Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When O-acetyl-4-(hydroxyamino)quinoline 1-oxide (Ac-4HAQO) reacts with double-stranded DNA at 37 degrees C the major products, N2-guanine, C8-guanine, and N6-adenine adducts, are formed in the proportions of 5:3:2, respectively. When the reaction is carried out with single-stranded DNA at 0 degree C, the products are found in the ratio 1:7:2. Unique 174-bp DNA fragments were modified in these ways and used as substrates for the 3'-5' exonuclease activity of T4 DNA polymerase. The results obtained showed that the exonuclease is blocked by the N2-guanine adduct but not the other two adducts. Interpretation of the cleavage patterns suggested that the enzyme stopped 2 nucleotides before the N2-guanine adduct. The N2-guanine adduct lies in the minor groove of the DNA double helix, while the other two adducts are found in the major groove. Apparently, only the former hinders progression of the enzyme.
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PMID:The N2-guanine adduct but not the C8-guanine or N6-adenine adducts formed by 4-nitroquinoline 1-oxide blocks the 3'-5' exonuclease action of T4 DNA polymerase. 210 34

The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides and succinimides demonstrated cytotoxicity against the growth of a number of cultured cell lines. The substituted succinimides were more effective than the unsubstituted succinimide derivative in reducing cell growth. On the other hand, phthalimide demonstrated more potent cytotoxicity than its N-substituted derivatives. Three representative examples N-[2-pyridinyl-1-oxide) methyl] phthalimide 8, 1-[N-2-phthalimidoethyl]-3,4-dihydroiso-quinoline 12, and 1-[N-(2-(1,2,3,4-tetrahydro-2-quinolinyl)] ethylphthalimide 14 were shown to inhibit L1210 leukemia DNA synthesis whereas RNA synthesis was not inhibited at 25-100 uM. All three agents inhibited the activities of DNA polymerase alpha, PRPP-amido transferase, nucleoside kinases, and dihydrofolate reductase. The cellular pool levels of d[GTP], d[CTP], and d[TTP] were reduced after 60 minutes incubation at 100 uM. The DNA molecule itself was not a target of these agents.
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PMID:The cytotoxicity of N-Pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide. 757 4

The quinoline U-78036 represents a new class of non-nucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The agent possesses excellent antiviral activity at nontoxic doses in HIV-1-infected lymphocytes grown in tissue culture. Enzymatic kinetic studies of the HIV-1 reverse transcriptase (RT)-catalyzed RNA-directed DNA polymerase function were carried out in order to determine whether the inhibitor interacts with the template-primer or deoxyribonucleotide triphosphate (dNTP) binding sites of the polymerase. The data were analyzed using steady-state or Briggs-Haldane kinetics assuming that the template-primer binds to the enzyme first followed by the dNTP and that the polymerase functions processively. The calculated rate constants are in agreement with this model. The results show that the inhibitor acts as a mixed to noncompetitive inhibitor with respect to both the template-primer and the dNTP binding sites of the enzyme. Hence, U-78036 inhibits the RNA-directed DNA polymerase activity of RT by interacting with a site distinct from the template-primer and dNTP binding sites. Moreover, the potency of U-78036 is dependent on the base composition of the template-primer. The equilibrium constants for various enzyme-substrate-inhibitor complexes were at least seven times lower for the poly(rC).(dG)10-catalyzed system than the one catalyzed by poly(rA).(dT)10. In addition, the inhibitor does not impair the DNA-dependent DNA polymerase activity and the RNase H function of HIV-1 RT nor does it inhibit the RNA-directed DNA polymerase activity of the HIV-2, avian myoblastoma virus, and murine leukemia virus RT enzymes.
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PMID:The quinoline U-78036 is a potent inhibitor of HIV-1 reverse transcriptase. 768 7

Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.
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PMID:Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors. 1185 Feb 54

The design, synthesis and biological evaluation of novel seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and the seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) analogues of the duocarmycins are described. These novel analogues (4-7) were designed on the premise that the lone pair of electrons on the furano-oxygen atom could enter into conjugation with the isocyclopropylfurano[e]indolone (iso-CFI) alkylating moiety, formed from the loss of HCl in compounds 4-7. The seco-iso-CFI DNA alkylating pharmacophore was synthesized through a well precedented approach of 5-exo-trig aryl radical cyclization with a vinyl chloride. In our studies, in addition to the formation of the seco-iso-CFI product, an equal amount of an unexpected seco-CFQ product was also generated during the radical cyclization reaction. Like CC-1065 and adozelesin, using Taq DNA polymerase stop and thermal cleavage assays, the seco-iso-CFI compounds (4 and 6) and the seco-CFQ compounds (5 and 7) were shown to preferentially alkylate the adenine-N3 position within the minor groove of long stretches of A residues. A MM2 energy optimized molecular model of a 1:1 complex of compound 6 with DNA reveals that the iso-CFI compound fits snugly within the minor groove. Using a MTT based experiment, the cytotoxicity of compounds 4-7 were determined against the growth of murine leukemia (L1210), mastocytoma (P815) and melanoma (B16) cell lines. The concentrations of compounds required to inhibit the growth of these tumor cells by 50% is in the range of 10(-8)M. These compounds were also tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a high level of activity against selected solid tumors. At a concentration of 0.0084 microM (based on the IC(50) of compound 17 (seco-CBI-TMI) against the growth L1210 cells), while compounds 4 and 17 were toxic against murine bone marrow cells as judged by a colony forming study of freshly isolated murine progenitor hematopoeitic cells, compound 5, a seco-CFQ compound, was significantly less toxic. Flow cytometric analysis of P815 cells that had been incubated for 24h with compounds 4 and 5 at their cytotoxic IC(50) concentrations indicated the induction of apoptosis in a large percentage of cells, thereby suggesting that this might be the mechanism by which the iso-CFI compounds kill cells.
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PMID:Novel furano analogues of duocarmycin C1 and C2: design, synthesis, and biological evaluation of seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) analogues. 1211 Mar 16

A macrocyclic tetraamine zinc(II) complex appended with two quinoline groups, Zn(2+)-1,7-bis(4-quinolylmethyl)-1,4,7,10- tetraazacyclododecane (Zn(2+)-Q2-cyclen), was successfully used as a novel additive to suppress nonspecific products in DNA polymerase chain reaction (PCR). In the presence of Zn(2+)-Q2-cyclen, the Tm drop of 20-bp heteroduplexes containing a noncomplementary basepair was greater than that of the corresponding homoduplex (i.e., primer DNA). Here, we applied such preferential DNA melting to a specificity-enhanced PCR using micromolar concentrations of Zn(2+)-Q2-cyclen. We demonstrated the selective amplification of target DNA fragments (i.e., the human heart sodium channel Nav1.5 gene) from genomic DNA or a cDNA library. The optimum condition for the specificity-enhanced PCR could be determined in the concentration range of 1-50muM of Zn(2+)-Q2-cyclen.
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PMID:A heteroduplex-preferential Tm depressor for the specificity-enhanced DNA polymerase chain reactions. 1564 89

Heterocyclic arylamines are highly mutagenic and cause tumors in animal models. The mutagenicity is attributed to the C8- and N2-G adducts, the latter of which accumulates due to slower repair. The C8- and N 2-G adducts derived from 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were placed at the G1 and G3 sites of the NarI sequence, in which the G3 site is an established hot spot for frameshift mutation with the model arylamine derivative 2-acetylaminofluorene but G1 is not. Human DNA polymerase (pol) eta extended primers beyond template G-IQ adducts better than did pol kappa and much better than pol iota or delta. In 1-base incorporation studies, pol eta inserted C and A, pol iota inserted T, and pol kappa inserted G. Steady-state kinetic parameters were measured for these dNTPs opposite the C8- and N 2-IQ adducts at both sites, being most favorable for pol eta. Mass spectrometry of pol eta extension products revealed a single major product in each of four cases; with the G1 and G3 C8-IQ adducts, incorporation was largely error-free. With the G3 N 2-IQ adduct, a -2 deletion occurred at the site of the adduct. With the G1 N 2-IQ adduct, the product was error-free at the site opposite the base and then stalled. Thus, the pol eta products yielded frame-shifts with the N 2 but not the C8 IQ adducts. We show a role for pol eta and the complexity of different chemical adducts of IQ, DNA position, and DNA polymerases.
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PMID:Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site. 1683 18

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is found in cooked meats and forms DNA adducts at the C8- and N2-positions of dGuo after appropriate activation. IQ is a potent inducer of frameshift mutations in bacteria and is carcinogenic in laboratory animals. We have incorporated both IQ-adducts into the G1- and G3-positions of the NarI recognition sequence (5'-G1G2CG3CC-3'), which is a hotspot for arylamine modification. The in vitro replication of the oligonucleotides was examined with Escherichia coli pol I Klenow fragment exo-, E. coli pol II exo-, and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), and the extension products were sequenced by tandem mass spectrometry. Replication of the C8-adduct at the G3-position resulted in two-base deletions with all three polymerases, whereas error-free bypass and extension was observed at the G1-position. The N2-adduct was bypassed and extended by all three polymerases when positioned at the G1-position, and the error-free product was observed. The N2-adduct at the G3-position was more blocking and was bypassed and extended only by Dpo4 to produce an error-free product. These results indicate that the replication of the IQ-adducts of dGuo is strongly influenced by the local sequence and the regioisomer of the adduct. These results also suggest a possible role for pol II and IV in the error-prone bypass of the C8-IQ-adduct leading to frameshift mutations in reiterated sequences, whereas noniterated sequences result in error-free bypass.
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PMID:Translesion synthesis past the C8- and N2-deoxyguanosine adducts of the dietary mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI recognition sequence by prokaryotic DNA polymerases. 1711 39

A new target in AIDS therapy development is HIV-1 integrase (IN). It was proven that HIV-1 IN required divalent metal cations to achieve phosphodiester bond cleavage of DNA. Accordingly, all newly investigated potent IN inhibitors contain chemical fragments possessing a high ability to chelate metal cations. One of the promising leads in the polyhydroxylated styrylquinolines (SQLs) series is (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinoline carboxylic acid (1). The present study focuses on the quinoline-based progenitor (2), which is actually the most probable chelating part of SQLs. Conventional and synchrotron low-temperature X-ray crystallographic studies were used to investigate the chelating power of progenitor 2. Mg2+ and Cu2+ cations were selected for this purpose, and three types of metal complexes of 2 were obtained: Mg(II) complex (4), Cu(II) complex (5) and mixed Mg(II)-Cu(II) complexes (6 and 7). The analysis of the crystal structure of complex 4 indicates that two tridentate ligands coordinate two Mg2+ cations, both in octahedral geometry. The Mg-Mg distance was found equal to 3.221(1) A, in agreement with the metal-metal distance of 3.9 A encountered in the crystal structure of Escherichia coli DNA polymerase I. In 5, the complex is formed by two bidentate ligands coordinating one copper ion in tetrahedral geometry. Both mixed Mg(II)-Cu(II) complexes, 6 and 7 exhibit an original arrangement of four ligands linked to a central heterometallic cluster consisting of three octahedrally coordinated magnesium ions and one tetrahedrally coordinated copper ion. Quantum mechanics calculations were also carried out in order to display the electrostatic potential generated by the dianionic ligand 2 and complex 4 and to quantify the binding energy (BE) during the formation of the magnesium complex of progenitor 2. A comparison of the binding energies of two hypothetical monometallic Mg(II) complexes with that found in the bimetallic magnesium complex 4 was made.
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PMID:Crystal and electronic structures of magnesium(II), copper(II), and mixed magnesium(II)-copper(II) complexes of the quinoline half of styrylquinoline-type HIV-1 integrase inhibitors. 1748 11

We describe in this paper that the synthetic chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid (compound A) and its free aglycogene base (compound B) inhibit, with low cytotoxicity, the replication of herpes simplex virus type 1 and 2 (HSV-1 and HSV-2). Compound A inhibited HSV-1 replication in Vero cells with an EC(50) of 1.3 and 1.4 microM for an acyclovir (ACV)-sensitive strain and an ACV-resistant strain of this virus, respectively. Additionally, it inhibited HSV-2 replication with an EC(50) of 1.1 microM. Compound B also inhibited the ACV-sensitive and -resistant HSV-1 strains, and HSV-2 at EC(50) values of 1.7, 1.9 and 1.6 microM, respectively. Time-of-addition assays, performed with compound A, suggested that this molecule at an early time point of the HSV replication cycle. Kinetic assays demonstrated that compounds A and B inhibit the HSV DNA polymerase activity in a noncompetitive fashion, with a K(i) equal to 0.1 and 0.2 microM, respectively. Taken together, our results suggest that compounds A and B represent promising lead molecules for further anti-HSV drug design.
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PMID:Inhibition of HSV-1 replication and HSV DNA polymerase by the chloroxoquinolinic ribonucleoside 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3-carboxylic acid and its aglycone. 1793 12


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