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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 4beta-[(4' '-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivatives (11-23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13-18, 20-22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C(4)-modified new derivatives exhibited superior activity profiles, particularly against drug-resistant cell lines, to those of 1. Preliminary metabolism studies on compounds 16 and 20 revealed that 20 was relatively resistant to metabolism by rat serum and liver enzymes, while 16 was metabolically unstable.
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PMID:Antitumor agents. 234. Design, synthesis, and biological evaluation of novel 4beta-[(4' '-benzamido)-amino]-4'-o-demethyl-epipodophyllotoxin derivatives. 1545 57

Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4'-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4'-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.
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PMID:Synthesis and biological study of a new series of 4'-demethylepipodophyllotoxin derivatives. 1565 72

Microsporidia have emerged as causes of infectious diseases in AIDS patients, organ transplant recipients, children, travelers, contact lens wearers, and the elderly. These organisms are small single-celled, obligate intracellular parasites that were considered to be early eukaryotic protozoa but were recently reclassified with the fungi. Of the 14 species of microsporidia currently known to infect humans, Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common causes of human infections and are associated with diarrhea and systemic disease. Species of microsporidia infecting humans have been identified in water sources as well as in wild, domestic, and food-producing farm animals, raising concerns for waterborne, foodborne, and zoonotic transmission. Current therapies for microsporidiosis include albendazole which is a benzimidazole that inhibits microtubule assembly and is effective against several microsporidia, including the Encephalitozoon species, but is less effective against E. bieneusi. Fumagillin, an antibiotic and anti-angiogenic compound produced by Aspergillus fumigatus, is more broadly effective against Encephalitozoon spp. and Enterocytozoon bieneusi but is toxic when administered systemically to mammals. Gene target studies have focused on methionine aminopeptidase 2 (MetAP2) for characterizing the mechanism of action and for identifying more effective, less toxic fumagillin-related drugs. Polyamine analogues have shown promise in demonstrating anti-microsporidial activity in culture and in animal models, and a gene encoding topoisomerase IV was identified in Vittaforma corneae, raising prospects for studies on fluoroquinolone efficacy against microsporidia.
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PMID:Microsporidiosis: an emerging and opportunistic infection in humans and animals. 1577 37

Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.
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PMID:Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. 1589 69

The meeting covered basic research on DNA topoisomerases and aspects of DNA topoisomerase-directed therapy, which will be the main topic of this report. In terms of cancer therapy, the focus of the meeting was clearly on camptothecins (CPTs) and related compounds, that stabilize covalent DNA intermediates of topoisomerase I. Results were presented showing that these drugs might act in a tumor-specific manner because tumor cells have defects in degradation pathways of DNA-linked topoisomerase I. On the other hand, a DNA-tyrosine phosphodiesterase has been discovered, which removes topoisomerase I from its covalent DNA-linkage and thus might be a new mechanism of drug resistance. Reports on recent clinical trials of first-generation water soluble CPT analogs (topotecan; SmithKline Beecham, and irinotecan; Yakult Honsha KK), confirmed earlier findings that these drugs have major limitations due to the half-life of the active lactone form and other pharmacokinetic factors, resulting in a major schedule dependency of the toxicity. Solutions to that problem will possibly come from an oral application regimen or liposomal packaging of the drugs. Several new CPT analogs at preclinical stages of development might also improve on these problems by providing a greater stability of the lactone ring, higher DNA-binding affinity, and reduced water solubility. New drugs might be developed from a number of new non-CPT compounds, which inhibit the activity of DNA topoisomerases, but do not stabilize the DNA-linked form of the enzymes. Some of these compounds display reasonable preclinical anticancer activity. A second focus of the meeting was on therapeutic targeting of microbial DNA topoisomerases. On the one hand, the antibiotic potential of the quinolones has been extended to Gram-positive pathogens, particularly Streptococcus pneumoniae. On the other hand, cloning and biochemical characterization of the DNA topoisomerases of eukaryotic parasites, such as Plasmodium falciparum or Candida albicans, have been completed and the search for specific inhibitors targeting these enzymes are under way.
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PMID:DNA topoisomerases in therapy--tenth conference. 6-8 October 1999, Amsterdam, The Netherlands. 1611 55

The viable but non-culturable (VBNC) stage of Helicobacter pylori may represent a problem of public health concern, since these cells cannot be detected by traditional culture methods. In this study, the direct viable count method (DVC) was modified and adapted to H. pylori analysis by testing different times of incubation and concentrations of DNA-gyrase inhibitors. The DVC procedure was combined with fluorescent in situ hybridization (FISH) for the specific detection of viable cells of H. pylori (DVC-FISH). Incubation with 0.5 microg/ml of novobiocin for 24 h provided the optimal conditions for obtaining 3-5 times the original size of Helicobacter viable cells. Field work performed with various types of water (freshwater and seawater) using the DVC-FISH approach enabled us to confirm the presence of VBNC H. pylori cells in 16 of the 45 analyzed samples. The combination of the modified DVC procedure with FISH can provide a rapid and specific method to detect and identify viable cells of H. pylori in environmental samples.
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PMID:A combination of direct viable count and fluorescent in situ hybridization for estimating Helicobacter pylori cell viability. 1638 Feb 34

Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-soluble salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivatives irinotecan and topotecan did not cause haemorrhagic cystitis because of their higher physicochemical stability and solubility at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhoea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitising solubilisers. Leukopenia and thrombocytopenia occur in 65% and 80%, respectively, of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhoea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clinical pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concentration-time curve values and steady-state concentrations for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metabolism may be associated with a higher risk for secondary malignancies.
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PMID:Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. 1652 21

Real-time quantification of Pseudomonas aeruginosa was performed in various wastewater systems including clinical, municipal wastewaters and inflow from a wastewater treatment plant. The highest concentrations of P. aeruginosa-specific targets were detected in clinical wastewaters. Limitations of the detection system resulting from inhibition or cross-reaction were identified. Ciprofloxacin-resistant P. aeruginosa strains were isolated after specific enrichment from clinical and municipal wastewaters. In some cases they were also cultivated from effluent of a wastewater treatment plant, and from its downstream river water. A total of 119 isolates were phenotypically characterized as ciprofloxacin-resistant via antibiogram testing. Subsequently, the fluoroquinolone-resistance-mediating mutations in the genes gyrA codon positions 83 and 87, gyrB codon position 466 and parC codon positions 87 and 91 were determined by mini-sequencing. Ciprofloxacin resistance was mainly associated with mutations in gyrA codon position 83 and parC mutation in codon positions 87 or 91 of the bacterial gyrase and topoisomerase II genes. All ciprofloxacin-resistant P. aeruginosa strains were compared with genotypes from clinical data of fluoroquinolone-resistant P. aeruginosa infections. The results were in agreement with data from clinical analyses, with the exception that no gyrA 87 and no gyrB mutations were found in ciprofloxacin-resistant P. aeruginosa wastewater isolates.
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PMID:Real-time PCR detection of Pseudomonas aeruginosa in clinical and municipal wastewater and genotyping of the ciprofloxacin-resistant isolates. 1681 59

Novel substituted triptycene bisquinones and 1, 4-anthracenediones were synthesized and screened for their anti-cancer activities. A number of analogs were synthesized utilizing various synthetic transformations and found to elicit interesting antitumor effects. Analogs included water-soluble pro-drugs and ammonium salts. These potent antitumor drugs are DNA topoisomerase inhibitors that induce DNA strand breaks, inhibit DNA, RNA and protein syntheses and reduce tumor cell proliferation in the nanomolar range in vitro. They induce cytochrome c release, caspase-9, -3 and -8 activities, poly(ADP)-ribose polymerase-1 (PARP) cleavage, and internucleosomal DNA fragmentation by a mechanism which involves caspase-2 activation but not Fas signaling. Moreover, these drugs remain effective in multidrug-resistant tumor cells and have the advantage of blocking nucleoside transport and inducing a rapid loss of mitochondrial transmembrane potential. Based on their effects in tumor cells and isolated mitochondria, it is hypothesized that these drugs might, directly and indirectly, target components of the permeability transition pore to induce mitochondrial permeability transition and the release of proapoptotic factors. This review provides a summary of synthetic efforts and mechanistic endeavor.
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PMID:Syntheses, molecular targets and antitumor activities of novel triptycene bisquinones and 1,4-anthracenedione analogs. 1684 33

A polymerase chain reaction (PCR) method based on the gyrB (encoding gyrase B or topoisomerase II) gene sequence was developed for the detection of Vibrio vulnificus in seafood. The gyrB primers detected all laboratory isolates of V. vulnificus and did not cross react with other Vibiro and non-Vibrio species examined in this study. The sensitivity of detection of V. vulnificus by gyrB PCR was 300 CFU/g in artificially seeded oyster homogenate without enrichment while, 30 CFU/g could be detected following 18 h enrichment in alkaline peptone water (APW). The gyrB-specific PCR was employed for the direct detection of V. vulnificus in oyster enrichment broths. The assay detected V. vulnificus in 75% of natural oyster samples after 18 h enrichment in APW. The gyrB-based PCR described here offers a simple and specific one step PCR method for the detection of V. vulnificus in seafood enrichment broths.
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PMID:A gyrB-based PCR for the detection of Vibrio vulnificus and its application for direct detection of this pathogen in oyster enrichment broths. 1685 84


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