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)

Two widely used biological buffers [tris(hydroxymethyl)aminomethane (TRIS) and phosphate] covalently react with the topoisomerase II inhibitor clerocidin, affecting the drug's reactivity profile. Comprehensive analytical and structural analysis obtained by LC/MS, MS/MS, NMR, and IR techniques shows that these buffers form reversible and irreversible adducts through reactions with chemical groups, such as carbonyls, aldehydes, and epoxide. Analysis of the kinetic data on adducts formation suggests two parallel mechanisms for the inhibition of drug activity. The first involves modulation of the reactivity of the epoxide group obtained by elimination of the spiro system and relief of ring strain. This effect does not abolish epoxide reactivity and is more evident for the TRIS adduct, which can count on intramolecular stabilization of the form devoid of the spiro system. The second mechanism involves the slow nucleophilic attack to the epoxide ring, which results in permanent deactivation of the functional group responsible for topoisomerase II inhibition. This effect is predominant in phosphate buffer and is more evident for longer reaction times. These results provide a compelling reminder that the activity of chemically complex drugs in biological systems can be severely altered by buffer interactions, which may not be immediately predictable from the identity of the active group(s) and may require a more detailed knowledge of the subtle effects induced by vicinal groups.
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PMID:Effects of common buffer systems on drug activity: the case of clerocidin. 1508 91

Clerocidin (CL) is a topoisomerase II poison, which cleaves DNA irreversibly at guanines (G) and reversibly at cytosines (C). Furthermore, the drug can induce enzyme-independent strand breaks at the G and C level. It has been previously shown that G-damage is induced by alkylation of the guanine N7, followed by spontaneous depurination and nucleic acid cleavage, whereas scission at C is obtained only after treatment with hot alkali, and no information is available to explain the nature of this damage. We present here a systematic study on the reactivity of CL towards C both in the DNA environment and in solution. Selected synthetic derivatives were employed to evaluate the role of each chemical group of the drug. The structure of CL-dC adduct was then characterized by tandem mass spectrometry and NMR: the adduct is a stable condensed ring system resulting from a concerted electrophilic attack of the adjacent carbonyl and epoxide groups of CL towards the exposed NH(2) and N3, respectively. This reaction mechanism, shown here for the first time, is characterized by faster kinetic rates than alkylation at G, due to the fact that the rate-determining step, alkylation at the epoxide, is an intramolecular process, provided a Schiff base linking CL and C can rapidly form, whereas the corresponding reaction of G N7 is intermolecular. These results provide helpful hints to explain the reversible/irreversible nature of topoisomerase II mediated DNA damage produced by CL at C/G steps.
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PMID:Concerted bis-alkylating reactivity of clerocidin towards unpaired cytosine residues in DNA. 1549 53

Doxorubicin (trade name Adriamycin) is a widely used anticancer agent which exhibits good activity against a wide range of tumors. Although the major mode of action appears to be normally as a topoisomerase II poison, it also exhibits a number of other cellular responses, one of which is the ability to form adducts with DNA. For adduct formation doxorubicin must react with cellular formaldehyde to form an activated Schiff base which is then able to form an aminal (N-C-N) linkage to the exocyclic amino group of guanine residues. The mono-adducts form primarily at G of 5'-GCN-3' sequences where the chromophore of the drug is intercalated between the C and N base pair. The structure of the adducts has have been well defined by 2D NMR, mass spectrometry and X-ray crystallography. The formation of these anthracycline adducts in cells grown in culture has been unequivocally demonstrated. The source of formaldehyde in cells can be endogenous, provided by coadministration of prodrugs that release formaldehyde or by prior complexation of anthracyclines with formaldehyde. Since the adducts appear to be more cytotoxic than doxorubicin alone, and also less susceptible to drug-efflux forms of resistance, they offer new approaches to improving the anticancer activity of the anthracyclines.
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PMID:The power and potential of doxorubicin-DNA adducts. 1603 66

Mannich bases of gatifloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. The compounds were tested in-vitro against a panel of 58 human tumour cell lines derived from nine neoplastic diseases. Among them compound 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-(3'-sulphadoximino)-1'-(5-bromoisatinyl) methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (6) emerged as a potent anticancer agent being more active than standard DNA topoisomerase II inhibitor, etoposide against 30 cancer cell lines.
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PMID:Synthesis and in-vitro cytotoxicity evaluation of gatifloxacin Mannich bases. 1626 36

The aryl tetralin lignans are synthesized by Podophyllum sps. and are in great demand worldwide due to their use in synthesis of topoisomerase inhibitors. However, the sustained production of these aryl tetralin lignans requires large-scale harvesting from the natural environments, which has resulted in the plant-endangered status. In view of the difficulties in their total chemical synthesis, cultivation and failure of metabolic engineering approaches, there is a need to search for alternative sources of production of aryl tetralin lignans. We unequivocally established the methodology for isolation, identification, and characterization of a novel fungal endophyte (Trametes hirsuta) that produces aryl tetralin lignans consistently as shown by HPLC, LC-MS, LC/MS-MS and (1)H NMR. The lignans produced by the microorganism are biologically active, and exhibit potent antioxidant, anticancer and radioprotective properties. This strategy promises to improve the production of these therapeutically important compounds at lower costs.
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PMID:The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans. 1637 85

Resveratrol oligomers, nepalensinol A, B and C, were isolated from the stem of Kobresia nepalensis (Cyperaceae). The structures were established on the basis of chemical properties and spectroscopic evidence including 2D NMR spectroscopic analysis. Nepalensinol A, B and C showed a potent inhibitory effect on topoisomerase II -- stronger than etoposide (VP-16), a topoisomerase II inhibitor used as an anti-cancer drug. Nepalensinol B, in particular, exhibited the most potent activity with an IC(50) of 0.02 microg/ml.
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PMID:Stilbenoids of Kobresia nepalensis (Cyperaceae) exhibiting DNA topoisomerase II inhibition. 1637 91

Four new resveratrol oligomers, nepalensinols D-G, were isolated from the stem of Kobresia nepalensis (Cyperaceae). The structures were determined by detailed NMR spectral analysis. The compounds were assessed for their inhibitory activity against human topoisomerase II, a potential target of anti-tumor agents. These stilbenoids showed potent inhibitory activity against human topoisomerase II with IC50 values of 5-15 microM.
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PMID:Nepalensinols D-G, new resveratrol oligomers from Kobresia nepalensis (Cyperaceae) as potent inhibitors of DNA topoisomerase II. 1650 91

Plant polyphenols, as those present in teas, have been associated with several health benefits. In this study, the main objectives were to identify and characterize the phenolic compounds in Ardisia compressa tea (AC) responsible for topoisomerase inhibition using a bioassay directed approach and modern analytical techniques, and to determine the cytotoxicity against human colon carcinoma cells. Inhibition of topoisomerase was determined by yeast and human topoisomerase biochemical assays. Identification and characterization of AC phenolic compounds were carried out using combined HPLC, MS and NMR techniques. Cytotoxicity studies were conducted using two human colorectal adenocarcinoma cell lines, HT-29 and Caco-2. LC-MS analysis of AC confirmed the presence of gallic acid, epicatechin gallate, several proanthocyanidin dimers, kaempferol, naringenin and ardisin derivatives. Topoisomerase II catalytic inhibitory activity of AC was due mainly to phenolic compounds extracted in the butanolic fraction (IC50: 1.33 microg/ml). Purification of this fraction resulted in the isolation of several compounds: peak 10 (IC50: 8.32 microg/ml), peaks 12/14 (IC75: 2.85 microg/ml) and peak 15 (IC50: 7.16 microg/ml). Characterization of peak 15, the most active fraction, led to the isolation of a naringenin isomer (C15H12O5), which had a significantly higher catalytic anti-topoisomerase II activity (IC50: 7.16 microg/ml) than commercial naringenin (IC50: 88.1 microg/ml). AC was cytotoxic to HT-29 (IC50: 57.9+/-11.6 microg/ml) and Caco-2 cells (IC50: 81.0+/-27.5 microg/ml). These findings provide basic information and suggest the potential use of active flavonoids in Ardisia compressa tea as chemopreventive agents.
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PMID:Catalytic inhibition of human DNA topoisomerase by phenolic compounds in Ardisia compressa extracts and their effect on human colon cancer cells. 1654 Feb 25

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation, inhibition of topoisomerase II and cytochrome P450-mediated formation of covalent DNA adducts. This is the first report on the molecular mechanism of ellipticine oxidation by peroxidases (human myeloperoxidase, human and ovine cyclooxygenases, bovine lactoperoxidase, horseradish peroxidase) to species forming ellipticine-DNA adducts. Using NMR spectroscopy, the structures of 2 ellipticine metabolites were identified; the major product is the ellipticine dimer, in which the 2 ellipticine skeletons are connected via N(6) of the pyrrole ring of one ellipticine molecule and C9 in the second one. The minor metabolite is ellipticine N(2)-oxide. Using (32)P-postlabeling and [(3)H]-labeled ellipticine, we showed that ellipticine binds covalently to DNA after its activation by peroxidases. The DNA adduct pattern induced by ellipticine consisted of a cluster of up to 4 adducts. The 2 adducts are indistinguishable from the 2 major adducts generated between deoxyguanosine in DNA and either 13-hydroxy- or 12-hydroxyellipticine or in rats treated with ellipticine, or if ellipticine was activated with human hepatic and renal microsomes. The results presented here are the first characterization of the peroxidase-mediated oxidative metabolites of ellipticine and we have proposed species, 2 carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating 2 major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.
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PMID:Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine. 1706 55

Etoposide (VP-16), a DNA topoisomerase II poison widely used as an antineoplastic agent is also known to cause leukemia. One of its major metabolic pathways involves O-demethylation to etoposide catechol (etoposide-OH) by cytochrome P450 3A4 (CYP3A4). The catechol metabolite can undergo sequential one- and two-electron oxidations to form etoposide semi-quinone (etoposide-SQ) and etoposide quinone (etoposide-Q), respectively, which have both been implicated as cytotoxic metabolites. However, etoposide-Q is known to react with glutathione (GSH), which can protect DNA from oxidative damage by this reactive metabolite. In this study, etoposide-Q was reacted with GSH and the two etoposide-GSH conjugates were characterized. The major conjugate was etoposide-OH-6'-SG and the minor product was etoposide-OH-2'-SG. Etoposide-OH-6'-SG, which arose from Michael addition of GSH to etoposide-Q, was characterized by mass spectrometry and 2-D NMR. It was identified as the sole product from in vitro metabolism experiments using recombinant human CYP3A4 or liver microsomes incubated with etoposide in the presence of GSH. Etoposide-OH-6'-SG was also detected from incubations of etoposide-OH and GSH alone. Therefore, the presence of etoposide-OH, which can be formed from etoposide metabolism by CYP3A4, is essential for formation of the GSH conjugate. The oxidation of etoposide-OH to a quinone intermediate is likely the precursor in the formation of etoposide-OH-6'-SG.
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PMID:Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. 1716 90


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