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)

An array of novel 2-acyl-1,2-dihydroellipticines was prepared and evaluated for in vitro cytotoxicity in a variety of human cancer cell lines. The ellipticine analogs were also tested for inhibition of topoisomerase II in both decatenation and cleavable complex formation assays. Some of the new ellipticine derivatives were prepared by acylation of ellipticine with acid chlorides in tetrahydrofuran, followed by reduction of the intermediate 2-acylellipticinium ions with sodium cyanoborohydride. Others were synthesized by acylation of ellipticine with p-nitrophenyl chloroformate, reduction of the 2-acylellipticinium ion with sodium cyanoborohydride, and displacement of the p-nitrophenoxide anion with a variety of oxygen and nitrogen nucleophiles. The cytotoxicities of the new 2-acyl-1,2-dihydroellipticines varied widely, and correlated well with their topoisomerase II inhibitory activities.
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PMID:Synthesis of a series of cytotoxic 2-acyl-1,2-dihydroellipticines which inhibit topoisomerase II. 867 54

A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2-chloro substituent to DACA suppresses the stimulation of topoisomerase II-dependent DNA cleavage but increases stimulation of topoisomerase I cleavage. 2-Substitution also increases activity against the "atypical" multidrug resistant cell lines. Overall, the results suggest that augmentation of topoisomerase I-dependent activity in this series by appropriate chemical substitution in this series leads to circumvention of topoisomerase II-mediated multidrug resistance.
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PMID:From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives. 869 77

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
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PMID:Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. 889 41

The origin of cancer chemotherapy can be traced to the wartime discovery of the lymphotoxic action of nitrogen mustards. These and other bifunctional agents were later found to produce various types of DNA cross-links, and some of these agents continue to be mainstays of current therapy. The cellular pharmacology of these drugs was studied extensively during the 1970s and 1980s by means of DNA filter elution methodology. In the course of these investigations, DNA topoisomerases were discovered to be targets of anthracyclines and several other classes of anticancer drugs. DNA cross-linkers and topoisomerase blockers have generally similar cytotoxic mechanisms, which depend on DNA damage detection, DNA repair, cell cycle arrest, and cell death by apoptosis. The molecular control of these processes, involving oncogenes and tumor suppressor genes, is being revealed by current research. Cancer cells often have defects within these control systems, and these defects may confer selective sensitivity to appropriately designed drug therapy. Panels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities. Such correlations could guide the selection of drugs for therapy based on molecular diagnosis of individual tumors.
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PMID:Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture. 897 Nov 50

We studied the role of DNA topoisomerase II in the biological actions of a series of novel alkylaminoanthraquinones, including N-oxide derivatives designed as prodrugs liable to bioreductive activation in hypoxic tumour cells. Drug structures were based upon the DNA-binding anticancer topoisomerase II poison mitoxantrone with modifications to the alkylamino side chains. The agents included AQ4, 1,4-bis{[2-(dimethylamino)ethyl] amino}5,8-dihydroxy-anthracene-9,10-dione, and AQ6, 1{[2-dimethylamino)-ethyl]amino}4-{[2[(hydroxyethyl)amino]ethyl]- amino}5,8-dihydroxy-anthracene-9,10-dione, together with the corresponding mono-N-oxide (AQ6NO) and di-N-oxide (AQ4NO). The R3N(+)-O- modification renders the terminal nitrogen group electrically neutral and was found to reduce AQ6NO or effectively abolish AQ4NO-DNA binding. Comparative studies were carried out using two SV40-transformed fibroblast cell lines, MRC5-V1 and AT5BIVA, the latter being a relative overproducer of DNA topoisomerase II alpha. The inhibition of DNA topoisomerase II decatenation activity ranked according to DNA-binding capacity. A similar ranking was found for drug-induced DNA-protein cross-linking in intact cells, depending upon topoisomerase II availability. Inhibition of DNA synthesis in S-phase synchronized cultures ranked in the order of AQ6 > mitoxantrone > > AQ6NO and was independent of topoisomerase II availability. Cytotoxicity of acute 1-h exposures for all agents except the inactive AQ4NO was enhanced in the topoisomerase II-overproducing cell line. The results indicate an important role for enzyme targeting in anthraquinone action. However, DNA synthesis inhibition and cytotoxicity were greater than expected for AQ6, given its topoisomerase- and DNA-interaction properties, and parallel studies have provided evidence of an additional role for enhanced subcellular accumulation and nuclear targeting. The inactivity of AQ4NO and the retention of only partial activity of AQ6NO, allied with the effective topoisomerase II-targeting and high cytotoxic potential of their presumed metabolites, favour their use as prodrugs in tumour cells with enhanced bioreductive potential.
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PMID:DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. 905 61

A Chinese hamster ovary cell line resistant to okadaic acid (OA), OAR2-3 has a mutation of the protein phosphatase (PP) 2A alpha gene and expresses a multi-drug resistance (MDR) phenotype. In the present work, we isolated two additional OA-resistant variants, also showing MDR with a cross-resistance profile similar to that of OAR2-3, and with increased and decreased expressions of the P-glycoprotein (Pgp) and DNA topoisomerase (topo) II protein, respectively. Unlike OAR2-3, however, they had no mutation in the same region of the PP2A alpha gene. Except for OA-resistance in OAR2-3, the MDR was found to decrease in the absence of OA, and this decrease was again associated with changes in topo II- and Pgp-expressions. Thus, we conclude that 1) OA regulates the expressions of Pgp and topo II positively and negatively, respectively, resulting in reversible expression of MDR irrespective of genetic changes and 2) in OAR2-3, the mutation in the PP2A alpha gene confers stable resistance to OA. The MDR was also linked with collateral sensitivity to some drugs, like cisplatin and nitrogen mustard.
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PMID:Unstable expression of the multi-drug-resistant phenotype in Chinese hamster ovary cells resistant to okadaic acid. 912 89

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.
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PMID:Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. 934 21

The antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that mitindomide is a catalytic/noncleavable complex-forming-type inhibitor of topoisomerase II. The growth inhibitory effects of mitindomide and dexrazoxane toward a sensitive parent CHO cell line and the dexrazoxane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine dexrazoxane, were measured. The DZR cell line was shown to be 30-fold cross-resistant to mitindomide. Mitindomide, like dexrazoxane, was shown to inhibit cleavable complex formation by the topoisomerase II poison etoposide. The attenuated inhibition of etoposide-induced cleavable complexes in DZR compared with CHO cells was, likewise, very similar for dexrazoxane and mitindomide. Together these results suggest that mitindomide acts at the same site on topoisomerase II as does dexrazoxane and other bisdioxopiperazines. Various molecular parameters obtained by molecular modeling were compared for mitindomide and dexrazoxane. Mitindomide, which is conformationally very rigid, has highly coplanar imide rings, as does dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imide nitrogen bond distances, and polar and nonpolar surface areas were also very similar. Thus, it is concluded that mitindomide exerts its antitumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.
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PMID:Mitindomide is a catalytic inhibitor of DNA topoisomerase II that acts at the bisdioxopiperazine binding site. 935 75

DNA topoisomerases regulate the organization of DNA and are important targets for many clinically used antineoplastic agents. In addition, DNA topoisomerases modulate the cellular sensitivity toward a number of DNA damaging agents. Increased topoisomerase II activities were shown to contribute to the resistance of both nitrogen mustard- and cisplatin-resistant cells. Similarly, cells with decreased topoisomerase II levels show increased sensitivity to cisplatin, carmustine, mitomycin C and nitrogen mustard. Recent studies propose that topoisomerases may be involved in damage recognition and DNA repair at several different levels including: 1) the initial recognition of DNA lesions; 2) DNA recombination; and 3) regulation of DNA structure. The stress-activated oncogene suppressor protein p53 can modulate the activity of at least three different human topoisomerases, either directly by molecular associations or by transcriptional regulation. Since DNA topoisomerases have considerable recombinase activities, inappropriately activated topoisomerases in tumor cells lacking functional p53 may contribute to the genetic instability of these cells.
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PMID:DNA topoisomerases as repair enzymes: mechanism(s) of action and regulation by p53. 982 82

Topoisomerase II is a cellular target for a number of clinically relevant antitumor drugs. To elucidate the possible cellular target for the antiproliferation activity of cobalt salicylaldoxime (CoSAL), which inhibits 50% of leukemic cell proliferation at a concentration of 60 microM, DNA binding studies and studies of the action of this complex on topoisomerase II catalytic activities were carried out. The results from DNA binding studies show that CoSAL binds DNA strongly with a stoichiometric ratio of two drug molecules for five nucleotide bases and shows a mode of interaction similar to that of DNA groove binding agents. The results from topoisomerase II inhibition studies show that the complex inhibits the relaxation activity of topoisomerase II in a dose-dependent manner and poisons its activity through cleavage complex formation. To see if the hydroxyl group present on imine nitrogen is involved in topoisomerase II poisoning, we synthesized an analogue of CoSAL in which the hydroxyl group was replaced with semicarbazone. This complex too binds DNA with an affinity similar to that of CoSAL, but with a small difference in the mode of interaction; however, it marginally inhibits leukemic cell proliferation and does not inhibit topoisomerase II activity, which suggests the involvement of a hydroxyl group. An immunoprecipitation assay was conducted which showed that the cleavage complex formed in the presence of CoSAL contained 75% of the complex, while the other complex shows only 7. 65%. Cyclic voltametric spectra of the complexes in the presence of DNA show that they do not oxidize DNA. These results suggest that CoSAL shows a bidirectional mode of interaction with enzyme and DNA and inhibits topoisomerase II activity by forming a drug-mediated cleavage complex. Our data strongly suggest that topoisomerase II may be one of the cellular targets for antiproliferation activity of CoSAL.
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PMID:Topoisomerase II is a cellular target for antiproliferative cobalt salicylaldoxime complex. 1046 41


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