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PubMedDate not supplied

Antitumor combilexin. A thiazole-containing analogue of netropsin linked to an acridine chromophore.

We report the synthesis, DNA-binding properties and antitumor activity of ThiaNetGA, a hybrid molecule in which are conjugated a thiazole-lexitropsin and an intercalating anilinoacridine chromophore. This combilexin molecule binds to DNA via a bimodal process involving minor groove binding of the lexitropsin moiety and intercalation of the acridine moiety. The uptake and distribution of the hybrid in L1210 leukemia cells were investigated by ESR spectroscopy using a spin-labeled derivative. The nitroxide-containing conjugate accumulates preferentially in the cell nuclei and rapidly saturates the nuclear receptor sites. Both in vitro and in vivo assays indicate that the drug is practically nontoxic but exhibits moderate antitumor activity against P388 leukemia cells in mice.

Acridines↗
PubMed1985

Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A2.

The association of the antitumor antibiotic bleomycin A2 with DNA has been investigated by employing several 2-substituted thiazole-4-carboxamides, structurally related to the cationic terminus of the drug. With a 5'-32P-labeled DNA restriction fragment from plasmid pBR322 as substrate, these compounds have been shown to inhibit bleomycin-induced DNA breakage. Analogues possessing 2'-aromatic substituents on the bithiazole ring were more potent inhibitors than those carrying 2'-aliphatic groups, e.g., the acetyl dipeptide A2. The degree of inhibition was similar at all scission sites on DNA, and inclusion of the analogues did not induce bleomycin cleavage at new sites. DNA binding of bithiazole derivatives has also been studied by two complementary topological methods. Two-dimensional gel electrophoresis using a population of DNA topoisomers and DNA relaxation experiments involving calf thymus DNA topoisomerase I and pBR322 DNA reveal that bleomycin bithiazole analogues unwind closed circular duplex DNA. The inhibition and unwinding studies together support recent NMR studies suggesting that both bleomycin A2 and synthetic bithiazole derivatives bind to DNA by an intercalative mechanism. The results are discussed in relation to the DNA breakage properties of bleomycin A2.

Animals↗
PubMed1990

Mycophenolic acid and thiazole adenine dinucleotide inhibition of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: implications on enzyme mechanism.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) with the conversion of NAD to NADH. An ordered sequential mechanism where IMP is the first substrate bound and XMP is the last product released was proposed for Tritrichomonas foetus IMPDH on the basis of product inhibition studies. Thiazole adenine dinucleotide (TAD) is an uncompetitive inhibitor versus IMP and a noncompetitive inhibitor versus NAD, which suggests that TAD binds to both E-IMP and E-XMP. Mycophenolic acid is also an uncompetitive inhibitor versus IMP and noncompetitive versus NAD. Multiple-inhibitor experiments show that TAD and mycophenolic acid are mutually exclusive with each other and with NADH. Therefore, mycophenolic acid most probably binds to the dinucleotide site of T. foetus IMPDH. The mycophenolic acid binding site was further localized to the nicotinamide subsite within the dinucleotide site: mycophenolic acid was mutually exclusive with tiazofurin, but could form ternary enzyme complexes with ADP or adenosine diphosphate ribose. NAD inhibits the IMPDH reaction at concentrations greater than 3 mM. NAD substrate inhibition is uncompetitive versus IMP, which suggests that NAD inhibits by binding to E-XMP. TAD is mutually exclusive with both NAD and NADH in multiple-inhibitor experiments, which suggests that there is one dinucleotide binding site. The ordered mechanism predicts that multiple-inhibitor experiments with XMP and TAD, mycophenolic acid, or NAD should have an interaction constant (alpha) between 0 and 1. However, alpha was greater than 1 in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed2005

Two-photon absorption at telecommunications wavelengths in a dipolar chromophore with a pyrrole auxiliary donor and thiazole auxiliary acceptor.

Three new dipolar chromophores based on a diaklyaminophenyl donor, a pyrrole auxiliary donor, a thiazole auxiliary acceptor, and strong heterocyclic acceptors have been synthesized. For one of these compounds we have measured a very large non-degenerate two-photon cross section of ca. 1500 GM in the near-IR telecommunications range using a pump-probe technique. Calculations indicate the cross section for degenerate two-photon absorption is likely to be ca. 60% of this value.

Journal Article↗
PubMed2005

n-type organic field-effect transistors with very high electron mobility based on thiazole oligomers with trifluoromethylphenyl groups.

Novel thiazole oligomers and thiazole/thiophene co-oligomers with trifluoromethylphenyl groups were developed as n-type semiconductors for OFETs. They showed excellent n-type performances with high electron mobilities. A 5,5'-bithiazole with trifluoromethylphenyl groups forms a closely packed two-dimensional columnar structure leading to a high performance n-type FET. The electron mobility was enhanced to 1.83 cm2/Vs on the OTS-treated substrate.

Journal Article↗
PubMed2006

Asymmetric hydrogenation of trisubstituted olefins with iridium-phosphine thiazole complexes: a further investigation of the ligand structure.

New chiral bidentate phoshine thiazoles have been prepared and successfully applied as ligands in the homogeneous iridium-catalyzed asymmetric hydrogenation of aryl alkenes and aryl alkene esters. The ligands are designed to be highly modular and have one common chiral intermediate, from which diversity can be introduced at a late stage in the synthetic pathway. It was found that a six-member-ring backbone of the rigid ligand structure was preferred over seven- or five-member rings. In this study it is shown that the substituent pattern of the ligands has a major influence on the stereochemical outcome of the products. By applying the selectivity model proposed in this study, it is possible to match different substrates against different catalysts. In this way, good to excellent enantioselectivity can be obtained for typically difficult substrates. Geometrically different derivatives of alpha- and beta-methyl cinnamic acid ethyl esters were hydrogenated, to demonstrate the validity of the selectivity model and to verify the importance of steric and electronic matching of the catalyst and the substrate.

Journal Article↗
PubMed1986

Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogues stable to phosphodiesterase hydrolysis.

Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique phosphodiesterase present at high levels in TR-resistant tumors. Since accumulation of TAD, as regulated by its synthetic and degradative enzymes, appears to be an important determinant for sensitivity to the drug, a series of hydrolytically resistant phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit IMP dehydrogenase equivalent to TAD itself. Isosteric phosphonic acid analogues of TR and adenosine nucleotides were coupled with activated forms of AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected adenosine 5'-(alpha, beta-methylene)diphosphate with isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against IMP dehydrogenase in vitro. beta-Methylene-TAD (3), the most stable of the TAD phosphonate analogues, produced a depletion of guanine nucleotide pools in an experimentally induced TR-resistant P388 tumor variant that was superior to that obtained with TR in the corresponding sensitive line.

Adenine Nucleotides↗
PubMed1983

Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase.

The chemical synthesis of thiazole-4-carboxamide adenine dinucleotide (TAD), previously identified as the active anabolite of the oncolytic 2-beta-D-ribofuranosylthiazole-4-carboxamide (TR), has been achieved by three different approaches: (1) incubation of adenosine 5'-monophosphate (AMP) and 2-beta-D-ribofuranosylthiazole-4-carboxamide 5'-monophosphate (TRMP) with excess DCC in aqueous pyridine, (2) reaction of adenosine 5'-phosphoromorpholidate with TRMP in pyridine, and (3) reaction of adenosine-5'-phosphoric di-n-butylphosphinothioic anhydride with TRMP in the presence of AgNO3. While the first approach produced only traces of TAD, the last two afforded 31 and 16% yields, respectively, of isolated TAD. The synthetic material was indistinguishable from biosynthesized TAD as judged by its HPLC behavior, NMR, UV and mass spectra, enzymatic resistance to alkaline phosphatase and susceptibility to venom phosphodiesterase, IMP dehydrogenase inhibitory activity, and cytotoxicity. TAD and TR were equally effective against murine P388 leukemia when employed at equimolar doses.

Adenine Nucleotides↗
PubMed1997

Synthesis of nonhydrolyzable analogues of thiazole-4-carboxamide and benzamide adenine dinucleotide containing fluorine atom at the C2' of adenine nucleoside: induction of K562 differentiation and inosine monophosphate dehydrogenase inhibitory activity.

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogue 7 containing a fluorine atom at the C2' arabino configuration of the adenine nucleoside moiety was found to be a potent inducer of differentiation of K562 erythroid leukemia cells. This finding prompted us to synthesize its hydrolysis-resistant methylenebis(phosphonate) and difluoromethylenebis(phosphonate) analogues 8 and 9, respectively. Since both TAD and benzamide adenine dinucleotide (BAD) are potent inhibitors of inosine monophosphate dehydrogenase (IMPDH), the corresponding fluorine-substituted methylenebis(phosphonate) analogue 12 of BAD was also synthesized. Thus, 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (13) was converted in five steps into the corresponding methylenebis(phosphonate) analogue 18. Dehydration of 18 with DCC led to the formation of the bicyclic trisanhydride intermediate 19a, which upon reaction with 2',3'-O-isopropylidenetiazofurin (20) or -benzamide riboside (21) followed by hydrolysis and deprotection afforded the desired methylene-bridged dinucleotides 8 and 12, respectively. The similar displacement of the 5'-mesyl function of 2',3'-O-isopropylidene-5'-O-mesyltiazofurin (24) with the difluoromethylenebis(phosphonic acid) derivative gave the phosphonate 25 which was coupled with 13 to afford 26. The desired difluoromethylenebis(phosphonate) analogue 9 was obtained by deprotection with Dowex 50/H+. This compound as well as beta-CF2-TAD (4) showed improved differentiation-inducing activity over beta-CH2-TAD (3), whereas analogues containing the -CH2-linkage (8 and 12) were inactive.

Adenine Nucleotides↗
PubMed2003

Synthesis of 2,4-disubstituted thiazoles from (Z)-(2-acetoxyvinyl)phenyl-lambda3-iodanes: nucleophilic substitution of alpha-lambda3-iodanyl ketones with thioureas and thioamides.

In the presence of triethylamine, (Z)-(2-acetoxy-1-alkenyl)phenyl-lambda(3)-iodanes react with thioureas or thioamides in MeOH to give 2,4-disubstituted thiazoles directly in good yields. The reaction probably involves generation of highly reactive alpha-lambda(3)-iodanyl ketones through ester exchange of the beta-acetoxy group with liberation of methyl acetate, followed by nucleophilic substitutions with thioureas or thioamides.

Journal Article↗
PubMed1996

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles. Application of the Kharasch-Sosnovsky Reaction.

Using a modification of the Kharasch-Sosnovsky reaction, the oxidation of oxazolines and thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy group at C-4.

Journal Article↗
PubMed2002

Amaryllidaceae, sceletium, imidazole, oxazole, thiazole, peptide and miscellaneous alkaloids.

This review covers alkaloids classified in the plant families Amaryallidaceae and Sceletium. In addition alkaloids possessing imidazole, oxazole and thiazole structures are listed followed by alkaloids possessing peptide linkages. Finally miscellaneous alkaloids include those compounds found naturally which cannot be classified into known groups; a relative Pandora's box. A total of 620 structures has been reviewed from 218 references found in the literature for the period July 1999 to June 2000.

Alkaloids↗
PubMed2004

Diastereoisomeric dinuclear ruthenium complexes of 2,5-di(2-pyridyl)thiazolo[5,4-d]thiazole.

The first metal complexes of 2,5-di(2-pyridyl)thiazolo[5,4-d]thiazole (5) are described. X-Ray crystal structures are reported for the free ligand 5, a dinuclear copper complex 6 and the two diastereoisomers, 7meso and 7rac, of the dinuclear bis(2,2'-bipyridine)ruthenium complex. The two diastereoisomers of 7 and the 4,4'-dimethyl-2,2'-bipyridine analogue 8 are readily separated by cation exchange chromatography. 1H NMR and visible absorption spectra and electrochemical data for the four dinuclear ruthenium complexes reveal that these have relatively small HOMO-LUMO energy gaps and exhibit relatively weak metal-metal interactions.

Journal Article↗
PubMed2025

Click synthesis of some novel benzo[d]thiazole-1,2,3-triazole hybrid compounds with benzamide and/or benzoate tethers as EGFR-dependent signaling inhibitors against breast cancer.

The elaboration of anti-breast cancer agents targeting EGFR represents a promising strategy in medicinal chemistry. Consequently, under optimized Cu(i)-catalyzed click synthesis, a new library of 1,4-disubstituted 1,2,3-triazole-based benzo[d]thiazole scaffold carrying benzamide and/or benzoate tethers 5a-t was designed, synthesized, and characterized by appropriate spectral techniques. They were also screened for their in vitro anti-cancer activity against a panel of cancer cell lines, breast (T47D), prostate (PC3), lung (A549), and colon (HCT116) human cancer, along with normal fibroblast cells. Notably, the hybrid triazoles, 5p, 5s, and 5t emerged as the most potent candidates, especially against T47D, with IC50 values of 15, 26, and 28 μM, respectively. Compound 5p significantly induced apoptosis in T47D by 27.3-fold, causing total apoptosis of 19.39% compared to 0.71%, arresting cell proliferation at the G2/M phase. Regarding EGFR as the molecular target, among the tested compounds, 5p significantly inhibited EGFR by 96.8%, with an IC50 value of 65.6 nM, compared to erlotinib, having an IC50 value of 84.1 nM. Compound 5p showed promising PI3K/AKT/mTOR inhibition as the EGFR-dependent signaling pathway with IC50 values of 4.98 μM, 0.21 μM, and 0.49 nM, respectively, compared to their reference inhibitors. Finally, a molecular docking study highlighted the binding mode disposition and binding interactions with key amino acids as a promising EGFR inhibitor.

Journal Article↗
PubMed1990

Mechanism of peroxidative activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT): comparison with benzidine.

The mechanism of activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) was investigated by comparison with benzidine. In comparison with benzidine, ANFT has a higher electrochemical potential (approximately 700 mV) and is less effective as a reducing co-substrate for either prostaglandin H synthase (PHS) or horseradish peroxidase. Activation was monitored by measuring binding to protein (BSA) and DNA. ANFT binding to protein was reduced by indomethacin, a fatty acid cyclooxygenase inhibitor; phenol and aminopyrine, competitive reducing co-substrates; ascorbic acid, an antioxidant; and glutathione, thioether conjugate formation. These results are consistent with those previously reported for benzidine and demonstrate a peroxide co-substrate requirement, interaction of peroxidase with amine, formation of reactive intermediates and inactivation of reactive intermediates. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO), a radical trap, also reduced ANFT binding to protein. Similar results were observed whether activation by PHS or horseradish peroxidase was investigated. Peroxidative activation of ANFT and benzidine to bind DNA was inhibited by these test agents in a manner similar to that observed with protein except that DMPO did not reduce binding. In addition, 2-methyl-2-nitrosopropane and methyl viologen, which are radical traps, and methionine and p-nitrobenzyl-pyridine, which are strong nucleophiles, did not reduce ANFT or benzidine binding to DNA. These agents also did not prevent binding of benzidinediimine, the two-electron product of benzidine oxidation, to polydeoxyguanosine. Glutathione inhibited diimine binding by forming a conjugate. Results demonstrate that activation of ANFT to bind protein and DNA is similar to benzidine. Peroxidative activation of benzidine occurs by both one- and two-electron oxidation. A similar mechanism would explain ANFT binding to protein (one electron) and DNA (two electron).

Alkenes↗
PubMed1991

In vitro transformation of rat bladder epithelium by 2-amino-4-(5-nitro-2-furyl)thiazole.

To establish a rat urinary bladder carcinogenesis model in vitro, primary rat bladder epithelial cells were grown in media containing 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), the water-soluble metabolite of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT), for 4 weeks followed by long-term (4-7 months) exposure to control medium, sodium saccharin (NaS), or urea. Another set of cultures were exposed to ANFT, NaS and urea simultaneously. Several phenotypic changes were observed in the chemically exposed cell cultures, namely differences in cell morphology, increased growth rate and the ability to grow on plastic instead of rat-tail collagen support. All of the chemically exposed cultures were anchorage independent except one of those treated with NaS. The ANFT-treated cells followed by control medium or urea and cells treated with ANFT, NaS and urea were tumorigenic when transplanted to nude mice, whereas NaS or ANFT followed by NaS treatment were not. The tumors were carcinomas and their epithelial differentiation was verified by strong positive staining for cytokeratin. These studies demonstrate the urothelial transforming capability of ANFT in cell culture without the necessity for a long exposure to a secondary chemical.

Animals↗
PubMed1992

Mechanism of formation of the thioether conjugate of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT).

The formation of thioether conjugates is an important pathway for inactivation of certain carcinogens. This study assessed the mechanism by which the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT) forms a glutathione conjugate (ANFT-SG). Peroxidatic metabolism of ANFT, in the presence of glutathione, results in ANFT-SG formation. Both prostaglandin H synthase and horseradish peroxidase can catalyze this reaction. Metabolism of the reducing co-substrates ANFT, phenol, and aminopyrine elicit increases in oxidized glutathione (GSSG). ANFT-SG formation is potentiated by phenol and aminopyrine. tert-Nitrosobutane (tNB), a thiyl radical trap, prevented increases in both GSSG and ANFT-SG. Increasing concentrations of ANFT elicited corresponding increases in both GSSG and ANFT-SG. Peroxidatic metabolism of ANFT in the presence of glutathione, but not in the absence of glutathione, resulted in oxygen uptake. The formation of GSSG and oxygen uptake are consistent with the presence of thiyl radicals during ANFT metabolism. 5,5-Dimethyl-1-pyrroline N-oxide, a thiyl radical trap, was not as effective as tNB in inhibiting the formation of ANFT-SG and GSSG. Ascorbic acid, a reducing cosubstrate and antioxidant, was very effective in preventing ANFT-SG and GSSG formation, while the strong nucleophile methionine was ineffective. To clarify effects of different test agents, their effects on aminopyrine cation radical formation were assessed. Results are consistent with ANFT reacting with thiyl radicals to form ANFT-SG. ANFT appears to be a thiyl radical trap. Peroxidatic metabolism of ANFT probably results in the formation of a cation radical rather than a carbon-centered radical.

Carcinogens↗
PubMed1992

Ras involvement in cells transformed with 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in vitro and with N-[4-(5-nitro-2-furyl)-2-thiazoyl]formamide in vivo.

N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) administration to rats followed by sodium saccharin results in transitional cell carcinomas of the bladder, of which 24% harbor an activated H-ras gene. Since 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) is the mutagenic and carcinogenic metabolite of FANFT in vivo, we wished to examine ras activation in in vitro ANFT-transformed rat bladder epithelial cells as well as four cell lines established in culture from in vivo FANFT-induced rat bladder tumors. Screening by Western blotting revealed no enhanced levels of p21ras in ANFT-transformed cells nor in cells established in culture from FANFT-induced rat bladder carcinomas. Further investigations using immunohistochemical staining with a different pan-reactive p21 monoclonal antibody (Cetus Corporation) specific for this method, however, showed two groups of cells from FANFT-induced rat bladder tumors had enhanced immunoreactivity. Apart from this, p21ras expression of most of the cells groups varied little from the controls. We examined the reported hot spots (exons 1 and 2) of each of the ras genes (H-, K- and N-ras) by direct sequencing of amplified DNA. No mutations were present. We conclude, therefore, that ANFT transformation of primary rat bladder epithelial cells in vitro may not in this case be mediated by ras activation, although this is difficult to determine since others have observed that optimal culture conditions can select for certain populations of cells without ras activation.

Animals↗