Topoisomerase II Inhibitors: Chemical Biology

Rogojina, Anna T.; Gajewski, Stefan; Bahmed, Karim; Osheroff, Neil; Nitiss, John L.

doi:10.1007/978-1-4614-0323-4_11

Cited by 4 publications

(2 citation statements)

References 142 publications

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“…Notable antiproliferative effects were observed in several members of this class and further early preclinical studies performed with ICRF-159 (razoxane, a racemic mixture of dexrazoxane and levrazoxane, Figure ) demonstrated high antitumor activity and antimetastatic effects when combined with established anticancer drugs, including anthracyclines (ANT). , The same effect was found in its more soluble enantiomer dexrazoxane (ICRF-187, DEX) or another bisdioxopiperazine ICRF-154 . Further investigations disproved the validity of the metal chelation hypothesis for their anticancer effect and established catalytic inhibition of topoisomerase II (TOP2) as the key mechanism. , In-depth mechanistic studies generally supported the catalytic mode of TOP2 inhibition, − despite some studies that offered an alternative perspective. , DEX and other bisdioxopiperazines do not bind directly to the adenosine 5′-triphosphate (ATP)-binding pocket of TOP2 but instead they bind to the so-called DEX binding site where they bridge and stabilize a transient dimer interface between the two ATPase protomers of TOP2 . This site was confirmed by studies using mutated enzymes and later by the crystallization experiments.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions

et al. 2021

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Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure−activity relationships were demonstrated on stereoisomeric forms of 4,4′-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, mesoderivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions

et al. 2021

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“…The formation of a linearized DNA product under both tested concentrations indicates that compounds 43 and 44 also act as Topo IIα poisons. Topo IIα poisons increase the concentration of cleavage complexes by two non-mutually exclusive pathways they either inhibit the ability of the enzyme to ligate cleaved DNA molecules or increase the forward rate of enzyme-mediated DNA cleavage(Rogojina et al, 2012).…”

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Acridine derivatives as inhibitors/poisons of topoisomerase II

Kožurková

2021

J of Applied Toxicology

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The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.

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Targeting DNA Topoisomerase II in Antifungal Chemotherapy

Kondaka

Gabriel

2022

Molecules

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Topoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand the range of therapeutic options. In this review paper, we discussed the usefulness of fungal topo II as a molecular target for new drug discovery. On the basis of previously published data, we described structural and biochemical differences between fungal and human enzymes as well as a molecular basis of differential sensitivity to known anticancer drugs targeting the latter. This review focuses especially on highlighting the differences that may underlie the selectivity of action of new inhibitors. Distinct sites within fungal topo II in comparison with human counterparts are observed and should be further studied to understand the significance of those sites and their possible usage in design of new drugs.

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Topoisomerase II Inhibitors: Chemical Biology

Cited by 4 publications

References 142 publications

Structure–Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions

Structure–Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions

Acridine derivatives as inhibitors/poisons of topoisomerase II

Targeting DNA Topoisomerase II in Antifungal Chemotherapy

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