Footprinting Studies on the Sequence-Selective Binding of Tilorone to DNA

Bailly, Christian; Waring, Michael J.

doi:10.1177/095632029300400206

Cited by 7 publications

(3 citation statements)

References 71 publications

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“…For tilorone, the AT preference initially proposed on the basis of theoretical calculations (Chen et al, 1988) and spectroscopic measurements (Chandra & Woltersdorf, 1976) did not hold up when foot printing experiments were performed. In agreement with Sturm (198 2), we found that tilorone binds best to alternating purine-pyrimidine sequences which can contain both AT and GC base pairs (Bailly & Waring, 1993). For amiloride, the cleavage inhibition assays clearly evidenced the AT preference (Bailly et al, 1993a), but the chemical structure of this drug, a pyrazine derivative, is totally different from that of the thioxanthenones, not least in the lack of a polycyclic aromatic ring system.…”

Section: Discussionsupporting

confidence: 87%

“…It has been widely used to detect unusual DNA structures (Johnston & Rich, 1985;McLean & Wells, 1988;Palecek et al, 1989). In pharmacology, it has been applied with success to examine the structural changes in DNA induced by binding of mono-and bis-intercalating agents (Mclean & Waring, 1988;McLean etal., 1989;Bailly & Waring, 1993). The osmium tetroxidebis(pyridine) complex attacks the 5,6 double bond of pyrimidines in the major groove, most particularly at thymine residues.…”

Section: Resultsmentioning

confidence: 99%

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Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study

Bailly¹,

Waring²

1993

Biochemistry

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DNAase I footprinting has been used to probe the DNA sequence selectivity of the antitumor intercalating agents lucanthone (1), hycanthone (2), 6-chlorolucanthone (7), and four indazole analogs (IA-3-IA-6). The latter have a benzothiopyranoindazole chromophore substituted with a diethylaminoethyl side chain identical to that attached to the thioxanthenone chromophore of compounds 1, 2, and 7. IA-3 and IA-5 are lucanthone analogs bearing a methyl group at position 4, whereas IA-4 and IA-6 are hycanthone analogs bearing a hydroxymethyl group. IA-3 and IA-4 have an additional chloro group at position 6. Studies employing the 160-bp tyrT DNA fragment as substrate to assay inhibition of DNAase I-mediated cleavage show that both lucanthone and hycanthone bind preferentially to AT sites. They discriminate against GC-rich sequences as well as short runs of a single base, which are often cut more readily in the presence of the drugs compared to the control. The indazole analogs exhibit more pronounced selectivity of binding to AT sequences and promote enhanced DNAase I cleavage both at GC-rich sequences and at homooligomeric runs of adenines or thymines. The results of further DNAase I cleavage inhibition assays, performed with three more restriction fragments having different base pair arrangements, are fully consistent with those obtained with the tyrT fragment. They reveal that the preferred binding sequences for lucanthone, hycanthone, and the indazole analogs are predominantly composed of alternating A and T residues.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study

Bailly¹,

Waring²

1993

Biochemistry

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“…For instance, they could influence the folding of the DNA [203], induce cytokine-operation in general, and interferon-activities (endogenous reactions see also chapter 4.2.) in particular [314][315][316][317], and are capable of inhibiting both reverse transcriptases and telomerases [162,[317][318][319][320][321][322][323]; see Fig. (10).…”

Section: Supramolecular Relationshipmentioning

confidence: 99%

DNA-binding of Drugs Used in Medicinal Therapies

Bischoff¹,

Hoffmann²,

Жданов³

2004

Frontiers in Medicinal Chemistry - Online

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The interactions of various low-molecular weight substances with DNA are naturally relevant mechanisms in the cellular cycle and so also used in medicinal treatment. Depending on the particular drug structure, DNA-binding modes like groove-binding, intercalating and/or stacking, give rise to supramolecular assemblies of the polynucleotides, as well as influence the DNA-protein binding. In this review, we compare the underlying molecular structures, including general aspects of DNA sequences, with the benefit in medicinal treatment. While so far interest in this field had mainly been devoted to isolated nucleic acid/drug interactions, the present paper will focus on drug efficiencies generating and influencing supramolecular organizations and their complex sequence-dependent structure-activity codes. In particular, the attention will be directed to stereoelectronic relationships. Spatial enantioselective properties are discussed in details. As examples, the drug self-assemblies, as well as the influence of drugs on supramolecular DNA formations are described. A hypothetical connection between drug-influenced DNAtoroids and the formation of micronuclei in tissues will be interpreted. As an important group of medicines a variety of lipids appears, which could also be bound to chromatin and DNA as an individual molecules or as lipoproteins. Their upcoming importance on the regulation of lipid composition in genome, called lipidomics, is briefly described, too.

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Drug—DNA sequence‐dependent interactions analysed by electric linear dichroism

Bailly

Hénichart

Colson

et al. 1992

J of Molecular Recognition

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The interactions between 20 drugs and a variety of synthetic DNA polymers and natural DNAs were studied by electric linear dichroism (ELD). All compounds tested, including several clinically used antitumour agents, are thought to exert their biological activities mainly by virtue of their abilities to bind to DNA. The selected drugs include intercalating agents with fused and unfused aromatic structures and several groove binders. To examine the role of base composition and base sequence in the binding of these drugs to DNA, ELD experiments were carried out with natural DNAs of widely differing base composition as well as with polynucleotides containing defined alternating and non-alternating repeating sequences, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT),poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC). Among intercalating agents, actinomycin D was found to be by far the most GC-selective. GC selectivity was also observed with an amsacrine-4-carboxamide derivative and to a lesser extent with methylene blue. In contrast, the binding of amsacrine and 9-aminoacridine was practically unaffected by varying the GC content of the DNAs. Ethidium bromide, proflavine, mitoxantrone, daunomycin and an ellipticine derivative were found to bind best to alternating purine-pyrimidine sequences regardless of their nature. ELD measurements provided evidence for non-specific intercalation of amiloride. A significant AT selectivity was observed with hycanthone and lucanthone. The triphenyl methane dye methyl green was found to exhibit positive and negative dichroism signals at AT and GC sites, respectively, showing that the mode of binding of a drug can change markedly with the DNA base composition. Among minor groove binders, the N-methylpyrrole carboxamide-containing antibiotics netropsin and distamycin bound to DNA with very pronounced AT specificity, as expected. More interestingly the dye Hoechst 33258, berenil and a thiazole-containing lexitropsin elicited negative reduced dichroism in the presence of GC-rich DNA which is totally inconsistent with a groove binding process. We postulate that these three drugs share with the trypanocide 4',6-diamidino-2-phenylindole (DAPI) the property of intercalating at GC-rich sites and binding to the minor groove of DNA at other sites. Replacement of guanines by inosines (i.e., removal of the protruding exocyclic C-2 amino group of guanine) restored minor groove binding of DAPI, Hoechst 33258 and berenil. Thus there are several cases where the mode of binding to DNA is directly dependent on the base composition of the polymer. Consequently the ELD technique appears uniquely valuable as a means of investigating the possibility of sequence-dependent recognition of DNA by drugs.

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Footprinting Studies on the Sequence-Selective Binding of Tilorone to DNA

Cited by 7 publications

References 71 publications

Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study

Preferential intercalation at AT sequences in DNA by lucanthone, hycanthone, and indazole analogs. A footprinting study

DNA-binding of Drugs Used in Medicinal Therapies

Drug—DNA sequence‐dependent interactions analysed by electric linear dichroism

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