Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme

Froelich-Ammon, Stacie J.; McGuirk, Paul R.; Gootz, Thomas D.; Jefson, Martin R.; Osheroff, Neil

doi:10.1128/aac.37.4.646

Cited by 19 publications

(11 citation statements)

References 35 publications

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“…Over the past decade, several novel quinolones have been synthesized that display significant activity against eukaryotic type II topoisomerases [126][127][128][129][130][131][132][133][134]. These antineoplastic quinolones are cytotoxic and genotoxic to mammalian cells, and are active in mouse tumor models [127][128][129][131][132][133].…”

Section: Antineoplastic Quinolonesmentioning

confidence: 99%

Type II Topoisomerases as Targets for Quinolone Antibacterials Turning Dr. Jekyll into Mr. Hyde

Anderson¹,

Osheroff²

2001

CPD

178

187

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Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Although the founding members of this drug class had little clinical impact, successive generations include the most active and broad spectrum oral antibacterials currently in use. In contrast to most other anti-infective drugs, quinolones do not kill bacteria by inhibiting a critical cellular process. Rather, they corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks. A second unique aspect of quinolones is their differential ability to target these two enzymes in different bacteria. Depending upon the bacterial species and quinolone employed, either DNA gyrase or topoisomerase IV serves as the primary cytotoxic target of drug action. While this unusual feature initially stymied development of quinolones with high activity against Gram-positive bacteria, it ultimately opened new vistas for the clinical use of this drug class. In addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and in vivo tumor models. These antineoplastic quinolones represent a potentially important source of new anticancer agents and provide an opportunity to examine drug mechanism across divergent species. Because of the clinical importance of quinolones, this review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets.

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Section: Antineoplastic Quinolonesmentioning

confidence: 99%

Type II Topoisomerases as Targets for Quinolone Antibacterials Turning Dr. Jekyll into Mr. Hyde

Anderson¹,

Osheroff²

2001

CPD

178

187

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“…Since that initial report, a number of novel quinolones with activity against topoisomerase II, eukaryotic cells, or mammalian tumors have been described (8,9,18,19,31,32,37,(39)(40)(41). In contrast to clinically relevant quinolone antimicrobial agents, many of these latter compounds contain an aromatic substituent at the C-7 position (3,9,18,31,32,39,40).…”

mentioning

confidence: 99%

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

Elsea

McGuirk

Gootz

et al. 1993

Antimicrob Agents Chemother

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). However, the features of the drug that contribute to its activity towards mammalian systems have not been characterized. Therefore, CP-115,953 and a series of related quinolones were examined for their activity against calf thymus topoisomerase H and cultured mammalian cells. CP-115,953 stimulated DNA cleavage mediated by the type H enzyme with a potency that was -600-fold greater than that of the antimicrobial quinolone ciprofloxacin and -50-fold greater than that of the antineoplastic drug etoposide. As determined by the ability to enhance enzyme-mediated DNA cleavage, quinolone activity towards calf thymus topoisomerase H was enhanced by the presence of a cyclopropyl group at the N-1 ring position and by the presence of a fluorine at C-8. Furthermore, the 4'-hydroxyphenyl substituent at the C-7 position was critical for the potency of CP-115,953 towards the mammalian type H enzyme. In this regard, the aromatic nature of the C-7 ring as well as the presence and the position of the 4'-hydroxyl group contributed greatly to drug activity. Finally, the cytotoxicity of quinolones in the CP-115,953 series towards mammalian cells paralleled the in vitro stimulation of DNA cleavage by topoisomerase H rather than the inhibition of enzyme-catalyzed DNA relaxation. This correlation strongly suggests that these quinolones promote cell death by converting topoisomerase IT to a cellular poison.

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“…46,47 In other cases, the change in stereochemistry about a single bond in etoposide or in a tricyclic quinolone completely eliminates drug activity or even converts the interfacial poison into a catalytic inhibitor of topoisomerase II. 48,49 …”

Section: Resultsmentioning

confidence: 99%

Epimerization of Green Tea Catechins during Brewing Does Not Affect the Ability to Poison Human Type II Topoisomerases

Timmel

Byl

Osheroff

2013

Chem. Res. Toxicol.

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(−)-Epigallocatechin gallate (EGCG) is the most abundant and biologically active polyphenol in green tea (Camellia sinensis) leaves and many of its cellular effects are consistent with its actions as a topoisomerase II poison. In contrast to genistein and several other related bioflavonoids that act as interfacial poisons, EGCG was the first bioflavonoid shown to act as a covalent topoisomerase II poison. Although studies routinely examine the effects of dietary phytochemicals on enzyme and cellular systems, they often fail to consider that many compounds are altered during cooking or cellular metabolism. To this point, the majority of EGCG (and related catechins) in green tea leaves is epimerized during the brewing process. Epimerization reverses the stereochemistry of the bond that bridges the B- and C-rings, and converts EGCG to (−)-gallocatechin gallate (GCG). Consequently, a significant proportion of EGCG that is ingested during the consumption of green tea is actually GCG. Therefore, the effects of GCG and related epimerized green tea catechins on human topoisomerase IIα and IIβ were characterized. GCG increased levels of DNA cleavage mediated by both enzyme isoforms with an activity that was similar to that of EGCG. GCG acted primarily by inhibiting the ability of topoisomerase IIα and IIβ to ligate cleaved DNA. Several lines of evidence indicate that GCG functions as a covalent topoisomerase II poison that adducts the enzyme. Finally, epimerization did not affect the reactivity of the chemical substituents (the three hydroxyl groups on the Bring) that were required for enzyme poisoning. Thus, the activity of covalent topoisomerase II poisons appears to be less sensitive to stereochemical changes than interfacial poisons.

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Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme

Cited by 19 publications

References 35 publications

Type II Topoisomerases as Targets for Quinolone Antibacterials Turning Dr. Jekyll into Mr. Hyde

Type II Topoisomerases as Targets for Quinolone Antibacterials Turning Dr. Jekyll into Mr. Hyde

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

Epimerization of Green Tea Catechins during Brewing Does Not Affect the Ability to Poison Human Type II Topoisomerases

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