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Review
. 2020 Dec;35(1):1781-1799.
doi: 10.1080/14756366.2020.1821676.

DNA topoisomerases as molecular targets for anticancer drugs

Kamila Buzun  1 , Anna Bielawska  1 , Krzysztof Bielawski  2 , Agnieszka Gornowicz  1
Affiliations
Review

DNA topoisomerases as molecular targets for anticancer drugs

Kamila Buzun et al. J Enzyme Inhib Med Chem. 2020 Dec.

Abstract

The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.

Keywords: DNA topoisomerases; anticancer activity; anticancer drugs; cancer; topoisomerase inhibitors.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
General mechanism of action of topoisomerase I (a) Top I binds to the DNA, (b) single-strand DNA (in blue) splitting, (c) controlled rotation of free DNA strand (in red), (d) religation of cleaved DNA strand.
Figure 2.
Figure 2.
General mechanism of action of topoisomerase II (a) topoisomerase binds to the G-segment, (b) Top IIA- G-segment complex binds to T-segment, (c) Two ATP molecules are attached to the resulting complex, (d) G-segment cleavage in presence of Mg2+ ions, (e) T-segment transport through the created gap, (f) T-segment release and religation of G-segment broken strands and (g) hydrolysis of ATP molecules and release of the G-segment.
Figure 3.
Figure 3.
Chemical structure of camptothecin.
Figure 4.
Figure 4.
Chemical structures of camptothecins.
Figure 5.
Figure 5.
Chemical structures of noncamptothecins.
Figure 6.
Figure 6.
Chemical structure of etoposide.
Figure 7.
Figure 7.
Chemical structures of epipodophyllotoxins.
Figure 8.
Figure 8.
Chemical structures of doxorubicin.
Figure 9.
Figure 9.
Chemical structure of anthracyclines.
Figure 10.
Figure 10.
Chemical structure of mitoxantrone.
Figure 11.
Figure 11.
Chemical structure of amsacrine.
Figure 12.
Figure 12.
Chemical structure of vosaroxin.
Figure 13.
Figure 13.
Chemical structure of dexrazoxane.
Figure 14.
Figure 14.
Chemical structure of merbarone.
See this image and copyright information in PMC

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