A Strategy for Identifying Novel, Mechanistically Unique Inhibitors of Topoisomerase I

Hecht, Sidney M.; Berry, David E.; MacKenzie, Laurie; Busby, Robert; Nasuti, Christopher A.

doi:10.1021/np50082a001

Cited by 36 publications

(23 citation statements)

References 27 publications

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“…Quercetin and Related Natural Flavonoids-For the screening of topoisomerase I-targeted drug effects, we used a strategy based on the alteration of the electrophoretic mobility of pBR 322 plasmid DNA by the combined action of human topoisomerase I and inhibiting drugs (20). As shown in Fig.…”

Section: Inhibition Of Topoisomerase I-catalyzed Dna Religation Bymentioning

confidence: 99%

“…3b, which makes use of the selective binding of topoisomerase I-DNA complexes to nitrocellulose in the presence of SDS (20). Under these conditions topoisomerase I alone does not bind to the nitrocellulose filter.…”

Section: Inhibition Of Topoisomerase I-catalyzed Dna Religation Bymentioning

confidence: 99%

“…Moreover, the flavone structure also provides a template for the creation of a second class of topoisomerasetargeted drugs, which share the common structure of 6-substituted 3Ј,5Ј-dibromo-4Ј-hydroxy-3-methylflavones and selectively inhibit the cleavage half-reaction of topoisomerase I. In contrast to other substances known to inhibit the cleavage reaction of topoisomerase I, such as chebulagic acid (20) and ␤-lapachone (40), 6-substituted 3Ј,5Ј-dibromo-4Ј-hydroxy-3-methylflavones do not inhibit the DNA cleavage reaction itself, but interfere with the the binding of the enzyme to DNA.…”

Section: Potential Value Of Flavone Inhibitors Of Topoisomerase Imentioning

confidence: 99%

See 2 more Smart Citations

Selected Novel Flavones Inhibit the DNA Binding or the DNA Religation Step of Eukaryotic Topoisomerase I

Boege

Straub

Kehr

et al. 1996

Journal of Biological Chemistry

211

145

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Topoisomerases are involved in many aspects of DNA metabolism such as replication and transcription reactions. Camptothecins, which stabilize the covalent intermediate of topoisomerase I and DNA are effective, though toxic, drugs for cancer therapy. In this study, a new class of topoisomerase I inhibitors was identified, and their mode of action was characterized using recombinant human topoisomerase I preparations and human HL-60 leukemic cells. Quercetin and the related natural flavones, acacetin, apigenin, kaempferol, and morin, inhibit topoisomerase I-catalyzed DNA religation. In contrast to camptothecin, these compounds do not act directly on the catalytic intermediate and also do not interfere with DNA cleavage. However, formation of a ternary complex with topoisomerase I and DNA during the cleavage reaction inhibits the following DNA religation step. 3,3,4,7-Tetrahydroxy-substituted flavones stabilize the covalent topoisomerase I-DNA intermediate most efficiently. Enhanced formation of covalent topoisomerase I-DNA complexes was also demonstrated in human HL-60 cells. In contrast, synthetic 3,5-dibromo-4-hydroxy-3-methylflavones bind selectively to topoisomerase I in its non-DNA-bound form and block the following DNA binding step. As a consequence, these synthetic flavonoids are capable of counteracting topoisomerase I-directed effects of camptothecin. Inhibition of DNA binding is obtained by voluminous hydrophobic substituents in 6-position of the flavone structure. Our data show that selective inhibitors of both half-reactions of topoisomerase I can be derived from the flavone structure.

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Section: Inhibition Of Topoisomerase I-catalyzed Dna Religation Bymentioning

confidence: 99%

Section: Inhibition Of Topoisomerase I-catalyzed Dna Religation Bymentioning

confidence: 99%

Section: Potential Value Of Flavone Inhibitors Of Topoisomerase Imentioning

confidence: 99%

See 1 more Smart Citation

Selected Novel Flavones Inhibit the DNA Binding or the DNA Religation Step of Eukaryotic Topoisomerase I

Boege

Straub

Kehr

et al. 1996

Journal of Biological Chemistry

211

145

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“…The fruit of T. catappa contains cyanidin 3-glucoside, corilagin (8,9) (topoisomerase I and II inhibitor), xanthine oxidase inhibitor (10), ellagic acid (11) (anti-HIV), antiasthmatic compound, gallic acid (12), and pentosans (13). They are also reported to contain phytochemicals which are indicative of its potential in the treatment of diabetes, e.g., brevifolin carboxylic acid and ellagic acid, which are aldose reductase inhibitors (14,15).…”

Section: Introductionmentioning

confidence: 99%

Characterization and In Vitro Drug Release Studies of a Natural Polysaccharide Terminalia catappa Gum (Badam Gum)

et al. 2012

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Abstract. The main objective of the present study is the physicochemical characterization of naturally available Terminalia catappa gum (Badam gum [BG]) as a novel pharmaceutical excipient and its suitability in the development of gastroretentive floating drug delivery systems (GRFDDS) to retard the drug for 12 h when the dosage form is exposed to gastrointestinal fluids in the gastric environment. As BG was being explored for the first time for its pharmaceutical application, physicochemical, microbiological, rheological, and stability studies were carried out on this gum. In the present investigation, the physicochemical properties, such as micromeritic, rheological, melting point, moisture content, pH, swelling index, water absorption, and volatile acidity, were evaluated. The gum was characterized by scanning electron microscopy, differential scanning calorimetry (DSC), powder X-ray diffraction studies (PXRD), and Fourier transform infrared spectroscopy (FTIR). Gastroretentive floating tablets of BG were prepared with the model drug propranolol HCl by direct compression methods. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, in vitro drug release, and rate order kinetics. PBG 04 was selected as an optimized formulation based on its 12-h drug release and good buoyancy characteristics. The optimized formulation was characterized with FTIR, DSC, and PXRD studies, and no interaction between the drug and BG was found. Thus, the study confirmed that BG might be used in the gastroretentive drug delivery system as a release-retarding polymer.

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“…When it is associated with DNA, STN has the capacity to generate superoxide radicals by redox cycling with molecular oxygen (27). STN also has been found to be a potent inhibitor of topisomerase I (28). There was a substantial increase in the mutagenicity induced by STN in all strains that carry rfa mutations, which enhances permeability.…”

Section: Methodsmentioning

confidence: 99%

Detection and classification of mutagens: a set of base-specific Salmonella tester strains.

Gee

Maron²,

Ames³

1994

Proc. Natl. Acad. Sci. U.S.A.

116

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A deion and caon system for mutagens has been developed that identifi the six possible base-pair subtio mutat. A set of six Salmonella typhimunum (TA7001 to TA7006) strains has been constructed, each of which carries a unique missense mutation In the hs e biosynthetic operon. ]. addition to the his mutation, these strains carry different auxil features that enhance the mutability ofthe target his mutation. These include the R factor pKM101, which has the SOS-inducible mcAD system; a deletion of the The previous Salmonella mutagenicity test (2) has been used extensively over the past two decades to measure the mutagenic potential of many compounds. These strains have point mutations in the histidine biosynthetic operon that render them unable to grow in the absence of histidine; however, they are not diagnostic for the type of base-pair substitution caused by the mutagen.Each of the six strains described here, either with (TA7001-TA7006) or without (TA7041-TA7046) the rfa mutation, reverts by only one specific base-pair substitution out of the six possible changes. Reversion of the target mutation in a gene for histidine biosynthesis restores the mutant his gene to the wild type so that the cell can grow and form a colony without histidine. The number of colonies formed is a direct measure of the mutagenic potential of the test compound. The spontaneous reversion rates of the strains described here are considerably lower than that of the previous Salmonella tester strains (2), and their sensitivity to reversion by mutagens is comparable. In addition, the strains described here have added the ability to determine the spectrum of base substitutions.Two other systems that detect all six possible base substitutions without further genetic or biochemical analysis have been reported. The Saccharomyces cerevisiae system (3) is based on an essential Cys-22 residue in iso-icytochrome c encoded by the CYCI gene. The Escherichia coli system (4) has a mutational target on a plasmid in an active site glutamate residue in the (3-galactosidase gene.Since the point mutation is extrachromosomal, it can be transferred into various backgrounds such as those differing in mismatch repair. MATERIALS AND METHODSTarget Mutation (A-T --GaC) in Set 1. The mutation hisG177S (5) was recombined with a bacteriophage clone, M13mp9::his4 (6), deleted for part of the hisG gene (covering the hisG1775 mutation) and the hisD gene. Recombinant M13 phage were selected with an active hisD gene product that allowed growth on histidinol and were plaque-purified to prepare single-stranded DNA templates for dideoxynucleotide sequencing. The hisG1775 mutation was identified as a G-C -* APT transition in which the wild-type Gly-153 (GGT) was replaced by the mutant . No other mutations were found in hisG. The hisGl775 mutation is the basis of the TA7041 and TA7001 strains in set 1 (see Table 1).In Vitro Mu n . Target mutations for sets 2-5 were synthesized in DNA oligomers. These oligomers were used as primers to extend single-stranded M13 DNA temp...

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A Strategy for Identifying Novel, Mechanistically Unique Inhibitors of Topoisomerase I

Cited by 36 publications

References 27 publications

Selected Novel Flavones Inhibit the DNA Binding or the DNA Religation Step of Eukaryotic Topoisomerase I

Selected Novel Flavones Inhibit the DNA Binding or the DNA Religation Step of Eukaryotic Topoisomerase I

Characterization and In Vitro Drug Release Studies of a Natural Polysaccharide Terminalia catappa Gum (Badam Gum)

Detection and classification of mutagens: a set of base-specific Salmonella tester strains.

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