Diacridines — Double intercalators as chemotherapeutic agents

Canellakis, E.S.; Fico, Rosario; Sarris, Andreas H.; Shaw, Yeng-Jeng

doi:10.1016/0006-2952(76)90304-x

Cited by 21 publications

(14 citation statements)

References 11 publications

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“…These findings are supported by the fact that the hydroxyl radical is generated from the reaction of superoxide with hydrogen peroxide (10). Some antitumor agents with quinone moieties are known to cleave DNA under reduced conditions (1,2,14,15,22,26), and metal ions play important roles in their cleaving activities. On the basis of this notion, the effect of chelating agents was examined.…”

mentioning

confidence: 92%

Mechanism of action of dnacin B1, a new benzoquinoid antibiotic with antitumor properties

Tanida¹,

Hasegawa²,

Yoneda³

1982

Antimicrob Agents Chemother

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Dnacin B1 preferentially inhibited the incorporation of [3H]thymidine into acidinsoluble fractions in Escherichia coli. At a sublethal concentration, dnacin B1 caused filamentous growth in E. coli and induced prophage X. The antibiotic also showed potent bactericidal activity against repair-deficient E. coli strains, such as recA, recB, and polA strains. In in vitro studies, dnacin B1 raised the melting temperatures of various double-stranded DNAs. In addition, the antibiotic showed DNA-cleaving activity against PM2 DNA in the presence of reducing agents, and the activity was suppressed by scavengers for oxygen free radicals and an iron-specific chelator, desferrioxamine E. The stimulation of the generation of superoxide radical by dnacin B1 was confirmed by measuring the reduction of neotetrazolium. Therefore, it can be presumed that the primary cellular target of dnacin B1 is DNA in susceptible cells, and the autooxidation of DNA-bound dnacin B1 causes the generation of oxygen-free radicals that result in the damage of DNA and the inhibition of its synthesis.

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confidence: 92%

Mechanism of action of dnacin B1, a new benzoquinoid antibiotic with antitumor properties

Tanida¹,

Hasegawa²,

Yoneda³

1982

Antimicrob Agents Chemother

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“…Bifunctional intercalators were developed as anticancer drugs as early as the 1970s with the diacridines (Le Pecq et al, 1975;Canellakis et al, 1976) and 1980s with 7H-pyridocarbazole dimers (Pelaprat et al, 1980;Markovits et al, 1986;Garbay-Jaureguiberry et al, 1987). More recent are bisintercalators from amonafide, elinafide, imidazonaphthalimides, 9-aminoacridine, and anthracyclines (Brana et al, 2004;Nair et al, 2005).…”

mentioning

confidence: 99%

Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

Antony

Agama²,

Hollingshead³

et al. 2006

Mol Pharmacol

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Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G 1 with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744,aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.

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“…Indeed, all the evidence speaks strongly for their reversible reaction with DNA, and they do not / } . \ cause single-strand breaks in vitro (Wakelin et al, <10 1978(Wakelin et al, <10 , 1979 (Canellakis et al, 1976c). The most significant finding of the present work is that the A< .<" S""' >.'.…”

Section: Discussionmentioning

confidence: 99%

Intracellular DNA damage produced by a series of diacridines

Roos¹,

Wakelin²,

Henry³

1985

Biochemical Journal

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The intracellular DNA damage produced by a series of diacridines after a 2 h pulse treatment of L1210 cells in culture was investigated by using the alkaline-elution technique. Like other intercalating agents, diacridines produce single-strand breaks and protein-DNA links. There is a large increase in both types of damage as the alkane chain linking the two 9-aminoacridine residues is increased beyond five methylene groups, which is consistent with the previously observed change from monofunctional to bifunctional intercalation [Wakelin, Romanos, Chen, Glaubiger, Canellakis & Waring (1978) Biochemistry 17, 5057-5063]. For linker chains of less than six methylene groups these agents produce less DNA damage than does the parent 9-aminoacridine at the same drug concentration. Unlike the monofunctional intercalators previously investigated [Ross, Glaubiger & Kohn (1979) Biochim. Biophys. Acta 562, 41-50; Zwelling, Michaels, Erickson, Ungerleider, Nichols & Kohn (1981) Biochemistry 20, 6553-6563; Zwelling, Kerrigan & Michaels (1982) Cancer Res. 42, 2687-2691; Zwelling, Michaels, Kerrigan, Pommier & Kohn (1982) Biochem. Pharmacol. 31, 3261-3267], there is no correlation between the number of single-strand breaks and protein-DNA links produced by these diacridines.

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Diacridines — Double intercalators as chemotherapeutic agents

Cited by 21 publications

References 11 publications

Mechanism of action of dnacin B1, a new benzoquinoid antibiotic with antitumor properties

Mechanism of action of dnacin B1, a new benzoquinoid antibiotic with antitumor properties

Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

Intracellular DNA damage produced by a series of diacridines

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