Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:18820-84-3 (quinoline)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targeting of electron-affinic radiosensitizers to DNA via noncovalent binding (e.g., intercalation) may offer the potential for increasing sensitizing efficiency. However, it has been suggested that high-affinity DNA binding may compromise sensitization by restricting the mobility of sensitizers along the DNA, and by decreasing rates of extravascular diffusion in tumors. The weak DNA intercalator nitracrine (1-NC) is a more efficient radiosensitizer than related nitroacridines with higher DNA-binding affinities (Roberts et al., Radiat. Res. 123, 153-164, 1990). The present study investigates whether electron-affinic agents of even lower DNA-binding affinity may be superior to nitroacridines. The quinoline analog of 1-NC, 5-nitraquine (5-NO), was shown to have an intrinsic association constant for calf thymus DNA in 20 mM phosphate buffer which was 12-fold lower than that of 1-NC. 5-Nitraquine was not accumulated as efficiently as 1-NC by AA8 cells, but, despite a similar one-electron reduction potential, was 2- to 3-fold more potent than 1-NC as a hypoxia-selective radiosensitizer in vitro when compared on the basis of average intracellular concentration. Thus the radiosensitizing potency of 5-NQ appears not to be compromised by its low DNA-binding affinity. The cytotoxic mechanisms of 5-NQ and 1-NC appear to be similar (hypoxia-selective formation of DNA monoadducts), but 5-NQ is 1200-fold less potent than 1-NC as a cytotoxin. Despite this advantage, 5-NQ was not active in vivo as a radiosensitizer in SCCVII tumors. This lack of activity appears to be due to its relatively high toxicity in vivo (intraperitoneal LD50 of 105 mumol kg-1 in C3H/HeN mice), high one-electron reduction potential (-286 mV), and rapid metabolism to the corresponding amine in mice. The in vitro therapeutic index (hypoxic radiosensitizing potency/aerobic cytotoxic potency) of this weak DNA binder was lower than that of the non-DNA targeted radiosensitizer misonidazole, suggesting that DNA targeting enhances cytotoxicity more than radiosensitization. Development of useful DNA-targeted radiosensitizers may require the exploitation of DNA binding modes different from those of the nitroacridines and nitroquinolines.
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PMID:5-Nitro-4-(N,N-dimethylaminopropylamino)quinoline (5-nitraquine), a new DNA-affinic hypoxic cell radiosensitizer and bioreductive agent: comparison with nitracrine. 143 85

The cytotoxicity of transplatinum complexes of structural formula trans-[PtCl2(L)(L')] [L = L' = pyridine or thiazole, or L = quinoline (R' = methyl; R" = methyl, phenyl, or CH2phenyl) and L' = R'R"SO] has been studied in murine L1210 and human tumor cell lines. The results confirm previous observations that use of a sterically hindered planar ligand greatly enhances cytotoxicity, in comparison to trans-[PtCl2(NH3)2], such that in some cases cytotoxicity equivalent to that of the clinically used agent cisplatin [cis-[PtCl2(NH3)2]] is obtained. Results from both the panel of human ovarian carcinoma cell lines and the National Cancer Institute screening panel confirm a different pattern of cytotoxicity, with respect to cisplatin. The new trans-platinum complexes are also non-cross-resistant with cisplatin in both murine and human (human ovarian carcinoma panel) tumor cell lines. Preliminary mechanistic studies using both cis- and trans-[PtCl2(pyridine)2] in L1210 cells have been carried out, to delineate the reasons for both the dramatically enhanced cytotoxicity and the lack of cross-resistance with the clinically used agents. Intracellular uptake is enhanced for pyridine relative to ammine (NH3) complexes. The pyridine complexes also inhibit DNA synthesis, implying a role for DNA binding in their mechanism of action. Binding of the pyridine complexes to calf thymus DNA is, however, significantly less than for the analogous ammine complexes. The presence of trans-pyridine ligands results in steric hindrance, which retards the rate of reaction of trans-[PtCl2(pyridine)2], relative to trans[PtCl2(NH3)2], with other important biomolecules such as glutathione. The results point to a potential new class of platinum antitumor complexes acting by a new mechanism and with activity complementary to agents such as cisplatin.
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PMID:Activation of the trans geometry in platinum antitumor complexes: a survey of the cytotoxicity of trans complexes containing planar ligands in murine L1210 and human tumor panels and studies on their mechanism of action. 151 63

The direct acting mutagenic N2-hydroxylated metabolite of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) does not react with DNA. Upon acetylation of the N2-hydroxy-PhIP with acetic anhydride two products could be detected. Mass spectrometric analysis showed that both products were monoacetyl derivatives of N2-hydroxy-PhIP. One of the products did not show any reactivity towards DNA and is probably the N-acetyl derivative of N2-hydroxy-PhIP. The other product which is most likely to be N2-acetoxy-PhIP reacted with DNA and 2'-deoxyguanosine but not with 2'-deoxycytidine, 2'-deoxyadenosine or 2'-deoxythymidine. The PhIP-2'-deoxyguanosine adduct was purified and characterized by mass spectral, 1H and [13C]NMR analysis, showing that PhIP like the other cooked food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, had reacted with C-8 of guanine forming N2-(2'-deoxyguanosin-8-yl)-PhIP. HPLC analysis of enzymatically hydrolyzed calf thymus DNA which had been reacted with N2-acetoxy-PhIP showed one adduct which was chromatographically and spectroscopically identical to N2-(2'-deoxyguanosin-8-yl)-PhIP. HPLC separation followed by liquid scintillation counting of hydrolyzed liver DNA from a rat dosed with [3H]PhIP showed that radioactivity coeluted with the hydrolysis product of the synthetic PhIP-2-deoxyguanosine adduct, indicating that PhIP in vivo also forms an N2-(2'-deoxyguanosin-8-yl)-PhIP adduct.
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PMID:Reaction of the N2-acetoxy derivative of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with 2'-deoxyguanosine and DNA. Synthesis and identification of N2-(2'-deoxyguanosin-8-yl)-PhIP. 157 16

The polymeric DNA and model duplex oligonucleotide complexes of the bisquinoline analogue of echinomycin (2QN) have been studied by optical detection of triplet-state magnetic resonance (ODMR) spectroscopy, with the quinoline chromophores of the drug used as intrinsic probes. Plots of ODMR transition frequencies versus monitored wavelength revealed heterogeneity in the phosphorescence emission of 2QN which was ascribed to the presence of a major and minor conformation of the drug in aqueous solutions (referred to as the red and blue forms of 2QN, respectively, in this report). ODMR results, in conjunction with findings from low-temperature phosphorescence investigations, indicate that the quinoline chromophores of the major (red) form of 2QN are involved in aromatic stacking interactions in complexes with the natural DNAs from Escherichia coli, Micrococcus lysodeikticus, Clostridium perfringens, and calf thymus as evidenced by red shifts in the phosphorescence 0,0-band of the drug, reductions in the phosphorescence lifetime and zero-field splitting (zfs) D and E parameters, and polarity reversals of the ODMR slow passage signals upon complex formation between the analogue and DNA. The polarity reversals, which reflect shifts in the triplet-state sublevel populations induced by complex formation, apparently result from changes in the triplet sublevel decay constants upon binding to the natural DNAs. The 2QN complexes of the double-stranded alternating copolymers poly(dG-dC).poly(dG-dC) [abbreviated as poly[d(G-C)2]] and poly(dA-dT).poly(dA-dT) [abbreviated as poly(dA-dT).poly(dA-dT) [abbreviated as poly[d(A-T)2], the homopolymer duplexes poly(dG).poly(dC) [abbreviated as poly(dG.dC)] and poly(dA).poly(dT) [abbreviated as poly(dA.dT)], and the self-complementary oligonucleotides d(ACGT)2, d(TCGA)2, and d(ACGTACGT)2 were also investigated. The extent of reduction of the zfs D parameter (delta D) for the major form of 2QN upon complex formation with the polymeric DNAs was found to scale linearly with the standard free energy of the drug-DNA interaction (delta G degrees) calculated from previously reported binding studies for these targets [Fox, K. R., et al. (1980) Biochem. J. 191, 729-740]. This relationship between spectroscopic and thermodynamic properties of the 2QN-polynucleotide complexes is a consequence of the effects of base stacking interactions on the electronic states of the intercalator, which were postulated to arise from second-order shifts of the ground-state and the triplet-state energies of the complex on the basis of a modification of the solvent effect theory of van Egmond et al. [(1975) Chem. Phys. Lett. 34, 423-426].
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PMID:Optically detected triplet-state magnetic resonance studies of the DNA complexes of the bisquinoline analogue of echinomycin. 191 53

The quinoline-3-carboxamide LS 2616 administered to mice in drinking water increased spontaneous cytotoxicity against YAC-1 cells in a dose-dependent manner. The enhancement of spontaneous cytotoxicity was found to be mediated by NK cells, as judged by their lack of adherence to nylon wool columns, relative resistance to treatment with antibodies to Thy-1.2 and complement, and almost total abrogation after depletion of asialo-GM1+ cells. Enhancement of NK activity was evident after 2 days of treatment, was maximal after 4 days, and remained elevated during the 14-day exposure period studied. NK activity returned to control levels 4 days after cessation of treatment. NK activity was significantly increased in spleen, peripheral blood, lymph nodes, and bone marrow of LS 2616-treated mice, while activity in peritoneal exudate cells and thymus remained low. LS 2616 was able to elevate NK activity in several mouse strains studied, including mice homozygous for the beige gene. Serum interferon levels were not increased during treatment with LS 2616. Combined injection of the interferon inducer Poly I:C and LS 2616 did not increase NK activity above that of animals injected with Poly I:C alone. However, Poly I:C, in contrast to LS 2616, increased NK activity in peritoneal exudate cells. Studies at the single cell level revealed that LS 2616 increased NK activity by increasing the number of lytically active cells via recruitment of new target-binding cells and not by increasing the lytic activity of pre-existing binders.
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PMID:Augmentation of mouse natural killer cell activity by LS 2616, a new immunomodulator. 258 Sep

In mammalian hepatic cytosol both acetyltransferase and sulfotransferase are involved in the activation of N-hydroxy derivatives of arylamines and arylamides. The role of acetyltransferase is also shown in Salmonella, whereas no rigid evidence is provided on the role of sulfotransferase in Salmonella. In Ames mutagenesis test without S9-mix, the number of revertants of Salmonella typhimurium TA98 induced was 10-fold higher with 2-hydroxyamino-3-methylimidazo[4,5-f] quinoline (N-hydroxy-IQ) than with 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-hydroxy-Glu-P-1). The extents of the binding to calf thymus DNA of N-hydroxy-Glu-P-1 were, however, 3.9 to 8.6-fold higher than that of N-hydroxy-IQ in both acetyl CoA- and PAPS-fortified rat hepatic cytosol systems. To understand the mechanism causing the apparent discrepancy between the results of the mutation and DNA binding, the activating capacities of cytosols of S. typhimurium TA98 and TA98/1,8-DNP6 strains on the binding of N-hydroxy-Glu-P-1 and N-hydroxy-IQ have been examined in comparison with those of rat livers. Although both N-hydroxyarylamines were activated by hepatic cytosols in the presence of PAPS, no significant DNA binding of these N-hydroxyarylamines was detected in the presence of PAPS and either one of the two strains of bacterial cytosols. In addition, both cytosols of TA98 and TA98/1,8-DNP6 strains showed no measurable activity on the sulfation of p-nitrophenol, suggesting no capacity for sulfotransferase-mediated activation of N-hydroxyarylamines in Salmonella. On the contrary, the extents of the acetyl CoA-dependent binding of N-hydroxy-IQ in cytosols of TA98, but not of TA98/1,8-DNP6, were respectively 6- and 9-fold higher than those in hepatic cytosols of male and female rats, although the extents of the binding of N-hydroxy-Glu-P-1 were rather higher in hepatic than in bacterial cytosols. In addition, the covalent binding of N-hydroxy-2-acetylaminofluorene to DNA was detected in hepatic, but not in bacterial cytosols, although the binding of N-hydroxy-2-aminofluorene was detectable in both hepatic and bacterial cytosols in the presence of acetyl CoA. These results indicate that the metabolic activating capacities of Salmonella and rat liver cytosols differ qualitatively, and the difference in the substrate specificity of acetyltransferase between Salmonella and rat livers may be involved, in part, in the difference of their DNA damage in bacteria and mammals.
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PMID:Enzymatic acetylation and sulfation of N-hydroxyarylamines in bacteria and rat livers. 267 Mar 4

The authors' findings confirm the possibility of such forms. In 16.5% of cases lupus erythematosus transforms from the discoid form and in 6.9% of cases from the disseminated form, immunologically presenting as T- or B-dependent lupus erythematosus. The authors describe immunocorrecting therapy for various forms of the disease, including immunosuppression of T- and B-lymphocytes by the quinoline series drugs or by their combinations with corticosteroids, as well as immunostimulation of T-lymphocytes by the imidazole series drugs or by thymus hormones.
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PMID:[Transitory (presystemic) forms of lupus erythematosus and characteristics of their immunotherapy]. 274 40

The binding of a homologous series of alkyl-linked 4-aminodiquinolines to circular and linear DNAs was studied using viscometric titrations and equilibrium dialysis. The compounds are monofunctional intercalators with the capacity for intercalative binding reaching a peak for the heptane homologue. They show marked AT-base pair selectivity, which suggests that the non-intercalated quinoline ring may lie in the DNA minor groove. Affinities for calf thymus DNA increase as the alkyl chain is lengthened, falling in the range 6 to greater than 250 X 10(4) M-1 in a buffer of I 0.01. The association constant of the heptane diquinoline decreases with increasing ionic strength, 2.1 cations being released per bound dipositive ligand molecule. All the agents are growth inhibitory towards mouse leukemia cells in culture with IC50 values in the range 0.06-18 microM.
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PMID:Alkyl-linked diquinolines are monofunctional AT-selective DNA-intercalating agents. 289 46

8-Hydroxyguanine (8-OH-Gua) residues were formed in DNA of Ehrlich ascites cells exposed to the carcinogen 4-nitroquinoline 1-oxide. Formation of 8-OH-Gua was confirmed by chemical treatment of calf thymus DNA with the proximate metabolite of this carcinogen, 4-hydroxyaminoquinoline 1-oxide, together with seryl-adenosine monophosphate. The ratio of the rates of formations of 8-OH-Gua and the quinoline-bound adducts was about 0.2-0.3. A conceivable mechanism of formation of 8-OH-Gua is proposed.
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PMID:Formation of 8-hydroxyguanine residues in cellular DNA exposed to the carcinogen 4-nitroquinoline 1-oxide. 309 20

The 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a metabolite of the food mutagen--carcinogen IQ, was mutagenic to Salmonella TA98 (nitroreductase deficient). When either rat hepatic cytosol, NADPH (1 mM) or ascorbate (0.5 mM) was added to the mutagenicity assay, mutagenicity increased up to 15-, 10- and 50-fold respectively. In light of the effects of ascorbate and NADPH, it appears likely that hepatic cytosol may contain factors that protect N-hydroxy-IQ from oxidative decomposition. In contrast, hepatic monooxygenase metabolism of N-hydroxy-IQ decreased mutagenicity. When pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, was added to the mutagenicity assay, a dose-dependent inhibition of N-hydroxy-IQ mutagenicity was observed. 2,6-Dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O- acetyltransferase, did not inhibit the mutagenicity of N-hydroxy-IQ at concentrations which appear to selectively inhibit only bacterial sulfotransferase. The data suggest that bacterial O-acetyltransferase rather than sulfotransferase mutagenically activates N-hydroxy-IQ. N-hydroxy-IQ covalently bound to calf thymus DNA in vitro under non-enzymatic conditions at pH 7.4. Rat hepatic cytosolic O-acetyltransferase and sulfotransferase enhanced the covalent binding of N-hydroxy-IQ to DNA 30- and 5-fold respectively. The data suggest that the mutagenicity of N-hydroxy-IQ is due to the reactivity of N-hydroxy-IQ with DNA and the ability of N-hydroxy-IQ to be further activated by bacterial O-acetyltransferase.
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PMID:Mutagenicity and in vitro covalent DNA binding of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline. 316 8


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