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)

We report the synthesis, interaction with DNA, topoisomerase II inhibition, and cytotoxicity of two novel unfused aromatic dications derived from the antimicrobial agent furimidazoline. The central diphenylfuran core of furimidazoline has been replaced with a trithiophene (DB358) or a trifuran (DB669) unit and the terminal imidazoline groups were preserved. The strength and mode of binding of the drugs to nucleic acids were investigated by complementary spectroscopic techniques including spectrophotometric, surface plasmon resonance, circular and linear dichroism measurements. The trifuran derivative forms intercalation complexes with double-stranded DNA, whereas the mode of binding of the trithiophene derivative varies depending on the drug/DNA ratio, as independently confirmed by NMR spectroscopic studies performed with (A-T)7 and (G-C)7 oligomers. Two-dimensional NMR data provided a molecular model for the binding of DB358 within the minor groove of the AATT sequence of the decanucleotide d(GCGAATTCGC)(2). DNase I footprinting experiments confirmed the sequence-dependent binding of DB358 to DNA. The trithiophene derivative interacts preferentially with AT-rich sequences at low concentrations, but can accomodate GC sites at higher concentrations. DNA relaxation assays revealed that DB358 stimulated DNA cleavage by topoisomerase II, in contrast to DB669. The substitution of N-alkylamidines for the imidazoline terminal groups abolished the capacity of the drug to poison topoisomerase II. At the cellular level, flow cytometry analysis indicated that DB358, which is about six times more cytotoxic than the trifuran analogue, induced a significant accumulation of HL-60 human leukemia cells in the G2/M phase. The incorporation of thiophene heterocycles appears as a convenient procedure to limit the strict AT selectivity of dications containing an extended unfused aromatic system and to design cytotoxic DNA intercalating agents acting as poisons for human topoisomerase II.
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PMID:Novel dications with unfused aromatic systems: trithiophene and trifuran derivatives of furimidazoline. 1182 89

interaction of 7-amino-2-(6'-carboxy-2'-pyridyl)-6-methoxy-5,8-quinolinedione, an ABC ring analogue of the antitumour antibiotic streptonigrin, with zinc(II), oligonucleotides and DNA in the presence of zinc(II), and on the relaxation of DNA by topoisomerase II, has been studied. This ligand contains the key functional groups present in streptonigrin required for biological activity, but lacks the phenolic ring D which confers optical activity on streptonigrin. Variable temperature NMR experiments showed that in the presence of zinc(II) triflate, the methyl ester of the ligand forms a mixture of 1:1 and 1:2 metal:ligand bipyridyl complexes, whose relative stabilities are temperature dependent. Titrations of the water-soluble ligand with zinc(II) nitrate at room temperature showed that the predominant species present in aqueous solution at physiological pH is the 1:1 bipyridyl complex. The interaction of the ligand with the hexanucleotides d(GCATGC)2 and d(ATGCAT)2 was studied by 1H- and 31P-NMR spectroscopy. In the presence of 1 equiv of zinc(II) nitrate and 1 equiv of the ligand, small changes in chemical shifts of the proton resonances associated with the purine resonances were detected consistent with a weak interaction of the zinc(II) complex of the ligand with the oligonucleotides, possibly via a groove binding mechanism. UV-VIS titrations showed a weak interaction of the ligand with calf thymus DNA and poly(dG-dC)2 in the presence of zinc(II) but negligible interaction with poly(dA-dT)2. Gel electrophoresis experiments showed that, in contrast to streptonigrin, the ligand did not inhibit the relaxation of plasmid DNA by human topoisomerase II. These results show that the interaction of the ABC ligand with zinc(II), oligonucleotides, DNA and topoisomerase II is different to streptonigrin and hence the design of biologically active ABC ring analogues of streptongrin that operate via different mechanisms should be possible.
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PMID:The role of ring D in the antitumour antibiotic streptonigrin: metal complexation, DNA binding and topoisomerase inhibition by ABC ring analogues of streptonigrin. 1196 12

Two new pyrroloquinoline alkaloids, isobatzelline E (1) and batzelline D (2), together with the known compounds batzelline C (3), isobatzelline C (4), and makaluvamine D (5), were isolated from an Indopacific collection of the marine sponge Zyzzya fuliginosa; the known compounds makaluvamines A (9), H (10), J (7), K (8), and P (6) were obtained from Z. fuliginosa collected in Papua New Guinea. The structures were elucidated by interpretation of 1D (1)H and (13)C NMR spectra and 2D HSQC and HSQC-LR spectra. Compounds 1-10 were isolated because the crude extracts of both Zyzzya species inhibited HIV-1 envelope-mediated cell fusion. However, the inhibition profile observed for the pure compounds 1-10 mirrors that reported for the inhibition of topoisomerase II by other pyrroloquinolines, leaving open the possibility that the activity results from interactions with DNA-modifying enzymes.
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PMID:Batzelline D and isobatzelline E from the indopacific sponge Zyzzya fuliginosa. 1202 67

Three new lanostane-type triterpenoids (1-3) were isolated from the bark of Abies sachalinensis along with a known compound (4). The structures of 1-4 were characterized by spectroscopic methods including NMR and MS. Compound 4 and some derivatives were tested for inhibitory effects on in vitro DNA topoisomerases I and II and found to be selective catalytic inhibitors of topoisomerase II activity with IC(50) values in the range 43-76 microM.
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PMID:Triterpenoid constituents isolated from the bark of Abies sachalinensis. 1244 93

In this study we have identified a new structural motif for a ligand with G-quadruplex interaction that results in biological effects associated with G-quadruplex-interactive compounds. Fluoroquinolones have been reported to possess weak telomerase inhibitory activity in addition to their better known bacterial gyrase poisoning. Starting with a fluoroquinobenzoxazine, which has modest potency in a human topoisomerase II assay, we have designed a more potent inhibitor of telomerase that has lost its topoisomerase II poisoning activity. This fluoroquinophenoxazine (FQP) interacts with G-quadruplex structures to inhibit the progression of Taq polymerase in a G-quadruplex polymerase stop assay. In addition, we demonstrate by 1H NMR studies that this compound interacts with telomeric G-quadruplex structures by external stacking to the G-tetrad with both the unimolecular fold-over and the parallel G-quadruplex structures. A photocleavage assay confirms the FQP interaction site, which is located off center of the external tetrad but within the loop region. Molecular modeling using simulated annealing was performed on the FQP-parallel G-quadruplex complex to determine the optimum FQP orientation and key molecular interactions with the telomeric G-quadruplex structure. On the basis of the results of these studies, two additional FQP analogues were synthesized, which were designed to test the importance of these key interactions. These analogues were evaluated in the Taq polymerase stop assay for G-quadruplex interaction. The data from this study and the biological evaluation of these three FQPs, using cytotoxicity and a sea urchin embryo system, were in accord with the predicted more potent telomeric G-quadruplex interactions of the initial lead compound and one of the analogues. On the basis of these structural and biological studies, the design of more potent and selective telomeric G-quadruplex-interactive compounds can be envisaged.
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PMID:Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects. 1246 28

A novel inhibitor of topoisomerase II designated as 2070-DTI was isolated from the culture filtrate of Streptomyces sp. strain No. 2070. The structure was determined to be that of the known soyasaponin I on the basis of spectroscopic methods (NMR and MS). 2070-DTI strongly inhibited the decatenation activity of human placenta topoisomerase II in a noncompetitive manner, and weakly inhibited or was inert towards the relaxation activities of various topoisomerase I's and DNA-related enzymes. 2070-DTI is an inhibitor belonging to the cleavable complex-nonforming type without DNA intercalation.
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PMID:2070-DTI, a topoisomerase inhibitor produced by Streptomyces sp. strain No. 2070. 1500 14

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

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


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