Drugs Acting on the Beta Isoform of Human Topoisomerase II (p180)

Gatto, Barbara; Leo, Ester De

doi:10.2174/1568011033482486

Cited by 16 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transfer of chromosome 3 into the colorectal cancer cell line HCT116 introduces a wild-type copy of the hMLH1 gene but also the gene responsible for coding the topo IIα gene [102]. As 31 and indeed a number of other topo II poisons in addition target both isoforms (α and β) of topo II [103], the restored sensitivity is not only related to hMLH1. Interpretation of the real contribution of this MMR protein must therefore be treated with caution.…”

Section: Topoisomerase I/ii Inhibitorsmentioning

confidence: 99%

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Pors¹,

Patterson²

2005

CTMC

View full text Add to dashboard Cite

DNA Mismatch Repair (MMR) deficiency results in resistance to platinating and alkylating agents, DNA minor groove binders, inhibitors of topoisomerases and antimetabolites. The cellular MMR pathway, involving hMLH1 and MSH2, detects and repairs DNA frame shifts replication errors and regulates recombination events. Tumour cells are able to cope with DNA damage caused by chemotherapy as long as the MMR-process is disabled and hence there is a need to develop agents that (i) restore MMR proficiency or (ii) are hypersensitive in cells that are irreversibly MMR deficient. Decitabine is suggested to restore MMR function by reversal of gene promoter hypermethylation of hMLH1. However, when MMR is deficient due to gene mutation it is not feasible to design agents, since the absence of functional proteins that constitute the MMR machinery are not available as targets. The evidence that resistance to chemotherapy is associated with hMSH2 and/or hMLH1 deficiency has revealed a new paradigm for drug discovery of agents that positively exploit this phenotype to therapeutic advantage. Even more attractive is the development of agents that are hypersensitive in the absence of functional MMR to enable even more effective treatment. In this regard, established agents such as mitomycin C, camptothecin or novel hydroxyethylaminoanthraquinones may represent opportunities for exploitation of MMR-deficiency in tumour cells.

show abstract

Section: Topoisomerase I/ii Inhibitorsmentioning

confidence: 99%

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Pors¹,

Patterson²

2005

CTMC

View full text Add to dashboard Cite

show abstract

“…It has, therefore, been suggested that designing more specific drugs targeting only α-Topo II without stimulating β-Topo II which cause chromosome rearrangements, may be beneficial for cancer treatment [ 10 , 11 ]. α-Topo II concentration is known to increase 2-3 fold during G2/M phase of the cell cycle and orders of magnitude are higher in rapidly proliferating cells than in quiescent cell populations [ 12 , 13 ]. After binding to DNA, it produces a double-strand DNA break by nucleophilic attack on a pair of tyrosine residues [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents

Ayyamperumal

Tallapaneni

et al. 2021

Bioinformation

View full text Add to dashboard Cite

The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.

show abstract

“…This is in line with the isolation of amsacrine‐resistant mutants with modified β isoforms and further supports the role played by the amsacrine side chain even when connected to a different planar system. In addition, the presence of the β isoform in non‐proliferating cells suggests that drug preferentially aimed at this isoenzyme might be active in slow‐growing tumors, generally poorly responsive to chemotherapy . Finally, it is worth recalling the lack of cross‐resistance (Table ) with anthracycline resistant cells, which confirms the prevalence of the amsacrine related portion of the hybrids in recognizing the topoisomerase II‐DNA cleavable complex and, as a consequence, in affecting cytotoxic response.…”

Section: Discussionmentioning

confidence: 94%

Novel Ametantrone–Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents

Zagotto

Gianoncelli

Sissi

et al. 2014

Archiv der Pharmazie

View full text Add to dashboard Cite

The precise definition of the structural requirements for effective topoisomerase II poisoning by drug molecules is still an elusive issue. In the attempt to better define a pharmacophoric pattern, we prepared several conjugates combining the chemical features of two well-known topoisomerase II poisons, amsacrine and ametantrone. Indeed, an appropriate fusion geometry, which entails the anthracenedione moiety of ametantrone appropriately connected to the methanesulfonamidoaniline side chain of amsacrine, elicits DNA-intercalating properties, the capacity to inhibit the human topoisomerase IIβ isoform, and cytotoxic activity resembling that of the parent compounds. In addition, the properties of the lateral groups linked to the anthracenedione group play an important role in modulating DNA binding and cell cytotoxicity. Among the compounds tested, 10, 11, and 19 appear to be promising for further development.

show abstract

Drugs Acting on the Beta Isoform of Human Topoisomerase II (p180)

Cited by 16 publications

References 0 publications

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

DNA Mismatch Repair Deficiency, Resistance to Cancer Chemotherapy and the Development of Hypersensitive Agents

Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents

Novel Ametantrone–Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents

Contact Info

Product

Resources

About