The change of the torsion of the DNA helix caused by intercalation

Saucier, Jean-Marie; Festy, B.; Pecq, J.‐B. Le

doi:10.1016/s0300-9084(71)80065-2

Cited by 116 publications

(66 citation statements)

References 22 publications

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“…The DNA binding of ethidium bromide itself was measured by spectrofluorometry (14,15), with a photon-counting spectrofluorometer built in this laboratory (16) log Kap = log KE+ -log (1 + [H +] [1] where KH-1 is the dissociation constant of the equilibrium between the protonated and nonprotonated drug and a is the ratio of the DNA binding constants of the protonated and neutral form of the drug. The unwinding angle of the DNA helix caused by the intercalation of each molecule was measured with covalently closed circular DNA from PM2 phage DNA as described (18,19). The relaxation of the supercoiled DNA was followed by viscosimetry as described by Revet et al (20).…”

Section: Methodsmentioning

confidence: 99%

“…This determination is valid only if one is sure that all the molecules bound to the circular DNA are intercalated. This can be controlled, as recently shown (19), by measuring the increase in length of short DNA helices in solution as a function of the amount of bound drug. This determination was performed by viscosimetry of sonicated DNA (18 (36).…”

Section: Methodsmentioning

confidence: 99%

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A New Antitumoral Agent: 9-Hydroxyellipticine. Possibility of a Rational Design of Anticancerous Drugs in the Series of DNA Intercalating Drugs

Pecq

Nguyen-Dat-Xuong

Gosse

et al. 1974

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

216

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The designing of DNA intercalating drugs with high DNA affinity in the series of ellipticine has led to a new antitumoral agent, 9-hydroxyellipticine, which has a high DNA affinity, a high activity on L 1210 mice leukemia, and a lack of toxicity at therapeutic dose. The possible correlations among chemical structure, DNA reactivity, and pharmacological activity of DNA intercalating drugs are discussed.Except for the hormonal products, which can prevent specific cells from proliferating, and drugs acting on the immunological system, most of the presently used anticancerous agents are cytotoxic compounds acting preferentially on tumor cells. Presently used antitumoral agents are already highly specific. For instance, it has been shown in an appropriate experimental model that a cancerous cell could be about a million times more sensitive to bis-chlorethylnitrosourea than a normal cell (1). Further progress in specificity seems, therefore, very difficult, especially since the basis at the molecular level of this specific toxicity is poorly understood. A rigorous approach in the design of new anticancerous compounds seems, therefore, an almost insuperable task. Nevertheless, the mechanism of the cytotoxicity property itself can in some cases be understood; that is mainly true for drugs acting on DNA structure or metabolism, among which are most of the anticancerous agents. If cytotoxic compounds could be rationally designed, one could hope to have better chance of finding among them anticancerous agents, since at the same time one could study the specificity of their action and try to understand it.Among products susceptible to such an approach are DNA intercalating drugs, because DNA intercalation is a rather well-understood mechanism and because it is almost the only case where the structure of what is thought to be the pharmacological receptor is known at atomic resolution (2). On the other hand, there belong already to this class of compounds some of the most powerful anticancerous agents, such as actinomycin D, daunomycin, and adriamycin. Our reasoning was, therefore, very simple. If DNA is the real receptor of these drugs and if we are able to design DNA intercalating compounds with the highest possible affinity for DNA, we would have a much better chance of finding active anticancerous drugs among these compounds. If this reasoning is correct, for this class of compounds high DNA reactivity is a condition necessary for anticancerous activity but not a condition that is sufficient; high DNA reactivity is necessary for conferring a potential cytotoxicity but is insufficient for conferring a specificity directed towards the cancerous cells.With these assumptions, the approach to be taken is clear. First, DNA intercalating drugs with increasing DNA affinities must be synthesized. Second, the correlation between the DNA reactivity and the pharmacological activity must be studied. The ability of drugs to intercalate in DNA is conditioned by their stereochemical parameters, such as size, shape, and planarity...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A New Antitumoral Agent: 9-Hydroxyellipticine. Possibility of a Rational Design of Anticancerous Drugs in the Series of DNA Intercalating Drugs

Pecq

Nguyen-Dat-Xuong

Gosse

et al. 1974

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

216

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“…Calf thymus (42% G + C ) DNA was purchased from Boehringer and sonicated according to Saucier et al [30]. The purity of the DNAs was checked by analytical ultracentrifugation in CsCl gradient at 20°C.…”

Section: Dnasmentioning

confidence: 99%

“…The length increase of short calf thymus DNA segments (100 pg/ml) was measured by the increase of intrinsic viscosity of the DNA in the presence of increasing concentrations of drugs as reported by Saucier et al [30]. Experiments were performed at 25 "C in 0.2 M sodium acetate pH 5.…”

Section: Viscometrymentioning

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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“…Various planar polycyclic aromatic compounds, such as the acridines, which can intercalate in the DNA base-pair stack (1)(2)(3)(4)(5)(6)(7)(8)(9), are mutagens that cause additions or deletions of nucleotides (10)(11)(12). These errors appear to result from stabilization of a shifted pairing in a repetitive sequence in DNA by intercalation of the planar compound and subsequent addition or deletion of base pairs during replication or repair synthesis (11,13).…”

mentioning

confidence: 99%

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Ames

Gurney

Miller

et al. 1972

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

298

121

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Several carcinogenic metabolites of the carcinogen 2-acetyl-aminofluorene, especially 2-nitrosofluorene and N-hydroxy-2-aminofluorene, are potent frameshift mutagens for Salmonella typhimurium. 2-Nitrosonaphthalene, 2-nitrosophenanthrene, 4-nitroso-transstilbene, 4-nitrosobiphenyl, and 4-nitrosoazobenzene, all of which are metabolites or likely metabolites of carcinogenic aromatic amines, are also potent frameshift mutagens. These compounds may be frameshift mutagens of the class that intercalates into DNA and then reacts covalently with the DNA; various ultimate carcinogens may be of this type. The utility of a set of bacterial strains for detecting carcinogens as mutagens is shown.Various planar polycyclic aromatic compounds, such as the acridines, which can intercalate in the DNA base-pair stack (1-9), are mutagens that cause additions or deletions of nucleotides (10-12). These errors appear to result from stabilization of a shifted pairing in a repetitive sequence in DNA by intercalation of the planar compound and subsequent addition or deletion of base pairs during replication or repair synthesis (11,13). Mlutagens with this property are called frameshift mutagens because of the shift in the reading frame of the mRNA synthesized from the altered DNA template; thus they differ from mutagens that cause basepair substitutions (11). The potency of an intercalating agent as a frameshift mutagen may increase by 10-to 100-fold if it also contains a side chain that can react covalently with DNA (12,(14)(15)(16)(17).Since it seemed possible that the reactive forms of some carcinogens with planar ring systems could be frameshift mutagens that both intercalate and react with DNA, epoxides of polycyclic hydrocarbons were examined and found to be mutagens of this type (16). In this paper this question is examined further with certain known and potential metabolites of 2-acetylaminofluorene (18). The striking activity of 2-nitrosofluorene as a frameshift mutagen then led to tests of nitroso derivatives related to various other aromatic amine carcinogens. These studies have made use of a set of tester strains (14-16) of Salmonella typhimurium that were developed for detection and classification of mutagens. MATERIALS AND METHODSBacterial Test for Mutagens. The mutagenicity test uses four Salmonella strains that require histidine (14-16). The test measures the effect of a mutagen on the reversion to growth on a histidine-free medium of these tester strains. Three of the tester strains (TA1531, TA1532, and TA1534) were designed for detecting frameshift mutagens with different specificities; each strain has a frameshift mutation in one of the genes of the histidine operon. The fourth strain (TA1530) has a base-pair change in the histidine G gene, and is used to detect mutagens that cause base-pair substitutions. In addition, all four strains lack the excision repair system (because of a deletion through uvrB); this makes them much more sensitive to any mutagen that alters the DNA in a way that would normally be repai...

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The change of the torsion of the DNA helix caused by intercalation

Cited by 116 publications

References 22 publications

A New Antitumoral Agent: 9-Hydroxyellipticine. Possibility of a Rational Design of Anticancerous Drugs in the Series of DNA Intercalating Drugs

A New Antitumoral Agent: 9-Hydroxyellipticine. Possibility of a Rational Design of Anticancerous Drugs in the Series of DNA Intercalating Drugs

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

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

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