescence with AT8 and thiazin red combined with Gallyas method.

Different kinds of tau deposits were quantitatively investigated with thiazin red (TR), a fluorochrome that binds to fibrillary structures like neurofibrillary tangles (NFTs), in brains obtained at autopsy from patients with Alzheimer's disease (AD), Pick body (PB) disease, corticobasal degeneration (CBD) or diffuse NFTs with calcification (DNTC). After recording double-labeling fluorescence images with anti-paired helical filament tau (AT8) and TR, the sections were subjected to Gallyas method (GAL). This enabled three different staining properties to be compared on the identical neuron. AT8-positive neocortical neurons of AD and DNTC were fibrillary and uniformly positive for TR and GAL, consistently forming NFTs. NFTs lacking AT8 immunoreactivity (IR) were more frequent in DNTC than in AD, suggesting that evolution of NFTs is more accelerated in DNTC. Scarce TR staining in tau-positive neocortical neurons of CBD suggests their paucity of fibrillary structure. Since the affinity of TR for PB was not consistent, this may be dependent not only on the amount but also the characteristics of fibrillary structures. PBs were further characterized by the scarcity of GAL staining. This approach, which quantitatively clarifies differences between AT8-IR, TR and GAL, provides a morphological basis for further investigations of the different conformational states of tau from its deposition to fibril formation of various types.

Aged↗
PubMed1990

Detection of 2H-1,4-thiazine-5,6-dihydro-3-carboxylic acid (aminoethylcysteine ketimine) in the bovine brain.

2H-1,4-Thiazine-5,6-dihydro-3-carboxylic acid (trivial name: aminoethylcysteine ketimine) is a cyclic sulfur-containing imino acid detected in bovine brain extracts by means of three different procedures. Gas liquid chromatography of protein-free extracts of five bovine brains revealed the presence of this compound at concentrations ranging from 2 to 3 nmol/g wet weight of tissue. The enzymatic method based on the inhibition of D-amino acid oxidase activity by aminoethylcysteine ketimine together with an high-performance liquid chromatography procedure confirm the identification and quantitations obtained with gas liquid chromatography. The discovery of this compound structurally similar to pipecolic acid opens the question of its physiological role in the central nervous system.

Amino Acids, Sulfur↗
PubMed1983

Interaction between 1,4-thiazine derivatives and D-amino-acid oxidase.

Aminoethylcysteine-ketimine (2H-1,4-thiazine-5,6-dihydro-3-carboxylic acid) strongly inhibits D-amino-acid oxidase (D-amino-acid:oxygen oxidoreductase (deaminating), EC 1.4.3.3). The inhibition is purely competitive (Ki = 3.3 X 10(-7) M). Aminoethylcysteine-ketimine modifies the visible spectrum of the enzyme: the absorption maxima of bound FAD shift from 375-455 nm to 385-445 nm with a definite shoulder at 465 nm; the appearance of a large absorption band centered at 750 nm may be due to a charge-transfer complex formation. The dissociation constant for the aminoethylcysteine-ketimine-enzyme complex, calculated by a photometric procedure (4 X 10(-7) M), is in good agreement with kinetic data. The dicarboxylic analogue of this inhibitor (lanthionine-ketimine) is ineffective in D-amino-acid oxidase inhibition and does not produce any spectral modification of the enzyme. These results confirm structural requirements for D-amino-acid oxidase inhibitor reported by other researchers. Ketimine reduced forms (thiomorpholine-2-carboxylic acid and thiomorpholine-2,6-dicarboxylic acid) are chemically synthesized and checked as D-amino-acid oxidase substrates: only thiomorpholine-2-carboxylic acid is oxidized to aminoethylcysteine-ketimine (Km = 2 X 10(-4) M).

Amino Acids, Sulfur↗
PubMed1999

Folic acid-enhanced synergy for the combination of trimetrexate plus the glycinamide ribonucleotide formyltransferase inhibitor 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]thiazin -6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034): comparison across sensitive and resistant human tumor cell lines.

Folic acid (PteGlu)-enhanced intense synergy has been observed between nonpolyglutamylatable dihydrofolate reductase (DHFR) inhibitors and polyglutamylatable inhibitors of other folate-requiring enzymes, such as glycinamide ribonucleotide formyltransferase (GARFT) and thymidylate synthase. Since this phenomenon is potentially therapeutically useful, we explored its universality by examining the combined action of a DHFR inhibitor, trimetrexate (TMQ), with a GARFT inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]++ +thiazin-6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034), in eight human cultured cell lines. Using a 96-well plate cell growth inhibition assay, four ileocecal adenocarcinoma cell lines [HCT-8, HCT-8/DW2 (Tomudex-resistant), HCT-8/DF2 (Tomudex-/FdUrd-resistant), and HCT-8/50 (adapted to 50 nM PteGlu)], three head and neck carcinoma cell lines [A253, FaDu, and Hep-2/500 (FdUrd-resistant)], and a non-small cell lung carcinoma cell line [H460] were treated for 96 hr with TMQ + AG2034 in the presence of 23 or 40 microM PteGlu. Cell growth was measured with the sulforhodamine B assay at the end of this period. Drug interactions were assessed by fitting a 7-parameter model including a synergism parameter, alpha, to data with weighted nonlinear regression. Isobologram analysis was also applied. At 23 microM PteGlu, cells exhibited similar intensities of Loewe synergy for the combination of TMQ + AG2034. Loewe synergy was abolished in HCT-8/50 cells cultured and studied in 50 nM PteGlu. At 40 microM PteGlu, the intensity of the combined action in all cell lines was increased However, the most intense Loewe synergy was seen with HCT-8, HCT-8/DF2, H460, FaDu, A253, and Hep-2/500 cells, whereas the HCT-8/50 subculture showed less of the phenomenon, and PteGlu enhancement was the least with HCT-8/DW2, a subline deficient in folylpolyglutamate synthetase (FPGS). The universality of the PteGlu-enhanced intense synergy phenomenon is suggested. Impaired FPGS activity and low-folate adaptation prior to treatment significantly lessen the degree of PteGlu enhancement.

Adenocarcinoma↗
PubMed1989

Detection of 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid (lanthionine ketimine) in the bovine brain by a fluorometric assay.

A new sulfur imino acid, 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid (lanthionine ketimine), has been detected in the bovine brain by means of fluorometric and HPLC procedures. The fluorometric assay is based on the fluorescent property of the copper-ketimine interaction product at pH 11.5. Other ketimines do not fluoresce in these conditions. The fluorophore exhibits an excitation maximum at 353 nm and an emission at 462 nm and is stable for at least 24 h. In the test conditions the fluorescence is proportional to the ketimine concentration from 1 to 200 microM. Detection of endogenous lanthionine ketimine has been performed after a simple enrichment procedure (brain deproteinization and extraction with diethyl ether) which minimizes degradative by-reactions of the unstable ketimine. The concentration of this new sulfur imino acid in the brain ranges from 0.5 to 1 nmol/g in three different samples. Identification and quantitations were confirmed by an HPLC procedure which takes advantage of the selective absorption at 380 nm of the phenylisothiocyanate-ketimine adduct. The identification of lanthionine ketimine in nervous tissues may have important metabolic and physiological implications.

Amino Acids, Sulfur↗
PubMed2000

2H-Thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides as ocular hypotensive agents: synthesis, carbonic anhydrase inhibition and evaluation in the rabbit.

Novel non-chiral 2H-thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides were synthesized for evaluation as potential candidates for the treatment of glaucoma. All of the compounds prepared were potent high affinity inhibitors of human carbonic anhydrase II, Ki < 0.5 nM. Additionally, inhibition of recombinant human carbonic anhydrase IV was determined for selected compounds; these were shown to be moderate to potent inhibitors of this isozyme with IC50 values ranging from 4.25 to 73.6 nM. Of the compounds evaluated for their ability to lower intraocular pressure in naturally hypertensive Dutch-belted rabbits, 5a, 17a3, 17b1, 17b2, 17h2 and 17i1 showed significant efficacy (> 20% decrease) in this model following topical ocular administration.

Animals↗
PubMed1999

Influence of L-cysteine on the formation of bitter-tasting aminohexose reductones from glucose and L-proline: identification of a novel furo[2,3-b]thiazine.

Thermal treatment of a 1 + 1 mixture of glucose and L-proline led to the development of an intense bitter taste being reflected in high amounts of the bitter-tasting bispyrrolidino- (1) and pyrrolidinohexose reductones (2) formed. Heating the reaction mixture in the presence of L-cysteine drastically reduced the amounts of these aminohexose reductones and, thereby, the intensity of the bitter taste. Studies on the mechanism of the cysteine-induced reduction of the bitter taste revealed that the precursor of the aminohexose reductones, the hexose-derived acetylformoin (3), reacted more easily with L-cysteine to form the 7-hydroxy-4a,6-dimethyl-2H,3H,4aH-furo[2,3-b]thiazine (4), a previousely unknown Maillard reaction product, than with L-proline to the aminohexose reductones 1 and 2, thereby blocking the formation of bitter-tasting compounds.

Chromatography, High Pressure Liquid↗
PubMed1994

3-substituted thieno[2,3-b][1,4]thiazine-6-sulfonamides. A novel class of topically active carbonic anhydrase inhibitors.

3-Aminoalkyl derivatives of thieno[2,3-b][1,4]thiazine-6-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. The compounds described were found to be excellent in vitro inhibitors of carbonic anhydrase II and in vivo to lower intraocular pressure in three rabbit models of ocular hypertension. Compounds 20A, 20B, and 20C met the requirement of formulation as a 1% solution at pH 5.2, but none of the compounds described exhibited greater activity in the normotensive albino rabbit, the alpha-chymotrypsin-treated albino rabbit, or the normotensive pigmented rabbit than MK-927 or MK-507, the present clinical candidates.

Administration, Topical↗
PubMed1983

Preparation of 2-amino-4(3H)-oxopyrimido[5,4-b] [1,4]thiazines (5-thiapterins) and their evaluation as cofactors for phenylalanine hydroxylase.

Reaction of diethyl chloromalonate with beta-mercapto amines, 9, gave 1,4-thiazin-3-ones, 10, which were alkylated exclusively at the lactam oxygen with triethyloxonium tetrafluoroborate and subsequently condensed with guanidine to give the first reported 5-thiapterins, 8. Oxidation of 8 with m-chloroperoxybenzoic acid gave the S-oxides, 12. Both 8 and 12 were found to be good inhibitors of rat liver phenylalanine hydroxylase competitive with 6-methyltetrahydropterin, with 8 exhibiting lower Ki's than the corresponding 12. The 8-thiapterin 4 was a much poorer inhibitor.

Animals↗