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Query: CAS:18820-84-3 (quinoline)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New members of the cytotoxic indolo[2,3-b]quinoline family, with a methyl groups at N-5, N-6 (their presence stabilizes the positive charge of the molecule), were prepared using a modified Graebe-Ullmann reaction. The derivatives obtained were well soluble in water in a non-pH-dependent manner. They displayed strong antimicrobial activity against Gram-positive bacteria and pathogenic fungi (the MIC values fall between 0.0025 and 0.12 mM) and highly selective cytotoxicity in vitro against different human cancer cell lines: colon adenocarcinoma SW 707, lung carcinoma A 549, transitional cell carcinoma Hu 1703, and oral epidermoid carcinoma KB, in the range of 0.01 to 3.0 microM. They also stimulated the formation of topoisomerase-II-mediated DNA cleavage at concentration from 0.04 to 0.5 microM. These observations correspond well with the ability of the tested compounds to increase the melting temperature of calf thymus DNA (delta Tm being between 13 degrees C and 22 degrees C).
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PMID:Methoxy- and methyl-, methoxy-5,6,11-trimethyl-6H-indolo [2,3-b]quinolinium derivatives as novel cytotoxic agents and DNA topoisomerase II inhibitors. 971 22

Cooked food mutagens from fried meat and fish have recently been suggested to contribute to the etiology of breast cancer. Thus, the most prevalent of these compounds, i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, or rather its more mutagenic N-hydroxylated metabolite (N-OH-PhIP), forms DNA adducts in mammary cells, including human mammary epithelial (HME) cells. The objective of this study was to determine the involvement of estrogen sulfotransferase (EST), the only sulfotransferase identified in HME cells, in the further bioactivation of N-OH-PhIP. These studies were done in vitro using human recombinant EST and in intact HME cells. Human recombinant EST increased the covalent binding of [3H]N-OH-PhIP to calf thymus DNA approximately 3.5-fold in the presence of the sulfotransferase co-substrate 3'-phosphoadenosine-5'-phosphosulfate at each N-OH-PhIP concentration (1, 10 and 100 microM) (n = 6, P < 0.001). In contrast, EST did not catalyze the DNA binding of two other cooked food mutagens, N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, which are mainly hepatocarcinogens. Cultured HME cells displayed high EST activity, which could be completely inhibited by 1 microM estrone. When the cells were incubated with [3H]N-OH-PhIP, binding to native DNA occurred at 60-240 pmol/mg DNA. This binding was inhibited to 55% of control by 1 microM estrone (P < 0.01, n = 8), suggesting that EST plays a significant role in carcinogen bioactivation in human breast tissue.
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PMID:Bioactivation of the cooked food mutagen N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by estrogen sulfotransferase in cultured human mammary epithelial cells. 985 23

Meats cooked at high temperatures contain mutagenic heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In female Fischer 344 rats, IQ is a multiorgan carcinogen, whereas PhIP induces mammary adenocarcinomas. For IQ and PhIP, N-hydroxylation, catalyzed by microsomal cytochrome P-450 1A1 and/or 1A2, and then esterification, especially O-acetylation, are the principal steps leading to DNA adduct formation. Conjugated linoleic acid (CLA) is a mixture of conjugated linoleic acid isomers found in various meat and dairy products. We have examined the effect of dietary CLA on DNA adduct formation by PhIP and IQ in female Fischer 344 rats. Four-week-old animals were maintained on AIN-76A diet without or with CLA (4% wt/wt) and treated with IQ or PhIP (50 mg/kg by gavage) after two weeks. Animals were killed (4/group) one, four, and eight days later. DNA isolated from mammary epithelial cells, liver, colon, and white blood cells was analyzed for carcinogen-DNA adducts by 32P-postlabeling assays. On Day 1, dietary CLA significantly inhibited adduct formation (82.0%) in mammary epithelial cells in IQ--but not in PhIP-treated rats. In the colon, dietary CLA significantly inhibited PhIP-DNA adduct formation (18.7%) on Day 8 but increased IQ-DNA adduct formation (30.5%) on Day 8. Dietary CLA had no effect on adduct levels in liver or white blood cells. Calf thymus DNA was incubated with N-hydroxy-PhIP or -IQ in the presence of acetyl-CoA. Enzymatic activation was catalyzed by liver or mammary cytosol. A two-week pretreatment with 2% (wt/wt) dietary CLA had no effect on O-acetyltransferase-catalyzed IQ- or PhIP-DNA adduct formation. It is concluded, under certain conditions, that dietary CLA can lower IQ- and PhIP-DNA adduct formation. Overall, however, the major mode of action of CLA is probably by a mechanism other than the inhibition of the N-hydroxylation and subsequent O-acetylation of PhIP or IQ.
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PMID:Effects of dietary conjugated linoleic acid on DNA adduct formation of PhIP and IQ after bolus administration to female F344 rats. 1005 Feb 63

A series of new 5H-indolo[2,3-b]quinoline derivatives bearing methoxy and methyl groups at C-2 and C-9 was synthesized (according to the modified Graebe-Ullmann reaction). These compounds were evaluated for their antimicrobial and cytotoxic activity and tested as inhibitors of DNA topoisomerase II. Lipophilic and calf thymus DNA binding properties of these compounds were also established. In the SAR studies we used quantum-mechanical methodology to analyze the molecular properties of the drugs. All of the 5H-indolo[2,3-b]quinolines tested were found to inhibit the growth of gram-positive bacteria and pathogenic fungi at MIC ranging between 2.0 and 6.0 microM. They showed also cytotoxic activity in vitro against several human cancer cell lines of different origin (ID50 varied from 0.6 to 1.4 microM), and stimulated the formation of topoisomerase-II-mediated pSP65 DNA cleavage at concentration between 0.2 and 0.5 microM. The most active indolo[2,3-b]quinolines which had the greatest contribution to the increase in the Tm of DNA displayed also the highest DNA binding constants and the highest cytotoxic activity. The differences in DNA binding properties and cytotoxic activity seem to be more related to steric than electrostatic effects.
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PMID:Synthesis, and cytotoxic activity of some novel indolo[2,3-b]quinoline derivatives: DNA topoisomerase II inhibitors. 1063 55

Most human mammary carcinomas originate in the epithelial cells of the breast ducts. A potential role of heterocyclic amines (HAs) in the aetiology of this disease has led us to investigate peroxidase-catalysed and stromal (non-epithelial) activation of the HA 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), which may subsequently lead to DNA damage in the adjacent human mammary epithelial cells (HMECs). HAs are formed when proteinaceous foods are cooked at high temperature and some, but not all, can cause mammary tumours in rats. Myeloperoxidase (MPO) and lactoperoxidase (LPO) are peroxidase enzymes present in breast secretions. (32)P-post-labelling analysis showed that IQ-DNA adducts were formed after co-incubation of IQ (500 microM) with calf thymus DNA, hydrogen peroxide and either bovine LPO or horseradish peroxidase (HRP). The major HRP-mediated IQ-DNA adduct co-migrated on TLC and HPLC with the major adduct formed in HMECs, suggesting a common reactive intermediate (nitrenium ion). IQ-DNA adducts were also formed in extracellular DNA when phorbol myristate acetate-stimulated neutrophils (which activate IQ via MPO) were co-incubated with IQ (500 microM) and extracellular plasmid (4 +/- 1 adducts/10(8) nucleotides) or calf thymus DNA (6 +/- 2). Mean adduct formation was five to seven times greater in neutrophil DNA (31 +/- 20). Primary cultures of human mammary fibroblasts or epithelial cells isolated from reduction mammoplasty tissues (n = 4 individuals) were incubated with IQ (500 microM) and formed 2.5 and 14.8 adducts/10(8) nucleotides (mean values), respectively. Our results indicate the possible contribution of stromal cells and breast peroxidases to the metabolic activation of carcinogens in the mammary gland.
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PMID:Pathways of heterocyclic amine activation in the breast: DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) formed by peroxidases and in human mammary epithelial cells and fibroblasts. 1071 41

Optical methods, such as fluorescence, circular dichroism and linear flow dichroism, were used to study the binding to DNA of four symmetrical cyanine dyes, each consisting of two identical quinoline, benzthiazole, indole, or benzoxazole fragments connected by a trimethine bridge. The ligands were shown to form a monomer type complex into the DNA minor groove. The complex of quinoline-containing ligand with calf thymus DNA appeared to be the most resistant to ionic strength, and it did not dissociate completely even in 1 M NaCl. Binding of cyanine dyes to DNA could also be characterized by possibility to form ligand dimers into the DNA minor groove, by slight preference of binding to AT pairs, as well as by possible intercalation between base pairs of poly(dG)-poly(dC). The correlation found between the binding constants to DNA and the extent of cyanine dyes hydrophobicity estimated as the n-octanol/water partition coefficient is indicative of a significant role of hydrophobic interactions for the ligand binding into the DNA minor groove.
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PMID:Binding of symmetrical cyanine dyes into the DNA minor groove. 1102 52

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potential human carcinogen found in cooked food that requires initial metabolic activation by cytochrome P450s, primarily CYP1A2. The present study was conducted to examine whether recombinant human CYP1A2 expressed in insect cells mediates the metabolic activation of IQ and whether prenylflavonoids found in hops and beer would modulate the CYP1A2-mediated activation of IQ. The cDNA-expressed human CYP1A2 was found to strongly activate IQ as measured by the Ames Salmonella assay and by the covalent binding of IQ metabolites to calf thymus DNA and protein. Inhibition studies showed that the prenylchalcone xanthohumol and the prenylflavanones 8-prenylnaringenin and isoxanthohumol strongly inhibited the mutagenic activation of IQ mediated by cDNA-expressed human CYP1A2 in the Ames Salmonella assay. The three prenylflavonoids also markedly inhibited the human CYP1A2-mediated binding of IQ to metabolites that bind to DNA. The inhibition of the metabolic activation of IQ was paralleled by the inhibition of acetanilide 4-hydroxylase activity of human CYP1A2. Thus, xanthohumol, isoxanthohumol, and prenylflavanones 8-prenylnaringenin are potent inhibitors of the metabolic activation of IQ and may have the potential to act as chemopreventive agents against cancer induced by heterocyclic amines activated by CYP1A2.
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PMID:Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4, 5-f]quinoline, mediated by cDNA-expressed human CYP1A2. 1103 56

A zinc (II) complex with a macrocyclic tetraamine appended with an anthraquinone ((9,10-anthraquinon-2-yl)methyl-1,4,7,10-tetraazacyclododecane, ZnL, anthraquinonyl-cyclen) selectively recognizes consecutive G sequence in double-stranded DNA. The affinity of the Zn2+-anthraquinonyl-cyclen to consecutive dG groups in DNA was disclosed by comparison of K(app) values (=[DNA-bound ZnL]/[uncomplexed ZnL][uncomplexed nucleobase in DNA]) determined by the UV spectrophotometric titrations at pH 8, I=0.1 (NaNO3), and 25 degrees C for poly(dG) x poly(dC) (K(app) = 1.5 x 10(5) M(-1)), poly(dG-dC)2 (2.8 x 10(4) M(-1)), poly(dA-dT)2 (4.3 x 10(4) M(-1)), and calf thymus DNA (2.8 x 10(4) M(-1)). The corresponding K(app) values with the Zn2+-free ligand were 5.3 x 10(3) M(-1), 7.4 x 10(3) M(-1), 7.4 x 10(3) M(-1), and 5.9 x 10(3) M(-1), respectively. The selective recognition of consecutive G sequence was concluded from the DNase I footprinting of SV40 early promotor DNA fraction (197 bp) containing a TATA box and six GC boxes. The present finding is in remarkable contrast to the previous selective T-recognition by Zn2+-cyclen complexes appended with acridine, quinoline(s), and naphthalene(s) [J. Am. Chem. Soc. 121 (1999) 5426]. While the Zn2+-acridinyl-cyclen inhibited TATA binding protein from interacting with a TATA box consensus DNA [J. Inorg. Biochem. 79 (2000) 253], the present Zn2+-anthraquinonyl-cyclen inhibited the Sp1 transcriptional factor protein from interacting with a GC box-consensus DNA.
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PMID:Selective recognition of consecutive G sequence in double-stranded DNA by a zinc(II)-macrocyclic tetraamine complex appended with an anthraquinone. 1113 34

Ochratoxin A (OTA) is a potent renal carcinogen in male rats, although its mode of carcinogenicity is not known. The metabolism and covalent binding of OTA to DNA were investigated in vitro with cytochromes P450, glutathione S-transferases, prostaglandin H-synthase, and horseradish peroxidase. Incubation of OTA with rat or human liver microsomes fortified with NADPH resulted in formation of 4-(R)-hydroxyochratoxin A at low rates [10-25 pmol min(-1) (mg of protein)(-1)]. There was no evidence of OTA metabolism and glutathione conjugate formation with rat, mouse, or human kidney microsomes or postmitochondrial supernatants (S-9) [<5 pmol min(-1) (mg of protein)(-1)]. Recombinant human cytochromes P450 (P450) 1A1 and 3A4 formed 4-(R)-hydroxyochratoxin A at low rates [0.08 and 0.06 pmol min(-1) (pmol of P450)(-1), respectively]; no oxidation products of OTA were detected with recombinant human P450 1A2 or 2E1 or rat P450 1A2 or 2C11 [<0.02 pmol min(-1) (pmol of P450)(-1)]. Prostaglandin H-synthase produced small amounts of an apolar product [33 pmol min(-1) (mg of protein)(-1)], and OTA products were not formed with horseradish peroxidase. There was no evidence of DNA adduct formation when [(3)H]OTA was incubated with these enzyme systems in the presence of calf thymus DNA (<20 adducts/10(9) DNA bases); however, these enzymes catalyzed DNA adduct formation with the genotoxins aflatoxin B(1), 2-amino-3-methylimidazo[4,5-f]quinoline, benzo[a]pyrene, and pentachlorophenol. There was also no detectable [(3)H]OTA bound in vivo to kidney DNA of male Fischer-344 rats treated orally with [(3)H]OTA (1 mg/kg, 100 mCi/mmol, 24 h exposure, <2.7 adducts/10(9) DNA bases), based upon liquid scintillation counting. However, (32)P-postlabeling experiments did show evidence of DNA lesions with total adduct levels ranging from 31 to 71 adducts/10(9) DNA bases, while adducts in untreated rat kidney ranged from 6 to 24 adducts/10(9) DNA bases. These results do not support the premise that OTA or metabolically activated species covalently bind to DNA and suggest that the (32)P-postlabeled lesions are due to products derived from OTA-mediated cytotoxicity.
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PMID:Metabolism of ochratoxin A: absence of formation of genotoxic derivatives by human and rat enzymes. 1117 May 6

Heterocyclic amines are mammary carcinogens in rats and their N-hydroxy metabolites are substrates for subsequent metabolic activation by N-acetyltransferases (NAT) and sulfotransferases (SULT) in man. We investigated the expression of these enzymes in human breast tissue and the relationship between NAT genotype and NAT mRNA expression or enzyme activity. Immunohistochemical staining of sections of breast tissue identified expression of NAT1 and NAT2 protein in human mammary epithelial cells, but not in the stroma. We also measured the formation of DNA adducts of the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in calf thymus DNA after incubation of their promutagenic N-hydroxy metabolites with mammary cytosols prepared from reduction mammoplasty tissue. Experimental observations gained from use of enzyme cofactors and NAT and/or SULT inhibitors on cytosolic enzyme activity, recombinant NAT1 activity and heterocyclic amine-DNA adduct formation suggest that both NAT1 and SULT1A enzymes contribute significantly to the activation of N-hydroxylated heterocyclic amines in mammary tissue. NAT1 mRNA transcript levels were found to be two- to three-fold higher than mRNA transcripts of the NAT2 gene in reduction mammoplasty tissue and mammary epithelial cells. NAT1-specific p-aminobenzoic acid acetylation activity, but not NAT2-specific sulfamethazine acetylation activity, was detectable in mammary cytosols. There was no association apparent between NAT genotype and the levels of NAT mRNA or NAT enzyme activity, or between NAT1 genotype and IQ-DNA adduct formation mediated by mammary cytosols. Western blot analysis of mammary cytosolic protein showed detectable levels of SULT1A1 and SULT1A3.
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PMID:N-Acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. 1147 Sep 91


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