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)

10-[3-Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5] pyrrolo[2,3-g]isoquinoline (PZE) is an ellipticine derivative currently in clinical trials. PZE has been postulated to produce cellular DNA lesions by an uncommon mechanism. PZE-induced DNA damage was further investigated in L1210 cells in culture. PZE was highly cytotoxic for these cells (90% inhibitory concentration = 3.1 microM). The effects of PZE on cellular DNA were studied first by alkaline sucrose sedimentation, in comparison with those of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Like m-AMSA, PZE induced DNA strand breaks which were detected without a proteolytic treatment of the cell lysate. This result rules out the existence of covalent protein bridges sealing DNA termini at the break sites. PZE was less active than m-AMSA. DNA fragmentation was maximum at 5 microM and was lower at higher concentrations. The DNA effects of PZE were also studied by alkaline elution, and compared with those of Adriamycin and m-AMSA. Like Adriamycin, PZE induced single-strand breaks (SSBs) in a bell-shaped manner with respect to drug concentration. The maximum SSB frequency [1784 +/- 370 (SEM) rad equivalents)] was obtained at 16 microM. The kinetics of SSB reversion after drug removal was slower than in the case of m-AMSA. Similar bell-shaped curves were obtained for PZE-induced double-strand breaks and DNA-protein cross-links. PZE induced more double-strand breaks per SSB than did m-AMSA. However, as in the case of m-AMSA, PZE induced equal SSB and DNA-protein cross-link frequencies. These results suggest that PZE induces DNA breaks by inhibiting topoisomerase II as do other antitumor intercalators.
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PMID:Production of protein-associated DNA breaks by 10-[diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo [2,3-g]isoquinoline in cultured L1210 cells and in isolated nuclei: comparison with other topoisomerase II inhibitors. 283 Sep 64

Azonafide (2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de, h]isoquinoline-1,3-dione) is the parent of a new series of anthracene-containing antitumor agents. Its structure is based on amonafide but lacks a primary amine and has an anthracene chromophore rather than a naphthalene chromophore. Using a rat liver cytosol incubation and HPLC/MS detection, we have identified four metabolites resulting from in vitro metabolism of azonafide. These alkyl-modified derivatives include a mono- and a di-N'-desmethyl metabolite, an N'-oxide metabolite, and a carboxylic acid metabolite. Purified samples of these metabolites were analyzed for cytotoxic activity using a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium vital dye (mitochondrial reductase) assay and for inhibition of topoisomerase II (TOPO II) using a cell-free enzymatic system. Each metabolite had decreased cytotoxicity relative to azonafide with the following relative potencies in descending order: the mono-N'-desmethyl metabolite, di-N'-desmethyl metabolite, the N-oxide metabolite, and the carboxylic acid metabolite. Similarly, the N'-desmethyl metabolites retained TOPO II inhibitory activity but with lower potency than azonafide. The N-oxide and carboxylic acid metabolites did not inhibit TOPO II at 0. 05 and 0.5 microg/ml, respectively. Thus, metabolism of azonafide by rat liver cytosol represents a detoxification pathway rather than a bioactivation scheme for this DNA intercalator.
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PMID:Identification and characterization of in vitro metabolites of 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz [de,h]isoquinoline-1,3-dione (Azonafide). 945 95

DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2, 1-ethanediyl)]-bis(5-nitro-1H-benz[de]isoquinoline-1,3(2H)-dione] dimethanesulfonate) is a novel bis(naphthalimide) that has shown promising antitumor activity in a variety of preclinical model systems. The compound binds to DNA with high affinity and intercalates, but the mechanism of cell killing has not been elucidated. We have used yeast strains to test whether DMP-840 is active against either topoisomerase I or II. We found that temperature-sensitive top2 mutants resistant to etoposide or amsacrine also confer resistance to DMP-840. In addition, cells overexpressing yeast topoisomerase II were hypersensitive to the drug. By contrast, top1 deletions rendered cells hypersensitive to the drug. These results strongly suggest that DMP-840 acts against eukaryotic topoisomerase II and kills cells by converting the enzyme into a cellular poison. We verified that DMP-840 is active against eukaryotic topoisomerase II by demonstrating that the drug stimulates formation of a cleavage complex with purified yeast topoisomerase II in vitro. We also demonstrated that the drug is active against human topoisomerase II by showing that expression of human topoisomerase II restored sensitivity of resistant yeast cells to DMP-840. We have also directly demonstrated that DMP-840 acts as a poison against purified human topoisomerase II alpha. Taken together, these results indicate that DMP-840 acts like other intercalating topoisomerase II poisons; it kills eukaryotic cells by stabilizing the cleavage complex of topoisomerase II with DNA.
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PMID:The bis(naphthalimide) DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase II. 948 61

A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2. Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.
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PMID:Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons. 998 16

The DNA-binding properties of a series of 2-aza-anthracenedione (benz[g]isoquinoline-5,10-dione) derivatives bearing two 3-dimethylaminopropylamino side chains at different (6,9, 7,9 and 8,9) positions of the planar ring system have been investigated. The affinity for the nucleic acid is dramatically affected by the substitution pattern, the 6,9-regioisomer being substantially more effective than the 7,9- or the 8,9-congeners. This cannot be ascribed to different binding mechanisms, as all compounds are shown to intercalate into the double helix. Instead, the geometry of intercalation into DNA and the site specificity are extensively affected by the substitution pattern. The site preference is CA (or AC) for the 6,9-regioisomer, whereas it is TA (or AT) for the 8,9-congener, the 7,9-analogue lying in between. Molecular modeling studies are in agreement with the experimental results. Although the 6,9-regioisomer was remarkably cytotoxic, it stimulated topoisomerase II-mediated cleavage of DNA very poorly. Hence, a different mechanism of DNA damage is probably operating in 2-aza-anthracenediones as the main cell-killing event. Changes in affinity for DNA, intercalation geometry and sequence specificity can explain the different cytotoxic responses exhibited by the test drugs.
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PMID:Binding of bis-substituted 2-aza-anthracenedione regioisomers to DNA: effects of the relative positioning of the side chains. 1050 May 1

Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G(1) with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.
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PMID:Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. 1679 38

Lamellarin H has been shown to be active against the topoisomerase of the Molluscum contagiosum virus (MCV) and to have anti-HIV properties. 1-(3,4-dimethoxy-phenyl)-8,9-dimethoxy-2-(2,4,5-trimethoxy-phenyl)-pyrrolo[2,1-alpha] isoquinoline (intermediate 2) is the skeleton for the synthesis of lamellarin H and its derivatives. The synthesis of intermediate 2 is reported here in detail. The intermediate formed is identified by means of IR spectrum, UV spectrum, MS, (1)H NMR, (13)C NMR and melting point measurements.
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PMID:Pyrrolo[2,1-alpha]isoquinoline as a skeleton for the synthesis of bioactive lamellarin H. 1845 86

Chemical studies of the Chinese herb Corydalis saxicola Bunting led to the isolation and identification of 14 alkaloids, 1-14. Seven of these compounds, 4-9 and 11, were obtained from this plant for the first time. Feruloylagmatine (7) is the first guanidine-type alkaloid to be identified in the family Papaveraceae and in dicotyledonous plants. All of the isolated compounds were assayed for inhibitory activity against human DNA topoisomerase I. A DNA cleavage assay demonstrated that these alkaloids specifically inhibit topoisomerase through stabilization of the enzyme-DNA complex. Among the isolated alkaloids, (-)-pallidine (8) and (-)-scoulerine (11) showed strong inhibitory activities toward topoisomerase I that were comparable to camptothecin, a typical topoisomerase I inhibitor. A preliminary structure-activity relationship study suggested that the quaternary ammonium ion might play an important role in topoisomerase I inhibition by the isoquinoline alkaloids. These data indicated that DNA topoisomerase I inhibition represents probably one of the anticarcinogenic mechanisms of C. saxicola.
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PMID:DNA topoisomerase I inhibitory alkaloids from Corydalis saxicola. 1864 21

Bioactive alkaloids occupy an important position in applied chemistry and play an indispensable role in medicinal chemistry. Amongst them, isoquinoline alkaloids like berberine, palmatine and coralyne of protoberberine group, sanguinarine of the benzophenanthridine group, and their derivatives represent an important class of molecules for their broad range of clinical and pharmacological utility. In view of their extensive occurrence in various plant species and significantly low toxicities, prospective development and use of these alkaloids as effective anticancer agents are matters of great current interest. This review has focused on the interaction of these alkaloids with polymorphic nucleic acid structures (B-form, A-form, Z-form, H(L)-form, triple helical form, quadruplex form) and their topoisomerase inhibitory activity reported by several research groups using various biophysical techniques like spectrophotometry, spectrofluorimetry, thermal melting, circular dichroism, NMR spectroscopy, electrospray ionization mass spectroscopy, viscosity, isothermal titration calorimetry, differential scanning calorimetry, molecular modeling studies, and so forth, to elucidate their mode and mechanism of action for structure-activity relationships. The DNA binding of the planar sanguinarine and coralyne are found to be stronger and thermodynamically more favoured compared to the buckled structure of berberine and palmatine and correlate well with the intercalative mechanism of sanguinarine and coralyne and the partial intercalation by berberine and palmatine. Nucleic acid binding properties are also interpreted in relation to their anticancer activity.
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PMID:Polymorphic nucleic Acid binding of bioactive isoquinoline alkaloids and their role in cancer. 2081 27

The isoquinoline sulfonamide (H7) is an inhibitor of protein kinase C (PKC) that also inhibits the activity of cyclic nucleotide-dependent protein kinases. The effect of H7 on mitogen stimulation (G0 to G1 transition) of normal human lymphocytes and on their subsequent progression through the cell cycle was investigated and compared with the effect of this inhibitor on proliferation of human lymphocytic leukemic MOLT-4 cells. At H7 concentrations of 10 and 50 muM, the transition of G0 lymphocytes to the cell cycle was suppressed by 45 and 98%, respectively. The cell cycle progression of stimulated lymphocytes was unaffected at 10 muM H7, whereas, at 50 muM, the overall rate of progression was reduced by 50% with no evidence of cell arrest at a specific phase of the cycle. Similar concentrations of H7 (45 muM) suppressed proliferation of MOLT-4 cells by 50%, though, in the latter case, cells underwent transition to higher DNA ploidy, most likely via endoreduplication. Thus, the G0 to G1 transition appears to be the event most sensitive to H7. Exposure of MOLT-4 cells to 100 muM H7 for 24 h induced extensive apoptosis: activation of an endogenous nuclease with preference to internucleosomal linker DNA sections resulted in DNA degradation (revealed by agarose gel electrophoresis and loss of DNA measured by flow cytometry), which was paralleled by intracellular proteolysis, while the integrity of the plasma membrane, mitochondria and lysosomes was preserved. Morphological examination of these apoptotic cells confirmed DNA degradation. However, the perinuclear and fine-granular localization of the remaining DNA and lack of typical chromatin condensation and nuclear fragmentation differed from the classical pattern of apoptosis observed in other cell systems, suggesting that some events of apoptosis (nuclear fragmentation) may be affected by H7. The observed effects are consistent with the possible role of H7 in inhibition of PKC or its direct effect on the ATP-binding domain of DNA topoisomerase II, which shares homology with the H7 binding sites on PKC and the cyclic nucleotide-dependent protein kinases.
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PMID:The protein-kinase-C inhibitor h7 blocks normal human lymphocyte stimulation and induces apoptosis of both normal lymphocytes and leukemia molt-4 cells. 2157 14


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