scholarly journals Identification of potent catalytic inhibitors of human DNA topoisomerase II by structure-based virtual screening

MedChemComm ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 1142-1146 ◽  
Author(s):  
Guoqiang Dong ◽  
Ying Wu ◽  
Ying Sun ◽  
Na Liu ◽  
Shanchao Wu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Antiproliferative Activity ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Catalytic Inhibitor ◽  
Anticancer Drug Discovery

Structure-based virtual screening was performed and led to 14 novel Top2 catalytic inhibitors. Compound 8 was proven to be a Top2 catalytic inhibitor and showed good in vitro antiproliferative activity. It holds great potential for further hit-to-lead development in anticancer drug discovery.

The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

2012 ◽  
Vol 82 (1) ◽  
pp. 134-141 ◽  
Author(s):  
Céline Auzanneau ◽  
Danièle Montaudon ◽  
Rémi Jacquet ◽  
Stéphane Puyo ◽  
Laurent Pouységu ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Catalytic Inhibitor

NUP98 Translocation Breakpoints in Treatment-Related MDS Are Drug-Stimulated DNA Topoisomerase II Cleavage Sites.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1970-1970
Author(s):  
Christos P. Kolaris ◽  
Mingli Liu ◽  
Katie Foote ◽  
Peter D. Aplan ◽  
Harish G. Ahuja ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Chromosome Band ◽  
Nuclear Pore ◽  
Cleavage Sites ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Catalytic Inhibitor ◽  
Translocation Breakpoints ◽  
Dose Dependent

Abstract Chemotherapeutic DNA topoisomerase II (top2) poisons (i.e. agents that stabilize the top2 covalent complex and have the overall effect of increasing cleavage complexes) have been implicated in the treatment complication of leukemia characterized by balanced translocations, among which are translocations of the NUP98 gene at chromosome band 11p15. NUP98, which encodes a 98-kd docking protein in the nuclear pore complex, is disrupted by translocations in de novo and chemotherapy-related leukemias and has ~15 partner genes encoding proteins of diverse function. There have been no studies to delineate the mechanism whereby top2 poisons result in DNA damage leading to NUP98 translocations. Previously we described the TOP1 gene at chromosome band 20q11 as a recurring partner gene of NUP98 in 2 cases of treatment-related MDS (Ahuja 2000). The first patient was treated 9 years before for ALL with therapy including doxorubicin (ADR), daunorubicin and etoposide (VP). The second patient received VP and ADR in therapy for non-Hodgkin’s lymphoma and MDS was diagnosed 14 months after the primary cancer. In both cases, the NUP98 breakpoints were in intron 13 and the TOP1 breakpoints were in intron 7, though at distinct locations (Ahuja 2000). Sequencing of the breakpoint junctions on both derivative chromosomes showed near-precise recombinations relative to the germline sequences, indicating that the translocation breakpoints were at the sites of damage. Here, to interrogate whether drugs to which the patients were exposed stimulated formation of top2 cleavage complexes at these sites of damage, DNA substrates from germline NUP98 and TOP1 sequences were utilized in top2 in vitro cleavage assays, which entail trapping the cleavage complexes and mapping the cleavage sites in the sequence. ADR was examined over a range of concentrations because of its known effects of cleavage stimualtion at low concentrations and, at high concentrations, top2 catalytic inhibition due to intercalation. Etoposide and its catechol and quinone metabolites stimulated strong, heat stable top2 cleavage at several sites proximal to the NUP98 and TOP1 translocation breakpoints. At low concentration (~0.01μM) ADR also enhanced cleavage in a NUP98 substrate at several sites near the translocation breakpoint while dose-dependent cleavage diminution occurred at higher concentrations. Dose-response experiments with ADR are in progress using TOP1 substrates. Prior models based on the coincidence of in vitro top2 cleavage sites with cloned translocation breakpoints in MLL and partner genes or in PML and RARA and feasibility of resolution of the cleavage sites to form the respective breakpoint junctions have suggested drug-stimulated top2 cleavage as the relevant damage mechanism in other translocations (Whitmarsh 2003; Mistry 2003). The results of the present study support a model in which the chromosomal breakage leading to chemotherapy-related NUP98-TOP1 translocations is a consequence of drug-stimulated top2 cleavage also. Dose-dependent dual effects of ADR as a poison and a catalytic inhibitor of top2 function with respect to the sequence of a specific leukemia-associated gene have implications for its role in the genesis of translocations.

The in vivo distribution and dynamics of DNA topoisomerase II in Drosophila embryonic nuclei and chromosomes

1993 ◽  
Vol 51 ◽  
pp. 74-75
Author(s):  
Jason R. Swedlow ◽  
Neil Osheroff ◽  
Tim Karr ◽  
John W. Sedat ◽  
David A. Agard
Keyword(s):  
Topoisomerase Ii ◽  
Biochemical Characterization ◽  
Developmental Cycle ◽  
Dna Topoisomerase Ii ◽  
Chromosomal Distribution ◽  
Dna Topoisomerase ◽  
Ideal System ◽  
Dnase Treatment

DNA topoisomerase II is an ATP-dependent double-stranded DNA strand-passing enzyme that is necessary for full condensation of chromosomes and for complete segregation of sister chromatids at mitosis in vivo and in vitro. Biochemical characterization of chromosomes or nuclei after extraction with high-salt or detergents and DNAse treatment showed that topoisomerase II was a major component of this remnant, termed the chromosome scaffold. The scaffold has been hypothesized to be the structural backbone of the chromosome, so the localization of topoisomerase II to die scaffold suggested that the enzyme might play a structural role in the chromosome. However, topoisomerase II has not been studied in nuclei or chromosomes in vivo. We have monitored the chromosomal distribution of topoisomerase II in vivo during mitosis in the Drosophila embryo. This embryo forms a multi-nucleated syncytial blastoderm early in its developmental cycle. During this time, the embryonic nuclei synchronously progress through 13 mitotic cycles, so this is an ideal system to follow nuclear and chromosomal dynamics.

Antitumor Agents, 107. New Cytotoxic 4-Alkylamino Analogues of 4'-Demethyl-Epipodophyllotoxin as Inhibitors of Human DNA Topoisomerase II

1989 ◽  
Vol 52 (3) ◽  
pp. 606-613 ◽  
Author(s):  
Kuo-Hsiung Lee ◽  
Yasuhiro Imakura ◽  
Mitsumasa Haruna ◽  
Scott A. Beers ◽  
Lee S. Thurston ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Antitumor Agents ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna

The C-terminal domain of Saccharomyces cerevisiae DNA topoisomerase II

1994 ◽  
Vol 14 (5) ◽  
pp. 3197-3207
Author(s):  
P R Caron ◽  
P Watt ◽  
J C Wang
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nuclear Localization ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Mutant Proteins ◽  
Terminal Domain ◽  
Catalytically Active

A set of carboxy-terminal deletion mutants of Saccharomyces cerevisiae DNA topoisomerase II were constructed for studying the functions of the carboxyl domain in vitro and in vivo. The wild-type yeast enzyme is a homodimer with 1,429 amino acid residues in each of the two polypeptides; truncation of the C terminus to Ile-1220 has little effect on the function of the enzyme in vitro or in vivo, whereas truncations extending beyond Gln-1138 yield completely inactive proteins. Several mutant enzymes with C termini in between these two residues were found to be catalytically active but unable to complement a top2-4 temperature-sensitive mutation. Immunomicroscopy results suggest that the removal of a nuclear localization signal in the C-terminal domain is likely to contribute to the physiological dysfunction of these proteins; the ability of these mutant proteins to relax supercoiled DNA in vivo shows, however, that at least some of the mutant proteins are present in the nuclei in a catalytically active form. In contrast to the ability of the catalytically active mutant proteins to relax supercoiled intracellular DNA, all mutants that do not complement the temperature-dependent lethality and high frequency of chromosomal nondisjunction of top2-4 were found to lack decatenation activity in vivo. The plausible roles of the DNA topoisomerase II C-terminal domain, in addition to providing a signal for nuclear localization, are discussed in the light of these results.

scholarly journals Phaeophytins from Thyrsacanthus ramosissimus Moric. with inhibitory activity on human dna topoisomerase II-α

Química Nova ◽  
2012 ◽  
Vol 35 (11) ◽  
pp. 2222-2225 ◽  
Author(s):  
Analúcia Guedes Silveira Cabral ◽  
Fábio Henrique Tenório-Souza ◽  
Marcelo Dantas Moura ◽  
Sabrina Gondim Ribeiro Mota ◽  
Antônio Cláudio da Silva Lins ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna
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