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 analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
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PMID:Synthesis, topoisomerase I inhibitory activity, and in vivo evaluation of 11-azacamptothecin analogs. 770 14

Polyomavirus (Py) large tumor antigen (LT) was produced in mammalian or insect cells infected with a suitable viral expression vector, and purified by a procedure combining immunoprecipitation with ion-exchange chromatography. Fractions containing the bulk of LT displayed a DNA-relaxing activity (LT-topo) which could be attributed neither to topoisomerase II (topo II) nor to topoisomerase I (topo I) encoded by the cell or the viral vector. On the one hand, LT-topo relaxed pBR322 DNA in a reaction which, unlike that characteristic of topo II, was ATP-independent and inhibited by camptothecin. On the other hand, serum from scleroderma patients which strongly inhibited calf thymus topo I had no effect on LT-topo, which absolutely required Mg2+ ions to relax DNA. Thus, LT-topo is either inherent to LT or belongs to a LT-bound enzyme similar to, but distinct from, topo I.
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PMID:Topoisomerase activity associated with polyoma virus large tumor antigen. 777

Type I and II topoisomerase activities were partially purified from Pneumocystis carinii. The catalytic (strand-passing) activities of both enzymes were selectively inhibited by members of a series of dicationic-substituted bis-benzimidazoles compared with those of topoisomerases of mammalian (calf thymus) origin. The most active inhibitors of the parasite enzymes were also highly effective in an in vivo animal model of P. carinii pneumonia. Selected dicationic-substituted bis-benzimidazoles also strongly inhibited the induction of the topoisomerase I- and II-mediated cleavable complex, suggesting that the biologically active DNA minor groove-binding molecules inhibit the enzyme-DNA binding step of the topoisomerase reaction sequence. The apparent selectivities for the parasite enzymes and the low levels of toxicity to mammalian cells for the biologically active bis-benzimidazoles suggest that these compounds hold promise as effective therapeutic agents in the treatment of a life-threatening AIDS-related disease, P. carinii pneumonia.
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PMID:Selective inhibition of topoisomerases from Pneumocystis carinii compared with that of topoisomerases from mammalian cells. 781 Sep 95

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

Topoisomerase II alpha (170 kDa) expressed in human HL-60 cells is heterogeneous in charge. By two-dimensional electrophoresis and chromatofocussing two major subforms with pI of 6.5 and 6.7 can be resolved. By preparative anion-exchange chromatography we separated the known topoisomerase II isoenzymes (170/180 kDa) and in addition a late-eluting 170 kDa form, which has not been described before. The catalytic optimum of this late-eluting form is shifted to pH 9.4. It is more than 100-fold resistant to orthovanadate, amsacrine or etoposide, and has an increased salt stability. SDS-treatment induces covalent attachment of this enzyme fraction to calf thymus DNA in the absence of drug. The latter observations indicate an increase in DNA-binding. In the tightly DNA-bound state the late-eluting enzyme is not targeted by cleavable complex forming drugs. Accordingly, cells may become drug-resistant by expressing this form predominantly.
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PMID:Drug-sensitivity and DNA-binding of a subform of topoisomerase II alpha in resistant human HL-60 cells. 799 49

Fungal metabolites with an epi-oligothiadiketopiperazine structure, TAN-1496 A, C and E, were isolated from the culture broth of Microsphaeropsis sp. FL-16144. Their molecular formulas were determined to be C22H28N2O9S2, C22H28N2O9S3 and C22H28N2O9S4, respectively. Structures were determined by comparing the NMR data with those of known diketopiperazine antibiotics, sirodesmins. These metabolites inhibited the relaxation of supercoiled pBR322 DNA by calf thymus topoisomerase I but did not affect the decatenation of kinetoplast DNA by calf thymus topoisomerase II at concentration up to 500 microM. They strongly suppressed the growth of various murine and human tumor cells and induced apoptosis. Moreover, various derivatives were synthesized to investigate the relationship of their functional groups and biological activities.
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PMID:TAN-1496 A, C and E, diketopiperazine antibiotics with inhibitory activity against mammalian DNA topoisomerase I. 800 82

In order to clarify the mechanism of topoisomerase II mediated DNA cleavage activity caused by intercalators (9-anilinoacridines), antitumor activities against murine P388 and calf thymus DNA topoisomerase II mediated DNA cleavage activities of compounds m-AMSA, A4P73, A3P56, and A3P166 have been studied. A4P73 was found to have potent antitumor and DNA cleavage activities.
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PMID:[Topoisomerase II mediated DNA strand cleavage and antitumor activities against murine leukemia P388 of novel acridines]. 801 39

New naphthacenecarboxamide antibiotics, TAN-1518 A and B, were isolated from a culture broth of Streptomyces sp. AL-16012. Their structures were elucidated from their reactions and from spectroscopic analyses. The relaxation of supercoiled pBR322 DNA by calf thymus DNA topoisomerase I was inhibited by these metabolites as potently as by camptothecin. However, the decatenation of kinetoplast DNA by calf thymus DNA topoisomerase II was little affected by these agents. The major metabolite, TAN-1518 A, strongly suppressed the growth of various murine and human tumor cells, inducing apoptosis. Unlike camptothecin, TAN-1518 A did not stimulate cleavable complex formation in the nuclei of CHO-K1 cells and had weak activity in intercalating into DNA strands. This metabolite arrested the growth of human tumor cell lines in G1 phase of the cell cycle. These results suggest that TAN-1518 A and B are novel antitumor agents targeting topoisomerase I.
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PMID:New naphthacenecarboxamide antibiotics, TAN-1518 A and B, have inhibitory activity against mammalian DNA topoisomerase I. 804 52

The DNA binding properties and effects on topoisomerase II of MePyGA, an anilinoacridine derivative bearing an N-methylpyrrolecarboxamide unit at position 1', have been compared with those of its precursor glycylanilinoacridine and the structurally related antileukaemic drug amsacrine. Electric linear dichroism spectroscopy reveals that MePyGA intercalates its acridine chromophore between DNA base pairs with a preference for GC-rich sequences, whereas both its structural analogue lacking the N-methylpyrrole unit and amsacrine intercalate into DNA without any strong sequence preference. The effects of the test drug on the catalytic activities of topoisomerase II were studied in vitro using purified calf thymus enzyme and 32P-labeled DNA. MePyGA stabilizes the topoisomerase II-DNA covalent complex and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. The removal of the N-methylpyrrole unit abolishes both the GC-preferential binding to DNA and the topoisomerase II-mediated DNA cleavage. MePyGA and amsacrine stimulate the cleavage of DNA by topoisomerase II at different places: cleavage stimulated by amsacrine is consistent with the expected adenine requirement at position +1 whereas the predominant sites of DNA cleavage stimulated by MePyGA contain a cytosine at position +/- 1. This is the first instance where an anilinoacridine derivative differing only by the nature of the substituent at position 1' has been found to affect the catalytic activity of topoisomerase II differently. The spectroscopic and biochemical data lead to the conclusion that two functional domains can be identified in MePyGA: its anilino group can be regarded as a skeletal core to which are connected (i) the tricyclic acridine moiety which represents the DNA-binding domain and (ii) the N-methylpyrrole moiety which constitutes the topoisomerase II-targeted domain. The structure of the substituent at position 1' of the anilinoacridine chromophore evidently determines the location of the sites of DNA cleavage by topoisomerase II. These findings provide guidance for the synthesis and development of new topoisomerase II-targeted antitumor anilinoacridine derivatives.
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PMID:Stimulation of site-specific topoisomerase II-mediated DNA cleavage by an N-methylpyrrolecarboxamide-anilinoacridine conjugate: relation to DNA binding. 806 Sep 93

The benzophenanthridine alkaloids nitidine and fagaronine were characterized as inhibitors of topoisomerase I function. In common with the antitumor agent camptothecin, both nitidine and fagaronine stabilized the covalent binary complex formed between calf thymus topoisomerase I and DNA. The effects of these compounds were readily apparent at 0.15-0.3 microM concentrations. Both nitidine and fagaronine inhibited the topoisomerase I-mediated relaxation of supercoiled pSP64 plasmid DNA more effectively than camptothecin; unlike camptothecin, both of these benzophenanthridine alkaloids also bound directly to and mediated the unwinding of B-form DNA. Nitidine and fagaronine were also studied in comparison with camptothecin to determine the sequence specificity of DNA breaks produced from a 32P-end-labeled duplex in the presence of topoisomerase I. All three compounds produced very similar cleavage patterns. The specificity of nitidine and fagaronine for inhibiting topoisomerase I function was studied by measuring the effects of the compounds on the unknotting of P4 DNA by calf thymus topoisomerase II. Moderate inhibition of topoisomerase II-mediated unknotting was obtained, but only in the presence of high (i.e., 40 microM) concentrations of nitidine and fagaronine. In comparison, doxorubicin inhibited topoisomerase II to the same extent as nitidine and fagaronine when it was employed at 2.5 microM concentration and was strongly inhibitory when employed at 10 microM concentration.
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PMID:Inhibition of topoisomerase I function by nitidine and fagaronine. 811 20


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