Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 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

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

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 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

A total of 201 Staphylococcus aureus isolates were surveyed for susceptibility to ciprofloxacin and trovafloxacin. Of 66 methicillin-resistant isolates, 89% were ciprofloxacin resistant and 6% were also trovafloxacin resistant. Trovafloxacin-resistant strains had unusual patterns of quinoline resistance mutations in DNA topoisomerase genes, including two mutations in the A subunit (encoded by grlA) of topoisomerase IV.
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PMID:Topoisomerase mutations in trovafloxacin-resistant Staphylococcus aureus. 968 20

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

Marine organisms are a rich source for natural products. Pyrrolo[4,3, 2-de]quinolines and pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities. The isolation, structure proof, biological activities, chemical properties and synthesis have attracted the attention of chemists, biologists and pharmacists. The principal structural feature of these alkaloids is the core of a planar iminoquinone moiety which can intercalate into DNA and cleave the DNA double helix or inhibit the action of topoisomerase II. Of the makaluvamines, makaluvamine F and A are the most cytotoxic to the HCT 116 cell line. The enhanced toxicity of the makaluvamines towards xrs-6 cells shows that all of the makaluvamines, except makaluvamine B, act like m-AMSA and etoposide in inhibiting topo iso merases via cleavable complex formation, or via the direct induction of DNA double-strand breaks. They are also amongst the most potent inhibitors of topoisomerase II. Both makaluvamine A and C can decrease tumor size in a solid human tumor model. Discorhabdin A and C in contrast are of high cytotoxicity, but they exhibit no inhibition of topoisomerase II. As representatives of the derivatives of pyrido[4,3,2-mn]acridine, cystodytins, kuanoniamines and diplamine are the most potent to inhibit HCT replication. Eilatin, as a 1,10-phenanthroline derivative, can form complexes with metal ions. It has been shown that these metal complexes can bind to DNA by intercalation. The new members of the pyrrolo[4,3,2-de]quinolines and pyrido[4,3, 2-mn]acridines, such as veiutamine, discorhabdin G, tsitsikammamines, epinartins, arnoamines as well as sagitol are reviewed. Some successful syntheses of pyrrolo[4,3,2-de]quinoline ring system and pyrido[4,3,2-mn]acridine ring system are also reviewed in this article.
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PMID:Pyrroloquinoline and pyridoacridine alkaloids from marine sources. 987 13


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