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PubMed1979

4-Hydroxybenzyl alcohol. A metabolite produced during the biosynthesis of thiamine in Escherichia coli.

4-Hydroxybenzyl alcohol was identified by gas chromatography-mass spectrometry as a metabolite of Escherichia coli when it is grown on a medium containing no thiamine or 4-methyl-5-beta-hydroxyethyl thiazole. 4-Hydroxybenzyl alcohol was found to be derived from L-tyrosine and the amount produced was found to be inhibited by the addition of thiamine to the growth medium. The amount of 4-hydroxybenzyl alcohol produced, as measured by isotopic dilution, was shown to be equivalent to the amount of thiamine formed. Based on these observations, it was concluded that 4-hydroxybenzyl alcohol is the cleavage product produced during the biosynthesis of the thiazole moiety of thiamine from tyrosine.

Benzyl Alcohols↗
PubMed2006

Comparison of DNA and RNA quantification methods suitable for parameter estimation in metabolic modeling of microorganisms.

Recent developments in cellular and molecular biology require the accurate quantification of DNA and RNA in large numbers of samples at a sensitivity that enables determination on small quantities. In this study, five current methods for nucleic acid quantification were compared: (i) UV absorbance spectroscopy at 260 nm, (ii) colorimetric reaction with orcinol reagent, (iii) colorimetric reaction based on diphenylamine, (iv) fluorescence detection with Hoechst 33258 reagent, and (v) fluorescence detection with thiazole orange reagent. Genomic DNA of three different microbial species (with widely different G+C content) was used, as were two different types of yeast RNA and a mixture of equal quantities of DNA and RNA. We can conclude that for nucleic acid quantification, a standard curve with DNA of the microbial strain under study is the best reference. Fluorescence detection with Hoechst 33258 reagent is a sensitive and precise method for DNA quantification if the G+C content is less than 50%. In addition, this method allows quantification of very low levels of DNA (nanogram scale). Moreover, the samples can be crude cell extracts. Also, UV absorbance at 260 nm and fluorescence detection with thiazole orange reagent are sensitive methods for nucleic acid detection, but only if purified nucleic acids need to be measured.

Colorimetry↗
PubMed2004

Syntheses and evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and thiazoline derivatives.

3-Aryl-4-formylsydnone 4'-phenylthiosemicarbazones (3a-d) and 3-aryl-4-formylsydnone thiosemicarbazones (3e-h), which are precursors of 3-aryl-4-heterocyclic sydnones, are prepared by the condensation of 3-aryl-4-formylsydnones (1a-d) with 4'-phenylthiosemicarbazide (2a) and thiosemicarbazide (2b), respectively. The thiosemicarbazones 3 reacted with cyclic reagents such as ethyl chloroacetate (4a), ethyl 2-chloroacetoacetate (4b) and 2-bromoacetophenone (4c) to produce heterocyclic substituted sydnone derivatives 5-7 that possess 4-oxo-thiazolidine and thiazoline groups. The antioxidant activity of synthesized compounds 5a-7h was evaluated. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazole-5-carboxylic acid ethyl ester (6e-h) and 4-phenyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazoles (7e-h) exhibit the potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E.

Animals↗
PubMed2005

Phthalazine PDE IV inhibitors: conformational study of some 6-methoxy-1,4-disubstituted derivatives.

This report describes the detailed conformational analysis and synthesis of a series of phthalazine phosphodiesterase-type (IV) (PDE IV) inhibitors bearing either mono- or dichloro 4-methylenepyridine at the 'down' position of the phthalazine nucleus or different heterocycles at the 'top' position 4 of the phthalazine moiety. Both the mono- and dichloro 4-methylenepyridine units linked at carbon C1 of the phthalazine nucleus show identical conformational behaviour with the substituent preferentially oriented towards the external part of the molecule and the pyridine plane almost orthogonal to that of phthalazine ring. The heterocyclic five-membered rings linked at carbon C4 of phthalazine show quite different conformational behaviour. The 1,3-thiazole ring exists in a well-defined conformation almost coplanar with respect to the phthalazine nucleus while the 1,2,4-triazole and the 1,3-diazole heterocycles show a great conformational freedom with large torsion angles. Compound 3 bearing the thiazole ring at C4 displays the major biological activity, thus suggesting that a planar and rather rigid conformation of the pentacycle should favour the PDE IV inhibition capacity of this class of compounds.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

An efficient enzymatic synthesis of thiamin pyrophosphate.

Thiamin pyrophosphate was synthesized in 71% yield, on a multi-milligram scale, using overexpressed thiazole kinase, pyrimidine kinase, thiamin phosphate synthase, and thiamin phosphate kinase. This provides a facile route to isotopically labeled thiamin pyrophosphate from its readily available pyrimidine and thiazole precursors.

Base Sequence↗
PubMed2004

Peroxidase catalyzed formation of azine pigments--a convenient and sensitive method for the identification of human cells with positive myeloperoxidase reactivity.

A new and efficient method for the identification of human cells with positive myeloperoxidase reactivity was developed. This method is based on the myeloperoxidase catalyzed formation of p-naphthoquinone-thiazol-2-on-azine pigments and offers a number of advantages compared to standard methods. In addition, we report the horseradish peroxidase (HRP) catalyzed oxidative coupling of 2-hydrazono-4-thiazolines with alpha-naphthol. This transformation allows a new and efficient synthesis of p-naphthoquinone-thiazol-2-on-azines under mild conditions.

Catalysis↗
PubMed2005

Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors.

N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50=20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.

Amino Acid Sequence↗
PubMed1991

Cytotoxicity of tiazofurin and its arabinose and xylose analogues in K562 cells.

2-beta-D-Arabinofuranosylthiazole-4-carboxamide and 2-beta-D-xylofuranosyl-thiazole-4-carboxamide are sugar modified analogues of tiazofurin, a C-glycosyl nucleoside which after anabolism to the dinucleotide, TAD (thiazole-4-carboxamide adenine dinucleotide), exhibits antitumor activity. However, ara-T and xylo-T did not exhibit cytotoxicity. Compared to tiazofurin, only 12.5% of the ara-T and 8.8% of the xylo-T were metabolized to TAD derivatives by human myelogenous leukemia K562 cells. This was reflected in the finding that guanylate pools were not depressed after treatment with either tiazofurin derivative. These results provide evidence that the ribose moiety is essential for the metabolism and cytotoxicity of tiazofurin. This investigation should be helpful in the design of new analogues of tiazofurin for future clinical trials.

Adenine Nucleotides↗
PubMed2002

Synthesis and antibacterial activity of 1beta-methyl-2-(5-substituted thiazolo pyrrolidin-3-ylthio)carbapenem derivatives.

The synthesis of a new series of 1beta-methylcarbapenems having the substituted thiazolopyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the thiazole ring was investigated. A particular compound (28c) having 4'-amide substituted thiazole moiety showed the most potent antibacterial activity.

Anti-Bacterial Agents↗
PubMed2003

De novo synthesis of two new cytotoxic tiazofurin analogues with modified sugar moieties.

A divergent synthesis of two novel tiazofurin analogues, 2-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)thiazole-4-carboxamide (2) and 2-(3-acetamido-3-deoxy-beta-D-xylofuranosyl)thiazole-4-carboxamide (3), has been achieved starting from D-glucose. Both nucleoside analogues were evaluated for their in vitro cytotoxicity against several human leukaemia and solid tumour cell lines.

Antineoplastic Agents↗
PubMed2000

Novel C-4 heteroaromatic kainoid analogues: a parallel synthesis approach.

New C-4 thiazole 4, 5 and aminothiazole 6, 7 kainoid analogues were efficiently synthesised in five steps from commercially available (-)-alpha-kainic acid I and exhibited strong binding to the kainate receptors. A reactive alpha-bromoketone 10 was generated and reacted with thioamides and thioureas to form thiazole and aminothiazole heterocycles 11-14. Deprotection gave the new kainoid amino acids 4-7 in excellent yield.

Kainic Acid↗
PubMed1981

Interactions of a fragment of bleomycin with deoxyribodinucleotides: nuclear magnetic resonance studies.

Proton NMR spectroscopy was used to establish certain geometrical parameters of the complexes formed between N-(3-aminopropyl)-2'-(2-acetamidoethyl)-2,4'-bithiazole-4-carboxamide hydrochloride (BLMF), a fragment of bleomycin, and various deoxyribodinucleotides. All proton resonances in these compounds have been assigned; chemical shifts were recorded as functions of their concentration. In the complex formed between BLMF and pdG-dC, chemical shifts of the bithiazole protons (measured with respect to values extrapolated to infinite dilution) were displaced upfield by 0.4 ppm. Other proton resonances of BLMF were shifted upfield but to a lesser extent. After corrections are made for self-stacking, maximum values for induced chemical shifts of the bithiazole protons are reached at a dinucleotide/BLMF ratio of 2. Coupling sums for dinucleotides (12.5-13.7 Hz) were unchanged following complexation, suggesting that there is no marked change in sugar conformation when BLMF is bound. On the basis of these results and of molecular model building studies, we propose a three-dimensional structure for a BLMF:pdG-dc complex in which the thiazole rings are intercalated in the duplex and stack preferentially on the purines. Projected on the same plane, the horizontal axis connecting the center of both bithiazole rings in this configuration superimposes on the axis connecting the centers of the purine bases. In this complex, both thiazole protons extend into the minor groove and the positively charged terminal amine binds to the negatively charged phosphate group of DNA.

Binding Sites↗
PubMed2006

Structural insights into the function of the thiamin biosynthetic enzyme Thi4 from Saccharomyces cerevisiae.

The structure of thiazole synthase (Thi4) from Saccharomyces cerevisiae was determined to 1.8 A resolution. Thi4 exists as an octamer with two monomers in the asymmetric unit. The structure reveals the presence of a tightly bound adenosine diphospho-5-(beta-ethyl)-4-methylthiazole-2-carboxylic acid at the active site. The isolation of this reaction product identifies NAD as the most likely precursor and provides the first mechanistic insights into the biosynthesis of the thiamin thiazole in eukaryotes. Additionally, the Thi4 structure reveals the first protein structure with a GR(2) domain that binds NAD instead of FAD, raising interesting questions about how this protein evolved from a flavoenzyme to a NAD binding enzyme.

Amino Acid Sequence↗
PubMed2006

trans-Platinum planar amine compounds with [N2O2] ligand donor sets: effects of carboxylate leaving groups and steric hindrance on chemical and biological properties.

Replacement of NH3 by a planar amine L to give trans-[PtCl2(L)(L')] (L = NH3, L'= pyridine or substituted pyridine, quinoline, isoquinoline, thiazole; L = L'= pyridine, thiazole), greatly enhances the cytotoxicity of the transplatinum geometry. The "parent" compound trans-[PtCl2(NH3)2] is therapeutically inactive. Modification of the ligands to an [N2O2] donor set, where O represents an acetate leaving group, enhances the aqueous solubility while retaining the cytotoxicity of the parent chloride compounds. The effect of two mutual trans leaving groups with weak trans influence is to impart remarkable chemical stability on the structure. This strategy is analogous to the use of the inert dicarboxylate leaving groups in the clinical compounds carboplatin and oxaliplatin. In this paper, systematic modification of the steric effects of carrier pyridine groups and, especially, carboxylate leaving groups in trans-[Pt(O2CR)2(NH3)(pyr)] is shown to modulate aqueous solubility and hydrolysis to the activated aqua species. The results presented here demonstrate the utility of the "carboxylate strategy" in "fine-tuning" the chemical and pharmacokinetic properties in the design of clinically relevant transplatinum complexes.

Amines↗
PubMed1999

Synthesis, Structure, Biological Activity, and DNA Binding of Platinum(II) Complexes of the Type trans-[PtCl(2)(NH(3))L] (L = Planar Nitrogen Base). Effect of L and Cis/Trans Isomerism on Sequence Specificity and Unwinding Properties Observed in Globally Platinated DNA.

In order to establish fundamental structural requirements for the antitumor activation of the trans-platinum geometry, complexes of the general formulas [PtCl(2)(NH(3))L] (L = planar N donor) have been synthesized. The trans isomers, trans-[PtCl(2)(NH(3))(quinoline)] (3), trans-[PtCl(2)(NH(3))(thiazole)] (5), trans-[PtCl(2)(NH(3))(benzothiazole)] (7), and trans-[PtCl(2)(NH(3))(isoquinoline)] (8) and the cis isomers cis-[PtCl(2)(NH(3))(quinoline)] (4) and cis-[PtCl(2)(NH(3))(thiazole)] (6) were characterized by (1)H NMR and analytical data. In addition, the crystal structures of 3, 5, 7, and 8 were determined: 3, monoclinic, P2(1)/c, with a = 8.414(1) Å, b = 12.373(3) Å, c = 21.266(3) Å, beta = 96.78(1) degrees, V = 2198.3(6) Å(3), and Z = 8; 5, monoclinic, P2(1)/n, with a = 8.815(4) Å, b = 19.917(8) Å, c = 14.498(5) Å, beta = 103.30(3) degrees, V = 2477(2) Å(3), and Z = 12; 7, monoclinic, P2(1)/c, with a = 8.150(4) Å, b = 23.196(9) Å, c = 11.297(7) Å, beta = 90.94(4) degrees, V = 2135.3(2) Å(3), and Z = 8; 8, monoclinic, C2/c, with a = 19.043(4) Å, b = 8.570(2) Å, c = 29.127(6) Å, beta_ = 111.59(2) degrees, V = 4420(2) Å(3), and Z = 16. In all cases, the Pt coordination plane and L are mutually twisted with angles between planes of 50-68 degrees. Bulky quinoline in 3 produces intramolecular steric strain as evidenced by a short, nonbonding Pt.H8(quin) contact of 2.77 Å and concomitantly distorted Pt-N(quin)-C bond angles. The trans complexes 3, 5, 7, and 8 showed a significantly higher cytotoxicity in cisplatin-sensitive L1210 leukemia than trans-[PtCl(2)(NH(3))(2)] (2), with 3 and 5 being as potent as the corresponding cis isomers 4 and 6. In addition, the presence of the planar ligand greatly enhanced the activity of all of the compounds in cells resistant to cisplatin, cis-[PtCl(2)(NH(3))(2)] (1). Complex geometry and L play an important role in the binding of 1-7 to DNA. For synthetic poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) the order of binding affinities (r(b), drug-to-nucleotide ratio) was 2 > 1 > 6 > 5 > 4 > 7 > 3 and 5 > 6 > 7 > 3 > 2 > 1 > 4, respectively. Furthermore, 3 and 7, carrying large planar ligands, were remarkably effective at unwinding negatively supercoiled, closed circular pUC19 DNA (phi = 15 degrees and 17 degrees, respectively). The consequences of structural effects caused by L on target DNA with respect to possible biological consequences are discussed.

Journal Article↗
PubMed2001

A simple, high-resolution method for establishing DNA binding affinity and sequence selectivity.

Full details of the development of a simple, nondestructive, and high-throughput method for establishing DNA binding affinity and sequence selectivity are described. The method is based on the loss of fluorescence derived from the displacement of ethidium bromide or thiazole orange from the DNA of interest or, in selected instances, the change in intrinsic fluorescence of a DNA binding agent itself and is applicable for assessing relative or absolute DNA binding affinities. Enlisting a library of hairpin deoxyoligonucleotides containing all five base pair (512 hairpins) or four base pair (136 hairpins) sequences displayed in a 96-well format, a compound's rank order binding to all possible sequences is generated, resulting in a high-resolution definition of its sequence selectivity using this fluorescent intercalator displacement (FID) assay. As such, the technique complements the use of footprinting or affinity cleavage for the establishment of DNA binding selectivity and provides the information at a higher resolution. The merged bar graphs generated by this rank order binding provide a qualitative way to compare, or profile, DNA binding affinity and selectivity. The 96-well format assay (512 hairpins) can be conducted at a minimal cost (presently ca. $100 for hairpin deoxyoligonucleotides/assay with ethiduim bromide or less with thiazole orange), with a rapid readout using a fluorescent plate reader (15 min), and is adaptable to automation (Tecan Genesis Workstation 100 robotic system). Its use in generating a profile of DNA binding selectivity for several agents including distamycin A, netropsin, DAPI, Hoechst 33258, and berenil is described. Techniques for establishing binding constants from quantitative titrations are compared, and recommendations are made for use of a Scatchard or curve fitting analysis of the titration binding curves as a reliable means to quantitate the binding affinity.

Base Pairing↗
PubMed2005

Total synthesis of thiostrepton. Assembly of key building blocks and completion of the synthesis.

The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target molecule. Thus, the dehydropiperidine peptide core 2 was, after appropriate manipulation, coupled to the thiazoline-thiazole fragment 3, and the resulting product was advanced to intermediate 11 possessing the thiazoline-thiazole macrocycle. The bis-dehydroalanine tail equivalent 4 and the quinaldic acid fragment 5 were then sequentially incorporated, and the products so obtained were further elaborated to forge the second macrocycle of the molecule. Several roadblocks encountered along the way were systematically investigated and overcome, finally opening the way, through intermediates 20, 32, 44, 45, and 46, to the targeted natural product, 1.

Anti-Bacterial Agents↗
PubMed2000

Antioxidative activities of heterocyclic compounds formed in brewed coffee.

Typical volatile heterocyclic compounds found in brewed coffee extracts-pyrroles, furans, thiophenes, and thiazoles-were examined for antioxidative activity, which was determined by measuring the oxidative conversion of hexanal to hexanoic acid using gas chromatography. 2-Acetylpyrrole, 1-methylpyrrole, and pyrrole inhibited hexanal oxidation by 98, 87, and 78%, respectively, at a concentration of 500 microgram/mL over a period of 30 days. 2-Methylfuran, which inhibited hexanal oxidation by 90% at all concentrations tested (500, 200, and 100 microgram/mL) for a 30-day period, exhibited the greatest activity among furans tested. Similarly, 2-methylthiophene, which inhibited hexanal oxidation by almost 100% at a concentration of 500 microgram/mL over 30 days, exhibited the greatest activity among the thiophenes tested. In general, thiazoles were ineffective antioxidants at all concentrations tested. However, 4,5-dimethylthiazole was able to inhibit hexanal oxidation by 50% at the highest level tested (500 microgram/mL). 2-Acetylpyrrole, 2-methylfuran, and 2-methylthiophene at concentrations of 500, 200, and 100 microgram/mL and furan at a concentration of 500 microgram/mL exhibited antioxidative activities comparable to that of the synthetic antioxidant butylated hydroxytoluene at a concentration of 50 microgram/mL.

Aldehydes↗