Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents

2002 ◽  
Vol 45 (3) ◽  
pp. 721-739 ◽  
Author(s):  
Nigel Vicker ◽  
Luke Burgess ◽  
Irina S. Chuckowree ◽  
Rory Dodd ◽  
Adrian J. Folkes ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitors

Inhibitors of topoisomerases do not block the passage of human lymphocyte chromosomes through mitosis

1992 ◽  
Vol 103 (1) ◽  
pp. 105-115
Author(s):  
A.T. Sumner
Keyword(s):  
Chromosome Segregation ◽  
Human Lymphocyte ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Human Lymphocytes ◽  
Chromosome Breakage ◽  
Chromosome Condensation ◽  
Complete Fusion ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Inhibitors

Cultured human lymphocytes have been treated with a number of topoisomerase inhibitors, to see whether topoisomerase II is involved in the process of chromosome segregation at anaphase. Results were assessed by examination of cytogenetical preparations of spread chromosomes. Four effects were observed, although no inhibitor produced all four effects. These effects were: inhibition of entry into mitosis; chromosome breakage and rearrangement; inhibition of chromosome condensation; and inhibition of chromosome segregation. Evidence for the last was ambiguous. Although there was evidence that separation of chromatids was affected when cells were treated with colchicine as well as topoisomerase II inhibitors (most notably with nalidixic acid, which resulted in complete fusion of the chromatids), no evidence was obtained to show that, in the absence of colchicine, cells treated with inhibitors could not proceed through anaphase normally. The topoisomerase I inhibitor, camptothecin, differed from the topoisomerase II inhibitors in not showing any effect on chromosome condensation or any significant effect on segregation.

scholarly journals Drug resistance in topoisomerase-targeting therapy

2018 ◽  
Vol 72 ◽  
pp. 1073-1083 ◽  
Author(s):  
Karol Wtorek ◽  
Angelika Długosz ◽  
Anna Janecka
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Catalytic Domain ◽  
Cancer Drug ◽  
Anthracycline Antibiotics ◽  
Targeting Therapy

Drug resistance is a well-known phenomenon that occurs when initially responsive to chemotherapy cancer cells become tolerant and elude further effectiveness of anticancer drugs. Based on their mechanism of action, anticancer drugs can be divided into cytotoxic-based agents and target-based agents. An important role among the therapeutics of the second group is played by drugs targeting topoisomerases, nuclear enzymes critical to DNA function and cell survival. These enzymes are cellular targets of several groups of anticancer agents which generate DNA damage in rapidly proliferating cancer cells. Drugs targeting topoisomerase I are mostly analogs of camtothecin, a natural compound isolated from the bark of a tree growing in China. Drugs targeting topoisomerase II are divided into poisons, such as anthracycline antibiotics, whose action is based on intercalation between DNA bases, and catalytic inhibitors that block topoisomerase II at different stages of the catalytic cycle. Unfortunately, chemotherapy is often limited by the induction of drug resistance. Identifying mechanisms that promote drug resistance is critical for the improvement of patient prognosis. Cancer drug resistance is a complex phenomenon that may be influenced by many factors. Here we discuss various mechanisms by which cancer cells can develop resistance to topoisomerase-directed drugs, which include enhanced drug efflux, mutations in topoisomerase genes, hypophosphorylation of topoisomerase II catalytic domain, activation of NF-κB transcription factor and drug inactivation. All these events may lead to the ineffective induction of cancer cell death. Attempts at circumventing drug resistance through the inhibition of cellular efflux pumps, use of silencing RNAs or inhibition of some important mechanisms, which can allow cancer cells to survive therapy, are also presented.

Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors

2018 ◽  
Vol 144 ◽  
pp. 557-571 ◽  
Author(s):  
Manda Sathish ◽  
Botla Kavitha ◽  
V. Lakshma Nayak ◽  
Yellaiah Tangella ◽  
Ayyappan Ajitha ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Topoisomerase Ii Inhibitors

Design, synthesis, and biological and docking studies of novel epipodophyllotoxin–chalcone hybrids as potential anticancer agents

MedChemComm ◽  
2015 ◽  
Vol 6 (1) ◽  
pp. 94-104 ◽  
Author(s):  
Abid Hussain Banday ◽  
Vinod V. Kulkarni ◽  
Victor J. Hruby
Keyword(s):  
Click Chemistry ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Docking Studies ◽  
Efficient Synthesis ◽  
Design Synthesis ◽  
Topoisomerase Ii Inhibitors

Click-chemistry based design and efficient synthesis of podophyllotoxin–chalcone conjugates as potential topoisomerase-II inhibitors towards the development of better anticancer leads.

Synthetic Approaches to Various Class of Topoisomerase II Inhibitors

2017 ◽  
Vol 14 (5) ◽  
Author(s):  
Sanal Dev ◽  
Nishad Gabhe ◽  
S.R. Dhaneshwar ◽  
Monu Joy ◽  
Bijo Mathew
Keyword(s):  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitors ◽  
Synthetic Approaches

In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

2020 ◽  
Vol 19 (16) ◽  
pp. 2010-2018
Author(s):  
Youstina W. Rizzk ◽  
Ibrahim M. El-Deen ◽  
Faten Z. Mohammed ◽  
Moustafa S. Abdelhamid ◽  
Amgad I.M. Khedr
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Cancer Cell Lines ◽  
Bax Protein ◽  
Hybrid Molecules ◽  
Mcf 7

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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