Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA intercalating, ellipticine analog drug, 5,11-dimethyl-5H-indol[2,3-b]quinoline, is able to stabilize in vitro the topoisomerase II-DNA cleavable complex and to induce DNA breaks in BPV I episome in rat fibroblasts. Cytotoxicity studies with DC3F cells resistant to ellipticine strongly suggest that topoisomerase II is a cellular target involved in the mechanism of cytotoxic action of this carboline derivative.
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PMID:A carboline derivative as a novel mammalian DNA topoisomerase II targeting agent. 133 51

We established an etoposide (VP-16)-resistant human small-cell lung cancer cell line (H69/VP) by stepwise exposure to VP-16. The resistance of H69/VP to VP-16 was 9.4-fold that of the parent cell line (H69/P). H69/VP showed cross-resistance to Adriamycin (ADM), (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H-pyrano[3',4':6,7]indolizino [1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride trihydrate (CPT-11), teniposide (VM-26), vindesine (VDS) and vincristine (VCR). The amount of DNA topoisomerase II (topo.II) was nearly the same in H69/P and H69/VP cells. The catalytic activity of topo.II in H69/VP cells was lower than that in the H69/P line. Accumulation of [3H]-VP-16 in H69/VP was 6.1-7.5 times lower than that in H69/P. According to Northern blot analysis, the mdr-1 mRNA level in H69/VP was markedly higher than that in H69/P. These findings suggest that H69/VP has a typical multidrug resistance (MDR) phenotype and that alteration of the drug accumulation mediated by P-glycoprotein may play an important role in resistance to VP-16. Reduced topo.II activity may also be associated with VP-16 resistance.
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PMID:Characterization of an etoposide-resistant human small-cell lung cancer cell line. 197 50

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.
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PMID:Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1. 254 58

A series of 18 1-substituted 7-[3-[(ethylamino)methyl]-1- pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acids (N1 analogues of CI-934) were synthesized and evaluated for antibacterial activity and DNA-gyrase inhibition. Correlations between the inhibition of DNA gyrase and antibacterial potency were established. A quantitative structure-activity relationship (QSAR) was derived by using the antibacterial potency for each of 11 strains of bacteria and the Gram-negative mean. The equations indicated that antibacterial potency was strongly dependent on STERIMOL length and width and the level of unsaturation of the N1 substituent. Some strains also showed a dependence on the presence of heteroatoms (O, N, S) in the N1 group. No significant correlations between gyrase inhibition and combinations of these parameters were found. These QSAR results are discussed in conjunction with the conformational analyses from molecular modeling studies. The substituent that most enhanced the activity of the quinolone in all regards was the cyclopropyl group. This analogue, 1-cyclopropyl-7-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (PD 117558), demonstrated outstanding broad spectrum activity both in vitro and in vivo when compared to relevant standards.
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PMID:1-Substituted 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids. New quantitative structure-activity relationships at N1 for the quinolone antibacterials. 283 57

In furtherance of our SAR study on the chemistry and antitumor activity of fused nitrogen heteroaromatic compounds, a series of linear, methyl-substituted derivatives of 5H- and 6H-indolo[2,3-b]quinolines were synthesized according to the modified Graebe-Ullmann reaction. To establish the relationship between the physicochemical and biological activities of indolo[2,3-b]quinolines, their lipophilic properties, cytotoxic and antimicrobial activity, and ability to induce topoisomerase II dependent pSP65 DNA cleavage in vitro were investigated. We found that the antimicrobial and cytotoxic activity of indolo[2,3-b]quinolines was strongly influenced by the position, and the number of methyl substituents and the presence of methyl group at pyridine nitrogen was essential for the cytotoxicity of these compounds. All indolo[2,3-b]quinolines belonging to the 5H series, i.e., bearing a methyl group on the pyridine nitrogen, showed significant activity against procaryotic and eucaryotic organisms. They inhibited the growth of Gram-positive bacteria and pathogenic fungi at MIC range 3 x 10(-2) to 2.5 x 10(-1) mumol/mL, displayed cytotoxicity against KB cells ID50 in the range 2 x 10(-3) to 9 x 10(-3) mumol/mL, and stimulated the formation of calf thymus topoisomerase II mediated DNA cleavage at concentration between 0.4 and 10 microM. None of the indolo[2,3-b]quinolines belonging to the 6H series, i.e., lacking a methyl group on the pyridine nitrogen, was active in analogous tests. Of the investigated compounds, the most active was 2,5,9,11-tetramethyl-5H-indolo[2,3-b]quinoline, a compound bearing the highest number of symmetrically distributed methyl groups. The interaction of indolo[2,3-b]quinolines with DNA was studied by measuring the increase of calf thymus DNA denaturating temperature (Tm). The delta Tm values for the 5H series were found to be about 10 times as high as those for the 6H compounds. Indolo[2,3-b]quinolines with the highest number of methyl groups had the greatest contribution to the increase in the Tm of calf thymus DNA. The values of delta Tm reached 19 degrees C and 1.6 degrees C for the most substituted compounds of both series.
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PMID:Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: novel cytotoxic, DNA topoisomerase II inhibitors. 793 79

Acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide represent a new generation of antitumor intercalators related to amsacrine (m-AMSA), a classic topoisomerase II-targeted drug. We examined the ability of these tricyclic carboxamides to induce DNA lesions that reflect the stabilization of topoisomerase II cleavage complexes. DNA-protein cross-links (DPC) and DNA double-strand breaks (DSB) were assessed in mouse fibrosarcoma cells (line 935.1). DPC were rapidly formed and readily reversible. A bell-shape concentration dependence suggested a self-inhibition of DPC at higher drug levels. In isolated nuclei, DPC formation by 2-(4-pyridyl)quinoline-8-carboxamide required ATP and was inhibited by novobiocin, a topoisomerase II inhibitor. Acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide were also potent inducers of DSB. In contrast to DPC, however, DNA breaks continued to increase with drug concentration. These DSB were masked (presumably by non-covalently associated proteins) when analyzed by nucleoid sedimentation. Thus, while both DPC and DSB seemed to be topoisomerase mediated, at least some DSB appeared to lack the enzyme bound covalently. DNA lesions by tricyclic carboxamides occurred, in general, at drug concentrations comparable to those needed to inhibit cell survival. Also, the tricyclic carboxamides inhibited the catalytic activity of isolated topoisomerase II. The results indicate that tricyclic carboxamides interfere with the action of topoisomerase II. However, the mechanisms of enzyme inhibition by these drugs differ from the classical trapping of topoisomerase in covalent cleavage complex m-AMSA.
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PMID:Topoisomerase II mediated DNA lesions induced by acridine-4-carboxamide and 2-(4-pyridyl)quinoline-8-carboxamide. 814 68

A series of 6-fluoro-1,4-dihydro-4-oxo-3-quinoline- and 1,8-naphthyridinecarboxylic acids, substituted at the 7-position with carbon-linked side chains, was synthesized and evaluated for antibacterial activity and DNA-gyrase inhibition. Structural modifications focused on replacement of the heterocyclic nitrogen of the frequently found 1-piperazinyl and 3-amino-1-pyrrolidinyl side chains by an sp2- or an sp3-hybridized carbon. All new compounds displayed high in vitro and in vivo antibacterial activity. Potency relative to the standard nitrogenated agents was dependent on ring size and hybridization of the linking carbon atom of the side chain. Compounds with a 1,2,3,6-tetrahydro-4-pyridinyl substituent at C-7 were equipotent with their 1-piperazinyl analogs, whereas those having a 4-piperidinyl or a 3-amino-1-cyclopentenyl ring at C-7 were less active than the 1-piperazinyl or 3-amino-1-pyrrolidinyl substituted agents, respectively. This relative difference in antibacterial potency did not correlate with the observed activity against gyrase, where the majority of the new compounds were equally or more potent than their nitrogenated counterparts.
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PMID:Quinolone antibacterials: synthesis and biological activity of carbon isosteres of the 1-piperazinyl and 3-amino-1-pyrrolidinyl side chains. 839 12

A series of 1-azolylalkyl-4(1H)-quinolones has been synthesized and evaluated for cytotoxic activity both in vitro and in vivo. The effects on cytotoxicity of varying substitution on the quinoline moiety was investigated. The insertion of a 5-amino group proved to be the most effective modification, resulting in a several-fold increase in cytotoxicity in vitro. Previously reported results indicated that the activity of this class of compounds may involve topoisomerase inhibition, but investigation of the current compounds has ruled out this possibility. One compound, 13, showed in vitro cytotoxicity notably superior to Adriamycin, however it demonstrated only slight or no in vivo efficacy depending on the model used.
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PMID:Cytotoxic quinolines (Part 3). Synthesis of 1-azolylalkyl-4(1H)-quinolones as cytotoxic agents. 901 Jun 18

This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.
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PMID:Altered expression of gamma-glutamylcysteine synthetase, metallothionein and topoisomerase I or II during acquisition of drug resistance to cisplatin in human ovarian cancer cells. 911 51

Exposure of Staphylococcus aureus to 1 x MIC of the quinolone antibiotic pazufloxacin for 24 h, followed by plating on drug-free media, led to the emergence of small colony variants (SCVs) in addition to large colony variants (LCVs). However, following incubation with 0.25 or 4 x MIC of pazufloxacin, only LCVs were obtained. The SCVs were half as susceptible to pazufloxacin or ciprofloxacin as wild-type S. aureus, while the susceptibilities of LCVs were essentially unchanged. The reduced susceptibilities of SCVs did not result from mutations in the quinolone-resistance-determining regions of DNA gyrase and topoisomerase IV, since the sequences of these genes were identical to those of the wild-type. However, the SCVs accumulated pazufloxacin and ciprofloxacin to a lesser degree than did wild-type. Furthermore, their susceptibility to quinolones was almost unaffected by reserpine or verapamil, suggesting that the reduced uptake resulted from decreased permeability, rather than from an active efflux pump. The ability of various quinolones to induce emergence of SCVs in S. aureus, correlated with the presence of carbon-bonded substituents at the C-7 position of a quinoline or naphthyridine nucleus, or with the presence of a benzoxazine nucleus. In conclusion, pazufloxacin-induced SCVs represent a mutant that one might expect to be rapidly eliminated in vivo and, hence, not to survive as a quinolone-resistant pathogen. This finding suggests a novel approach for development of future quinolones.
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PMID:Characteristics of quinolone-induced small colony variants in Staphylococcus aureus. 922 37


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