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PubMed1990

Mediation of 8-hydroxy-guanine formation in DNA by thiazin dyes plus light.

We have discovered that methylene blue plus light mediates the formation of 8-OHdG in DNA. Methylene blue is one of several thiazin dyes and we report here that the other thiazin dyes tested, in combination with white light, are effective in mediating 8-OHdG formation in DNA. The effectiveness of light plus the thiazin dyes in forming 8-OHdG in DNA were as follows: methylene blue greater than azure B greater than azure A greater than toluidine blue greater than thionin. Two other compounds tested; riboflavin and fuschin acid, in combination with light, caused formation of very little, if any, 8-OHdG in DNA. Thiazin dye mediated formation of 8-OHdG in DNA was not inhibited by the spin trap alpha-phenyl-t-butyl nitrone, which supports our previous observations that oxygen free radical scavengers did not inhibit methylene blue plus light mediated 8-OHdG formation in DNA. Ascorbate addition to methylene blue plus DNA, in the absence of light, was ineffective in mediating 8-OHdG formation in DNA.

Animals↗
PubMed1978

[The suitability of further thiazine and quinoline dyes for topo-optical reactions on the plasmalemma (author's transl)].

The present studies prove that the thiazin dyes, azure B, azure C and thionin, and the quinolin dyes pinacyanol and its hydrochloride, are suitable for topo-optical staining of the plasmalemma. On the membrane surface the orientated bound dye molecules become stabilized, and with subsequent precipitation the anisotropic effect is reinforced. On optical analysis, the thiazin dye molecules (azure B, AZURE C and Thionin) are bound radially on the membrane. The molecules of the previously studied quinolin dye, N,N'-diethylpseudoisocyanide chloride are bound parallel to the membrane, while pinacyanol and its hydrochloride, like the thiazin dyes, are bound in the radial position.

Birefringence↗
PubMed1990

Interaction of platinum complexes of thiazin and xanthene dyes with hyperthermia.

In an attempt to develop platinum-containing drugs for use with hyperthermia that would be relatively nontoxic at 37 degrees C but would become very cytotoxic at 42 degrees or 43 degrees C, several nuclear dyes were complexed to the tetrachloroplatinum(II) dianion (PtCl4) at a ratio of 2:1. The cytotoxicity of PtCl4 complexes of three thiazin dyes (thionin, azure B, and methylene blue), the xanthene dye pyronin Y, and the thiazole dye thioflavin was examined in exponentially growing euoxic and hypoxic EMT6 cells in vitro at 37 degrees, 42 degrees, and 43 degrees C and at pH 7.40 and 6.45. Of the thiazin dye complexes, the cytotoxicity of Pt(methylene blue)2 was most enhanced at hyperthermic temperatures. Both Pt(pyronin Y)2 and Pt(thioflavin)2 also became markedly more cytotoxic at 42 degrees and 43 degrees C at pH 6.45 vs pH 7.40. In vivo tumor excision assays in the FSaIIC fibrosarcoma showed that with each of the thiazin dye-platinum complexes, hyperthermia enhanced cell kill [most effectively on Pt(methylene blue)2] but was not dose-modifying. For both Pt(pyronin Y)2 and Pt(thioflavin)2, however, administration of 43 degrees C, 30-min hyperthermia to the tumor immediately after i.p. drug injection was dose-modifying. Tumor growth delay studies in the FSaIIC tumor system demonstrated that, as with the in vitro studies, Pt(pyronin Y)2 and Pt(methylene blue)2 were most enhanced by hyperthermia [tumor growth delay increased by 4.8- and 3.0-fold, respectively, vs only 1.3-fold for cisplatin (CDDP)]. Examination of intracellular platinum levels after exposure of EMT6 cells to 25 microM of drug for 1 h at 37 degrees and 42 degrees C and at pH 7.40 and 6.45 showed that each platinum-dye complex achieved platinum levels that were 100-600 times higher at 37 degrees C and pH 7.40 than those obtained using CDDP. The platinum levels for each drug dropped markedly when exposure took place at pH 6.45. Exposure at 42 degrees C only moderately increased platinum levels in cells exposed to these drugs. Thus, for several of these drugs the level of cytotoxicity observed was in great part independent of the intracellular platinum levels achieved. Pt(pyronin Y)2 is an effective drug for use with hyperthermia, and further studies using this combination with and without radiation are under way.

Animals↗
PubMed2006

Synthesis, structural characterization and influence on the phagocytic activity of human neutrophils of thiazoline and thiazine derivative ligands and their zinc(II) complexes.

The zinc(II) complexes dichloro[2-(3,4-dichlorophenyl)imino-kappaN-(2-thiazolin-kappaN-2-yl)thiazolidine]zinc(II) (1) and dichloro[2-(3,4-dichlorophenyl)imino-kappaN-(4H-5,6-dihydro-1,3-thiazin-kappaN-2-yl)tetrahydrothiazine]zinc(II) (2) have been isolated and characterized in the solid state by X-ray diffraction, elemental analysis and IR spectra. In both complexes, the environment around the zinc(II) ion may be described as a distorted tetrahedral geometry, with the metallic atom coordinated to two chlorine atoms [Zn-Cl(1)=2.218(1)A; Zn-Cl(2)=2.221(1)A], one imino nitrogen [Zn-N(3)=2.042(2)A] and one thiazoline nitrogen [Zn-N(1)=2.022(2)A] in complex 1 and to two chlorine atoms [Zn-Cl(1)=2.216(1)A; Zn-Cl(2)=2.192(1)A], one imino nitrogen [Zn-N(3)=2.045(2)A] and one thiazine nitrogen [Zn-N(1)=2.039(2)A] in complex 2. In addition, we also report in this study the crystal structure of the 2-(3,4-dichlorophenyl)imino-N-(2-thiazolin-2-yl)thiazolidine (TdTn) ligand as well as the synthesis and characterization by X-ray diffraction, (1)H and (13)C NMR spectra, elemental analysis, IR and electronic spectra of the 2-(3,4-dichlorophenyl)imino-N-(4H-5,6-dihydro-1,3-thiazin-2-yl)tetrahydrothiazine (TzTz) ligand. Besides, we study the phagocytic function in humans neutrophils treated with each complex and ligand aforementioned.

Crystallography, X-Ray↗
PubMed1999

Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.

Crystallography, X-Ray↗
PubMed1995

Antimalarial dyes revisited: xanthenes, azines, oxazines, and thiazines.

In 1891 Guttmann and Ehrlich (P. Guttmann and P. Ehrlich, Berlin Klin. Wochenschr. 28:953-956, 1891) were the first to report the antimalarial properties of a synthetic, rather than a natural, material when they described the clinical cure of two patients after oral administration of a thiazine dye, methylene blue. Since that time, sporadic reports of the antimalarial properties of several xanthene and azine dyes related to methylene blue have been noted. We report here the results from a reexamination of the antimalarial properties of methylene blue. Janus green B, and three rhodamine dyes and disclose new antimalarial data for 16 commercially available structural analogs of these dyes. The 50% inhibitory concentrations for the chloroquine-susceptible D6 clone and SN isolate and the chloroquine-resistant W2 clone of Plasmodium falciparum were determined by the recently described parasite lactate dehydrogenase enzyme assay. No cross-resistance to chloroquine was observed for any of the dyes. For the 21 dyes tested, no correlation was observed between antimalarial activity and cytotoxicity against KB cells. No correlation between log P (where P is the octanol/water partition coefficient) or relative catalyst efficiency for glucose oxidation and antimalarial activity or cytotoxicity was observed for the dyes as a whole or for the thiazine dyes. The thiazine dyes were the most uniformly potent structural class tested, and among the dyes in this class, methylene blue was notable for both its high antimalarial potency and selectivity.

Animals↗
PubMedDate not supplied

Antimycobacterial activity of some pyrido-1,2-thiazine derivatives.

The 3-benzoylpyrido-1,2-thiazine-1,1-dioxides 1 and the related pyrazolopyrido-1,2-thiazine-5,5-dioxides 2 with a 4-arylpiperazin-1-ylpropyl side chained by the nitrogen atom of the thiazine ring were evaluated in vitro against Myobacterium tuberculosis H37Rv. Some of the tested compounds proved to be potent antimycobacterial agents and for the most active of them (1a,b) minimum inhibitory concentrations (MIC = 3.13 and 6.25 microg/ml, respectively) were determined. The correlation between mycobacterium growth inhibition and the lipophilicity (logPcalc.) within the series of derivatives 1 and 2 was studied.

Anti-Bacterial Agents↗
PubMed2004

Antitumor in vitro evaluation of certain derivatives of pyrido-1,2-thiazines.

We report an antitumor in vitro evaluation of a small series of 3-phenyl(methyl)pyrazolo[4, 3-c] pyrido [3,2-e]-1,2-thiazines 4 and the related 3-benzoyl (acetyl)-4-hydroxypyrido [3,2-e]-1,2-thiazines 5 bearing a 3-(4-arylpiperazin-1-yl) propyl group at the nitrogen atom of the thiazine ring. Five of the seven pyridothiazines 5 tested and one compound from the series 4 (five compounds) exhibited in cell experiments a significant antitumor activity against several types of human tumor cells [GI50 values 3-54 mM/L]. The action of the most active compound 5f against some leukemia and melanoma cell lines was observed at sub mM/L doses at the GI50 level.

Antineoplastic Agents↗
PubMed1990

Cytotoxicity, radiosensitization, and DNA interaction of platinum complexes of thiazin and xanthene dyes.

Complexes of the platinum(II) tetrachlorodianion with positively charged nuclear dyes have been prepared in an effort to produce neutral molecules which could gain ready access to the nuclear DNA where the platinum(II) tetrachlorodianion could function as a radiosensitizing and a bifunctional alkylating agent. The thiazin dyes Thionin, Azure B, and Methylene Blue, the aminoxanthene dye Pyronin Y, and the thiazole dye Thioflavin have each been complexed to the platinum(II) tetrachlorodianion(PtCl4) in a ratio of 2:1(dye:PtCl4). Studies of the interaction of these complexes and of the dyes with the pBR322 plasmid superhelical DNA demonstrated that while each complex and dye readily associated with the DNA in a dose-dependent manner, only Pt(Thioflavin)2 and Thioflavin produced irreversible DNA changes (single-strand breaks). In exponentially growing EMT6 cells the cytotoxicity of these drugs was assessed in normally oxygenated and hypoxic cells at both pH 7.4 and 6.45. At concentrations ranging from 1 to 500 microM, Pt(Methylene Blue)2 was significantly more cytotoxic than the other thiazin dye complexes Pt(Thionin)2 and Pt(Azure B)2. The cytotoxicity of Pt(Thionin)2 and Pt(Methylene Blue)2 was increased in normally oxygenated and hypoxic cells at low pH. Both Pt(Pyronin Y)2 and Pt(Thioflavin)2 were more toxic than the thiazin complexes. Pt(Pyronin Y)2 was most cytotoxic to normally oxygenated cells at normal pH and hypoxic cells at low pH, while Pt(Thioflavin)2 was most cytotoxic to cells at low pH under both oxygenation conditions. In vitro studies of the radiosensitizing properties of these agents in EMT6 cells demonstrated that exposure to 100 microM for 1 h before and during irradiation (except for Pt[Thioflavin]2, which was assayed at 25 microM) resulted in enhancement rations of 2.5, 1.9, 1.5, and 1.5 for Pt(Azure B)2, Pt(Thionin)2, Pt(Pyronin Y)2, and Pt(Thioflavin)2, respectively, in hypoxic cells. In contrast, Pt(Methylene Blue)2 (and Methylene Blue) proved to be a radioprotector of normally oxygenated cells and did not sensitize hypoxic cells to the cytotoxic effects of radiation. In the FSaIIC fibrosarcoma in vivo administration of each drug at 100 mg/kg intraperitoneally (ip) 15 min prior to irradiation (except for Pt[Thioflavin]2, which was given at 1 mg/kg ip) showed that, with single radiation fractions of 10 and 20 Gy, dose-modifying factors of 2.1, 1.8, 1.5, and 1.2 were produced by Pt(Azure B)2, Pt(Thionin)2, Pt(Pyronin Y), and Pt(Methylene Blue)2, respectively, after correcting for growth delays induced by the drug alone. In comparison, misonidazole at 1 g/kg ip produced a dose-modifying factor of 1.4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

New heterocyclic structures. thiazolo[3,2-a][1,2,5] thiadiazolo[3,4-d]pyrimidine and [1,2,5]thiadiazolo[3',4':4,5] pyrimido[2,1-b][1,3]thiazine. biological assays.

6,7-Dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo [3,4-d]pyrimidin-9-one, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3',4':4,5]pyrimido [2,1-b][1,3]thiazin-10-one and its 3-methyl derivative were prepared by reacting 6,7-diamino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one, 7,8-diamino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one or its 3-methyl derivative with N-thionylaniline. A reaction mechanism is proposed. The compounds and the sodium salts of (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl) sulfamic acid and its 3-methyl derivative were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. Coli, Proteus mirabilis, P. vulgaris, Pseudomonas aeruginosa, Salmonella spp, Staphylococcus spp, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, and for antiviral activity on Herpes simplex virus type 1 and Vescicular stomatitis virus. None of the compounds showed antiviral activity or exhibited biological activity against gram-negative, gram-positive bacteria or against mycetes.

Animals↗
PubMed2005

[Synthesis of thieno[2,3-d]pyrimidines from 6-imino-6H-1,3-thiazine hydroperchlorates].

Mechanism of ring transformation reactions starting from substituted 6-imino-6H-1,3-thiazine hydroperchlorates is depending upon the substituent in position 5 of the thiazine nucleus. Starting from 4-methylthio-2-phenyl-6-imino-6H-1,3-thiazin-5-carbonitrile hydroperchlorat various 6-substituted 5-amino-4-methylthio-2-phenylthieno[2,3-d]pyrimidines can be obtained by reaction with acceptor substituted halogenmethanes under basic conditions in an one pot synthesis.

Indicators and Reagents↗
PubMed1996

Photodynamic damage to HeLa cell microtubules induced by thiazine dyes.

The aim of this study was to analyze possible alterations of the microtubule cytoskeleton of cultured cells subjected to photodynamic treatments with the thiazine dyes methylene blue or toluidine blue. Indirect immunofluorescence labeling of alpha-tubulin was performed in HeLa cells after 1 or 18 h of incubation with thiazines followed by red-light irradiation for 15 min [leading to surviving fractions (SF) of about 65% (SF65) or 1% (SF1), respectively]. Untreated control cells showed the normal distribution of interphase microtubules, whereas considerable or severe disorganization of the microtubule network was observed after SF65 or SF1 photodynamic treatments, respectively. A great amount of blebs showing homogeneous fluorescence was also found on the cell surface after SF1 treatments. Possible mechanisms responsible for the photodamage to microtubules induced by thiazine dyes are briefly discussed.

Coloring Agents↗
PubMed2001

Synthesis of thiadiazole, dithietane, and imine derivatives of the [1,2]dithiolo[1,4]thiazine ring system.

We report the synthesis of some new polysulfur-nitrogen heterocyclics by cycloaddition reactions to the thioketo group of readily available tricyclic 1,2-dithiole-3-thiones. Thus treatment of bis[1,2]dithiolo[1,4]thiazine ketothione 1 with diaryl nitrile imines generated from hydrazonoyl chlorides 2a-g gave [1,3,4]thiadiazolylidenyl[1,2]dithiolo[1,4]thiazines 4a-g in high yield. Compounds 4a-f, bearing the same substituents in both aryl groups, were stable but the analogous 4g,h with a p-nitrophenyl group on carbon gave the bis[1,2]dithiolo[1,4]thiazine dione 9, probably by cycloreversion and hydrolysis during chromatography. Treatment of 1, the bis[1,2]dithiolopyrrole ketothione 13, and dithione 12 with ethoxycarbonyl azide 11 gave imines 12 and 15 and bisimine 16, respectively, by an alternative fragmentation of the initial cycloadduct in which the 1,2-dithiole ring is retained. Reaction of 1 with TosMIC gave the imino-1,3-dithietane 17.

Journal Article↗
PubMed2003

Reactions of 5-mercaptoazoles and pyridine-2-thiones with acetylenic esters. Selectivity of the formation of novel fused thiazin-4-ones and thiazolidin-4-ones.

A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate with 5-mercaptoazoles and pyridine-2-thiones has been carried out and as a result, a number of novel imidazo[1,5-b]thiazin-4-ones 6a,b, pyrazolo[1,5-b] thiazin-4-ones 15a-f, imidazo[1,5-b]thiazol-4-ones 7a,b and thiazolo[3,2-a]pyridines 21a-c have been prepared. The influence of the size of the ring of the starting "cyclic" thioamides on the size of the fused ring in the reaction products has been established. The preferred formation of a six-membered thiazine ring took place in the reactions of 5-mercaptoazoles. In contrast, the five membered thiazolidine ring is formed in reactions of pyridine-2-thiones. In both cases the product is a five-membered ring fused to a six-membered heterocycle.

Journal Article↗
PubMed1989

Synthesis of imidazo[4,5-d][1,3]thiazine ribosides and related compounds of biological interest.

Several tri-O -acetyl-1-beta-D -ribofuranosyl- and 2-acetoxyethoxymethylimidazo[4,5-d][1,3]thiazine derivatives 5-10 were synthesized from imidazo[4,5-d][1,3]thiazine 4 and tetra-O -acetyl-beta-D -ribofuranose or 2-acetoxyethoxymethyl acetate by fusion method. In each case, depending on the substituent on position 5 of thiazine skeleton, only N3 isomer or both N1 and N3 isomers (in different ratios) were obtained.

Acyclovir↗
PubMed2005

Studies on the chemistry of thienoanellated O,N- and S,N-containing heterocycles. Part 30: synthesis and pharmacological properties of thieno[2,3-b][1,4]thiazines with potential vasopressin receptor antagonistic activity.

A series of new nonpeptide vasopressin antagonists with a 6-ethyl-thieno[2,3-b][1,4]thiazine or 6-benzyl-thieno[2,3-b][1,4]thiazine skeleton and structural modifications of the aryl side chain were synthesized in this study. The effects on guinea pig heart and smooth muscle preparations were investigated. In the presence of AVP the compounds showed an antagonistic effect. The compounds did not change spontaneous rate in right atria and exerted a slight but not significant negative inotropic effect in papillary muscles. The relaxing effect on vascular smooth muscle and terminal ileum was far more pronounced. Generally the relaxing effect on terminal ilea was more potent maybe due to difference in V1a receptor density. Our results demonstrate that compounds with an ethyl group in position six on the thienothiazine ring (14, 16, 18 and 22) exerted the most potent relaxing activity in terminal ilea, whereas compounds with a phenyl ring in position six reduced this effect.

Animals↗
PubMed2001

Synthesis and microbiological activity of some 4-butyl-2H-benzo[1,4]thiazin-3-one derivatives.

The synthesis and physicochemical properties of 4-butyl-2H-benzo[1,4]thiazin-3-one derivatives are described. These new compounds were synthesised by alkylation in 4-N position and acylation and/or alkylation of 6-NH2 by phase transfer catalysis. Acid hydrolysis of 6-alkylacylamino group yielded 6-alkylamino-4-butyl-2H-benzo[1,4]thiazin-3-ones. The antimicrobial in vitro activity was determined on five compounds.

Anti-Infective Agents↗
PubMed2001

Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure and benzodiazepine receptor binding.

In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and position of the substituents on the arylidene ring.

Animals↗