Interaction of the Nonintercalative Antitumour Drugs SN-6999 and SN-18071 with DNA: Influence of Ligand Structure on the Binding Specificity

Luck, G.; Reinert, K.E.; Baguley, Bruce C.; Zimmer, Christoph

doi:10.1080/07391102.1987.10507699

Cited by 23 publications

(22 citation statements)

References 33 publications

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“…2, Table I). A significantly different change observed in viscometric titrations between SN-6999 [30] and SN-18071 (Reinert, K.E., unpublished data) supports this interpretation. Pentamidine, which is an ineffective ligand, too, can form two hydrogen bonds only as well as van der Waals contacts and induces a narrowing [31] instead of a widening of the minor groove.…”

Section: Resultssupporting

confidence: 73%

Studies on the ability of minor groove binders to induce supercoiling in DNA

et al. 1993

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The effect of various non-intercalating minor groove binders on closed circular DNA in the presence of topoisomerase I has been studied by means of agarose gel electrophoresis. Analogues of the netropsin series (lexitropsins) and SN-6999 can effectively produce positive supercoils, as indicated by analysis of the topoisomers in the presence of chloroquine and the evaluated linking number changes. Analogues of the distamycin series are less effective, and bisquaternary ammonium heterocycles, as well as DAPI and pentamidine, were found to be ineffective ligands. The large differences observed in the ability of minor groove binders to induce positive supercoils are discussed.Minor groove binder; Plasmid DNA; Supercoiling

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Section: Resultssupporting

confidence: 73%

Studies on the ability of minor groove binders to induce supercoiling in DNA

et al. 1993

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“…The structures of these compounds resemble those of various bis-cationic antitumor compounds such as diamidines, phthalanilides, and bis-quaternary ammonium heterocycles (1), which are generally believed to interact with DNA by binding in the minor groove (6,(11)(12)(13). Related bis-cationic trypanocides such as berenil, stilbamidine, and phthalanilides are known to induce petite mutants in Saccharomyces cerevisiae (8) in an assay which provides an indication of antimitochondrial activity (9).…”

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confidence: 99%

Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs

Ferguson

Sundberg

1991

Antimicrob Agents Chemother

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A group of bis-cationic imidazo[1,2-a]pyridinium salts and related compounds, some of which exhibit in vivo trypanocidal activity, have been investigated for induction of petite mutagenesis in Saccharomyces cerevisiae. All of the compounds which are active trypanocides induce mutagenesis. There appears to be a correlation between trypanocidal activity and mutagenic activity which may have its structural origin in the spatial separation of the cationic centers.A series of imidazo[1,2-a]pyridinium and related heteroaromatic salts was recently reported to have good activity against the bloodstream form of Trypanosoma rhodesiense in mice (22). The structures of these compounds resemble those of various bis-cationic antitumor compounds such as diamidines, phthalanilides, and bis-quaternary ammonium heterocycles (1), which are generally believed to interact with DNA by binding in the minor groove (6, 11-13 For all experiments, the 1-ml sample was thawed, added to 10 ml of fresh medium, and grown for exactly 2 h before use.Microtiter assay for petite mutagenesis. The microtiter assay has been described in detail (7). Briefly, a log-phase culture was washed and then diluted into fresh growth medium. A 96-well microtiter tray (A/S Nunc, Roskilde, Denmark) was inoculated with (usually) 100-pd aliquots of the diluted yeast culture, and drugs were added at various dilutions to the wells to a maximum of 200 ,ug/ml. Drugs were dissolved in 50% ethanol, and dilutions were made so that there was no more than 1% ethanol in each well. Trays were incubated for 24 h at 30°C, an appropriate dilution was * Corresponding author.made from each well into saline, and 100 ,ul was plated onto each of three YC plates. Cell numbers were calculated so that the dilutions at this point were at least 1:104, thereby effectively washing drugs from cells by dilution (7).In some experiments, cells were tested in nongrowing conditions by diluting the cultures into 0.87% saline rather than complete medium. For a limited number of the compounds, samples were taken at various intervals in order to establish the rate of petite formation.Plates were incubated at 30°C for 3 days, and then all colonies were counted with an Artek model 880 counter. Scores of some plates were checked by manual counting. Colonies were then overlaid with tetrazolium in order to score petite colonies (16). Following a preliminary experiment to establish the correct concentration range, dose response of all drugs was tested at least twice and the data were compared for reproducibility. Maximum frequencies of petites were recorded. The dose to reduce numbers of yeast colonies to 50% of the value for the untreated control and the dose to convert 50% of the colonies to petite were both estimated by linear regression analysis. The presented data have been averaged. Table 1 gives the 50% lethal dose and 50% petite mutant conversion dose measured for the test compounds. Comparative data for berenil, stilbamidine, and the phthalanilides structures shown in Fig. 2 have been reported prev...

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“…Similar as for the well known minor groove binders netropsin (2,9), distamycin A (2,8,10) and CC-1065 (3) an AT sequence selectivity and minor groove interaction has been demonstrated for a series ofbisquaternary ammonium heterocycles (2,(11)(12)(13)(14)(15). Extensive solution studies have shown that their mode of interaction with DNA may be altered due to structural modifications of these ligands containing sixmembered aromatic ring systems, e.g., clear-cut differences were found in the AT sequence binding ability between the antitumor drugs SN-6999 and SN-18071 (13,15). In this paper we report the binding behaviour of three new model ligands which belong to the group of antitumor agents ofbisquaternary ammonium heterocycles (16) designated by SN-6113, SN-6131 and SN-6132 ( Figure 1).…”

Section: Introductionmentioning

confidence: 90%

“…Many nonintercalating drugs which interact with double helical DNA show AT base pair preference and binding within the minor groove of B-DNA (2,(3)(4)(5)(8)(9)(10). Similar as for the well known minor groove binders netropsin (2,9), distamycin A (2,8,10) and CC-1065 (3) an AT sequence selectivity and minor groove interaction has been demonstrated for a series ofbisquaternary ammonium heterocycles (2,(11)(12)(13)(14)(15). Extensive solution studies have shown that their mode of interaction with DNA may be altered due to structural modifications of these ligands containing sixmembered aromatic ring systems, e.g., clear-cut differences were found in the AT sequence binding ability between the antitumor drugs SN-6999 and SN-18071 (13,15).…”

Section: Introductionmentioning

confidence: 95%

DNA Binding of the Nonintercalative Ligands SN-6132, SN-6131 and SN-6113: Minor Variations of the Ligand Structure May Cause Changes in the Base Pair Preference

Luck

Störl

Baguley

et al. 1992

Journal of Biomolecular Structure and Dynamics

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The DNA binding selectivity of three ligands of a series of antitumor agents of bisquaternary ammonium heterocycles has been investigated by means of CD spectroscopy and melting measurements. From the spectroscopic results and binding data it is concluded that the agents SN-6132, SN-6131 and SN-6113 have relatively high affinity to AT base pair sequences whereas the binding to GC pairs is very low. The binding selectivity to AT base pair sequences decreases in the order netropsin > SN-6132 > SN-6113 > SN-6131. Poly(dA).poly(dT) has the highest binding preference for SN-6132 relative to that of SN-6131. The different binding behavior of the ligands is related to their distinct changes in the chemical structure and to the DNA minor groove properties which determines the adaptability of the ligands in the groove.

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Interaction of the Nonintercalative Antitumour Drugs SN-6999 and SN-18071 with DNA: Influence of Ligand Structure on the Binding Specificity

Cited by 23 publications

References 33 publications

Studies on the ability of minor groove binders to induce supercoiling in DNA

Studies on the ability of minor groove binders to induce supercoiling in DNA

Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs

DNA Binding of the Nonintercalative Ligands SN-6132, SN-6131 and SN-6113: Minor Variations of the Ligand Structure May Cause Changes in the Base Pair Preference

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