A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential

Corbett, Anita H.; Guerry, Philippe; Pflieger, Philippe; Osheroff, Neil

doi:10.1128/aac.37.12.2599

Cited by 24 publications

(15 citation statements)

References 40 publications

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“…Quinolones Act by Inhibiting DNA Religation Mediated by S. aureus Topoisomerase IV-As determined by their effects on DNA religation, drugs enhance DNA cleavage mediated by type II topoisomerases by two alternative (but not mutually exclusive) mechanisms (44,45). While some drug classes strongly inhibit enzyme-mediated DNA religation, others have little effect on this reaction.…”

Section: Resultsmentioning

confidence: 99%

Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV

Anderson¹,

Zaniewski²,

Kaczmarek³

et al. 1999

Journal of Biological Chemistry

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Quinolones are the most active oral antibacterials in clinical use and act by increasing DNA cleavage mediated by prokaryotic type II topoisomerases. Although topoisomerase IV appears to be the primary cytotoxic target for most quinolones in Gram-positive bacteria, interactions between the enzyme and these drugs are poorly understood. Therefore, the effects of ciprofloxacin on the DNA cleavage and religation reactions of Staphylococcus aureus topoisomerase IV were characterized. Ciprofloxacin doubled DNA scission at 150 nM drug and increased cleavage ϳ9-fold at 5 M. Furthermore, it dramatically inhibited rates of DNA religation mediated by S. aureus topoisomerase IV. This inhibition of religation is in marked contrast to the effects of antineoplastic quinolones on eukaryotic topoisomerase II, and suggests that the mechanistic basis for quinolone action against type II topoisomerases has not been maintained across evolutionary boundaries. The apparent change in quinolone mechanism was not caused by an overt difference in the drug interaction domain on topoisomerase IV. Therefore, we propose that the mechanistic basis for quinolone action is regulated by subtle changes in drug orientation within the enzyme⅐drug⅐DNA ternary complex rather than gross differences in the site of drug binding.

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Section: Resultsmentioning

confidence: 99%

Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV

Anderson¹,

Zaniewski²,

Kaczmarek³

et al. 1999

Journal of Biological Chemistry

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“…However, a body of literature indicates that anticancer drugs targeted to eukaryotic type II topoisomerases stimulate DNA cleavage in one of two primary fashions. They act either by inhibiting the ability of the enzyme to religate cleaved DNA molecules, or by increasing rates of enzyme-mediated DNA cleavage (37,(53)(54)(55)(56)(57)(58).…”

Section: Quinolone Mechanismmentioning

confidence: 99%

Topoisomerase IV Catalysis and the Mechanism of Quinolone Action

Anderson¹,

Gootz²,

Osheroff³

1998

Journal of Biological Chemistry

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Topoisomerase IV is a bacterial type II topoisomerase that is essential for proper chromosome segregation and is a target for quinolone-based antimicrobial agents. Despite the importance of this enzyme to the survival of prokaryotic cells and to the treatment of bacterial infections, relatively little is known about the details of its catalytic mechanism or the basis by which quinolones alter its enzymatic functions. Therefore, a series of experiments that analyzed individual steps of the topoisomerase IV catalytic cycle were undertaken to address these critical mechanistic issues. The following conclusions were drawn. First, equilibrium levels of DNA cleavage mediated by the bacterial enzyme were considerably (>10-fold) higher than those observed with its eukaryotic counterparts. To a large extent, this reflected decreased rates of DNA religation. Second, the preference of topoisomerase IV for catalyzing DNA decatenation over relaxation reflects increased rates of strand passage and enzyme recycling rather than a heightened recognition of intermolecular DNA helices. Third, quinolones stimulate topoisomerase IV-mediated DNA cleavage both by increasing rates of DNA scission and by inhibiting religation of cleaved DNA. Finally, quinolones inhibit the overall catalytic activity of topoisomerase IV primarily by interfering with enzyme-ATP interactions.Type II topoisomerases alter the topological state of the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate DNA segment (1-6). Eubacteria contain two distinct members of this enzyme class, DNA gyrase and topoisomerase IV (6). The most well characterized of the two, DNA gyrase, was discovered over 2 decades ago (7). It is unique among type II enzymes in that it is the only known topoisomerase (prokaryotic or eukaryotic) that is capable of introducing negative superhelical twists into relaxed DNA molecules (7). DNA gyrase plays critical roles in DNA replication, recombination, and transcription, as well as in the maintenance of genomic superhelical density (1,2,5,6,8,9).The second prokaryotic type II enzyme, topoisomerase IV, is comprised of the products of the parC and parE genes (10). Although it was long known that ParC and ParE both were required for proper chromosome segregation in Escherichia coli (11, 12), it was not realized until 1990 that these two polypeptides together constitute a novel type II topoisomerase (10). Consistent with its critical role in chromosome segregation, topoisomerase IV displays a prejudice for catalyzing intermolecular DNA strand passage events (i.e. catenation/decatenation reactions) as opposed to intramolecular events (i.e. DNA relaxation reactions) (13-16). This prejudice notwithstanding, topoisomerase IV appears to relax DNA in vivo, and recent evidence suggests that this relaxation activity plays an important role in maintaining levels of DNA supercoiling in E. coli (17).Beyond their essential physiological functions, prokaryotic type II topoisomerases are t...

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“…These compounds have been described as being DNA cleaving agents [1], DNA gyrase inhibitors [2][3][4][5][6][7], antiinflammatory [8][9][10], antiamoebic and analgesic [8,9], herbicidal [11], antimicrobial and antifungal [12], antiulcer [13], polymer dye additive [14], variolin alkaloids analogues [15][16][17], and nucleoside analogues agents [18,19]. Studies on benzene carcinogenesis and mutagenesis showed that p-benzoquinone which is the oxidation product of benzene reacts with deoxycitidine in the human body [20][21][22][23][24][25][26][27] to produce a pyrimido [1,6-a]benzimidazole structure as shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

“…These derivatives can be prepared by cyclocondensation of 1-(2-aminoaryl) urea with diethyl malonate, 2-substituted benzimidazolylacetates with carbonate esters [1][2][3][4][5][6], condensation of ketoisothiocyanates with orthophenylenediamines [8][9][10] and methyl 2-(bromomethyl)-1H-benzimidazole-1-carboxylate with tosylmethylisocyanides [15][16][17], reaction of 4-O-[(triisopropylphenyl)sulfonyl]-pyrimidine nucleosides with orthophenylenediamine [18][19] and direct or biomedia reaction of deoxycytidine with p-benzoquinone [20][21][22][23][24][25][26][27]. Other routes include condensation of 2-(3-aminopropyl)-benzimidazole with carbon disulfide [28], 2-(2-benzimidazolyl)acetonitrile and 2-(2-benzimidazolyl)ethylacetate [29][30][31][32][33][34][35][36], ring construction of pyrimido [4,5-b]- [1,5]benzodiazepines [37][38][39], reaction of 6-chloro [1,3]oxazine-2,4-diones with orthophenylenediamine [40] and cyclocondensation of (benzimidazol-2-ylmethyl)-triphenylphosphonium chloride [41][42][43].…”

Section: Introductionmentioning

confidence: 99%

A new route to pyrimido[1,6‐a]benzimidazole derivatives

Bakavoli

Rahimizadeh

Ebrahimi

et al. 2008

Journal of Heterocyclic Chem

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Cyclocondensation of orthophenylendiamines with 3‐bromopropionic acid in PPA afforded 2‐vinylbenzimidazoles which were subsequently converted to their corresponding 2‐(1,2‐dibromoethyl)‐1H‐benzimidazoles on treatment with bromine. Reaction of these compounds with aryl nitriles or aryl isocyanates in basic chloroform yielded 1‐arylpyrimido[1,6‐a]benzimidazoles and 2‐arylpyrimido[1,6‐a]‐benzimidazol‐3‐ones respectively.

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A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential

Cited by 24 publications

References 40 publications

Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV

Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV

Topoisomerase IV Catalysis and the Mechanism of Quinolone Action

A new route to pyrimido[1,6‐a]benzimidazole derivatives

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