Gelation of the genome by topoisomerase II targeting anticancer agents

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

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The Efficacy of Topoisomerase II-Targeted Anticancer Agents Reflects the Persistence of Drug-Induced Cleavage Complexes in Cells†

Biochemistry ◽

10.1021/bi800981j ◽

2008 ◽

Vol 47 (45) ◽

pp. 11900-11908 ◽

Cited By ~ 34

Author(s):

Omari J. Bandele ◽

Neil Osheroff

Keyword(s):

Anticancer Agents ◽

Topoisomerase Ii ◽

Drug Induced ◽

In Cells

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Translocation t(4;11)(q21;q23) and MLL gene rearrangement in acute lymphoblastic leukemia secondary to anti topoisomerase II anticancer agents

Leukemia & Lymphoma ◽

10.3109/10428199709114180 ◽

1997 ◽

Vol 25 (3-4) ◽

pp. 399-401 ◽

Cited By ~ 9

Author(s):

F. Nasr ◽

E. Macintyre ◽

A. M. Venuat ◽

C. Bayle ◽

P. Carde ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Anticancer Agents ◽

Topoisomerase Ii ◽

Gene Rearrangement ◽

Lymphoblastic Leukemia ◽

Mll Gene ◽

Mll Gene Rearrangement

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S16020 pyridocarbazole derivatives display high activity to lung cancer cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211214104926 ◽

2021 ◽

Vol 21 ◽

Author(s):

Gabriela Chabowska ◽

Helena Moreira ◽

Beata Tylińska ◽

Ewa Barg

Keyword(s):

Cell Viability ◽

Anticancer Agents ◽

Topoisomerase Ii ◽

Wide Spectrum ◽

A549 Cells ◽

Biological Evaluation ◽

Dna Intercalation ◽

P Glycoprotein ◽

Low Toxicity ◽

And Migration

Background: Despite the dynamic development of medicine, globally cancer diseases remain the second leading cause of death. Therefore, there is a strong necessity to improve chemotherapy regimens and search for new anticancer agents. Pyridocarbazoles are compounds with confirmed antitumor properties based on multimodal mechanisms, i.a. DNA intercalation and topoisomerase II-DNA complex inhibition. One of them, S16020, displayed a wide spectrum of activity. Objective: The aim of the study was to investigate the antitumor potency of six S16020 derivatives, synthesized according to the SAR (structure-activity relationship) method. Methods: The biological evaluation included influence on cancer cell viability, proliferation, and migration, as well as P-glycoprotein activity. NHDF, A549, MCF-7, LoVo, and LoVo/DX cell lines were used in the study. Results: All derivatives displayed low toxicity to normal (NHDF) cells at 1 and 2 µM (≤ 20% of cell growth inhibition). The highest reduction in cell viability was noted in A549 cells which was accompanied by significant disruption of cells proliferation and motility. Compound 1 exhibited the strongest cytotoxic, antiproliferative, and antimigratory effects, higher than the reference olivacine. A significant reduction in P-glycoprotein activity was found for derivatives 6 and 1. Conclusion: S16020 derivatives could be considered as potential candidates for new anticancer drugs.

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

Bioinformation ◽

10.6026/97320630017249 ◽

2021 ◽

Vol 17 (1) ◽

pp. 249-265

Author(s):

Selvaraj Ayyamperumal ◽

Keyword(s):

Molecular Docking ◽

Anticancer Agents ◽

Active Sites ◽

Topoisomerase Ii ◽

Binding Free Energy ◽

Free Energy Calculations ◽

Dynamics Simulation ◽

Docking Analysis ◽

Topo Ii ◽

Molecular Docking Analysis

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.

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Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking

10.1101/2020.06.08.141176 ◽

2020 ◽

Author(s):

Maria ◽

Zahid Khan

Keyword(s):

Molecular Docking ◽

Cell Division ◽

Binding Energy ◽

Cancer Cells ◽

Anticancer Agents ◽

Combinatorial Library ◽

Topoisomerase Ii ◽

Computational Study ◽

Binding Energies ◽

Potential Inhibitors

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

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Topoisomerases as anticancer targets

Biochemical Journal ◽

10.1042/bcj20160583 ◽

2018 ◽

Vol 475 (2) ◽

pp. 373-398 ◽

Cited By ~ 98

Author(s):

Justine L. Delgado ◽

Chao-Ming Hsieh ◽

Nei-Li Chan ◽

Hiroshi Hiasa

Keyword(s):

Anticancer Drugs ◽

Anticancer Agents ◽

Topoisomerase Ii ◽

Therapeutic Targets ◽

Strand Break ◽

Cancer Type ◽

Topoisomerase Inhibitors ◽

Topoisomerase Ii Poisons ◽

Topoisomerase Poisons ◽

Replication Fork Arrest

Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

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