DNA polyintercalating drugs: DNA binding of diacridine derivatives.

Pecq, J.‐B. Le; Bret, Marc Le; Barbet, Jacques; Roques, B. P.

doi:10.1073/pnas.72.8.2915

Cited by 188 publications

(142 citation statements)

References 19 publications

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“…As few as one or two lesions per 3000-base-pair plasmid are sufficient for the protein-DNA complexes to bind to the nitrocellulose filter. UvrA protein, independent of the UvrB protein, binds to ditercalinium-intercalated DNA with an affinity equal to that of the UvrAB-ditercalinium-DNA or (17). The ionic strength and the pH of the UvrABC endonuclease buffer are close to those of the buffer used in the ditercalinium binding studies (10).…”

Section: Resultsmentioning

confidence: 93%

The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli.

Lambert

Jones²,

Roques³

et al. 1989

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

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We have demonstrated that the noncovalent complex formed between DNA and an antitumor bifunctional intercalator, ditercalinium, is recognized in vitro as bulky covalent DNA lesions by the purified Escherichia coli UvrABC endonuclease. It was established that no covalent drug-DNA adduct was formed during the incubation ofthe drug with DNA or during subsequent incubation with the UvrAB proteins. The nucleoprotein-ditercalinium complexes appear different from those generated by repair of pyrimidine dimers. The UvrA protein is able to form a stable complex with ditercaliniumintercalated DNA in the presence of ATP, whereas both UvrA and UvrB proteins are required to form a stable complex with pyrimidine dimer-containing DNA. The apparent half-life of the UvrA-and UvrAB-ditercalinium-DNA complexes following removal of free ditercalinium is 5 min. However, if the free ditercalinium concentration is maintained to allow the intercalation of one molecule of ditercalinium per 3000 base pairs, the half-life of the UvrA-or UvrAB-ditercalinium-DNA complex is 50 min, comparable to that of the complex of UvrAB proteins formed with pyrimidine dimer-containing DNA.UvrABC endonuclease incises ditercalinium-intercalated DNA as efficiently as pyrimidine dimer-containing DNA. However, unlike repair of pyrimidine diners, the incision reaction is strongly favored by the supercoiling of the DNA substrate. Because UvrA-or UvrAB-ditercalinium-DNA complexes can be formed with relaxed DNA without leading to a subsequent incision reaction, these apparently dead-end nucleoprotein complexes may become lesions in themselves resulting in the cytotoxicity of ditercalinium. Our results show that binding of excision repair proteins to a noncovalent DNA-ligand complex may lead to cell toxicity.

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Section: Resultsmentioning

confidence: 93%

The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli.

Lambert

Jones²,

Roques³

et al. 1989

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

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“…We have previously shown that the dimerization of intercalating compounds can lead to a large increase in DNAbinding affinity [22,231. The maximum binding constant expected for a dimer was here shown to be about the square of the monomer binding constant.…”

Section: Discussionmentioning

confidence: 99%

“…advantage of the fact that the fluorescence of acridine dimers depends on the DNA (A + T) content to the fourth power [22]. The dye was first preincubated with one of the DNAs for 16 h, the equilibrium was then perturbed by a large excess of the other DNA, and the exchange reaction was observed.…”

Section: Exchange Kineticsmentioning

confidence: 99%

Acridine dimers: influence of the intercalating ring and of the linking‐chain nature on the equilibrium and kinetic DNA‐binding parameters

Markovits

Garbay‐Jaureguiberry

Roques

et al. 1989

European Journal of Biochemistry

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The rigidity of the linking chain of bifunctional intercalators in the ditercalinium series was shown to be critical for antitumor activity. In order to study the influence of the rigidity of the linking chain on the DNAbinding properties of DNA bifunctional intercalators, fluorescent 9-aminoacridine and 2-methoxy-6-chloro-9-aminoacridine analogues with chains of variable rigidity were synthesized.'H-NMR studies show that the conformation of 9-aminoacridine dimers is almost independent of the nature of the linking chain. A strong self-stacking of the aromatic rings of the 2-methoxy-6-chloro-9-aminoacridine is observed for dimers with flexible chains but not for those with rigid chains.All the dimers having a linking chain long enough to bisintercalate in DNA according to the excluded site model are indeed bisintercalators. The kinetic association constant of all monomers and dimers for poly-. The large increase of DNA binding affinity observed for the dimers is always associated with the expected decrease of the dissociation rate constant.The effect of chain rigidity and pH on the calf thymus DNA binding of 9-aminoacridine and 2-methoxy-6-chloro-9-aminoacridine dimers is quite different. In the series of 9-aminoacridine the pK, of the dimers remains high and therefore no difference of DNA-binding affinity is observed between pH 5 and 7.4. The rigidity of the linking chain does not significantly alter the DNA-binding affinity.In the 2-methoxy-6-chloro-9-aminoacridine series, the pK, of all dimers became smaller than the physiological pH and a dramatic decrease of DNA-binding affinity is observed when the pH is increased from pH 5 to 7.4. This decrease appears significantly smaller for dimers with rigid chains. A similar dramatic decrease of binding affinity at pH 714is not observed for poly[d(A-T)] for the alternating polymer at pH 7.4.Many DNA-intercalating drugs elicit antitumor properties [ 11. Among these are ellipticinium, acridine derivatives, anthracenedione and the antibiotics actinomycin D, daunorubicin and adriamycin. The antitumor properties of these drugs are in part related to their DNA-binding parameters [2 -71. In order to obtain new anticancer agents, it was logical to design molecules which bind to DNA with higher affinity. Such molecules might be able to compete in vivo with the DNA-binding proteins like repressors or polymerases. Several polyfunctional intercalators were synthesized or isolated and their DNA-binding properties studied [8 -211. As expected these compounds exhibited DNA-binding affinities much greater than their corresponding monomers [22 -241.Moreover, in the series of 7H-pyridocarbazole dimers, several molecules elicited strong antitumor activity [25, 261. These antitumor properties were strictly restricted to dimers connected by rigid chains like bis(ethy1piperidine) 127, 281. These observations led us to study the influence of the linking chain nature on the conformational properties of such dimersCorrespondence to J

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“…Drugs containing two intercalative chromophore groups have been synthesized in recent years (Le Pecq et al, 1975;Dervan and Becker, 1978). These include bis.acridine and bis eL~idium (as well as mixed acridine-ethidium) polyintercalating agents.…”

Section: Bis Intercalation --A Probe For 8 Kinked Structural Distortimentioning

confidence: 99%

“…An important class of intercalative drugs and dyes that has received considerable attention in recent years are the bis intercalators --bifunctional intercalating agents that have two chromophore groups separated by about 10.2 A (Wakelin and Waring, 1976;Ughetto and Waring, 1977;Le Pecq et al, 1975;Butour et al, 1978;Dervan and Becker, 1978). These molecules intercalate into DNA in a neighbor exclusion mode (Le., the intercalative chromophore groups are separated.…”

Section: Bis Intercalation --A Probe For 8 Kinked Structural Distortimentioning

confidence: 99%

Structural and Energetic Considerations of Wave Propagation in DNA

Sobell¹,

Lozansky²,

Lessen³

1979

Cold Spring Harbor Symposia on Quantitative Biology

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DNA polyintercalating drugs: DNA binding of diacridine derivatives.

Cited by 188 publications

References 19 publications

The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli.

The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli.

Acridine dimers: influence of the intercalating ring and of the linking‐chain nature on the equilibrium and kinetic DNA‐binding parameters

Structural and Energetic Considerations of Wave Propagation in DNA

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