Interest of Quantum Mechanical Calculations for the Design of Anticancerous Drugs in the Series of Ellipticines

Pecq, J.‐B. Le; Bret, Marc Le; Gosse, Charlie; Paoletti, Claude; Chalvet, O.; Dat-Xuong, N

doi:10.1007/978-94-010-1758-9_36

Cited by 18 publications

(19 citation statements)

References 17 publications

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“…In the first case, the removal of a single methyl group from ellipticine in position 11 causes a pKa drop of 3 units and, consequently, a 10-fold decrease of the DNA binding constant at pH 7.4. The KE + values of the two derivatives are similar.…”

Section: Resultsmentioning

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: Resultsmentioning

confidence: 99%

“…This study led to the selection of a new antitumoral agent, 9-hydroxyellipticine, which has high DNA affinity, a high activity on L 1210 mice leukemia, and a lack of toxicity at therapeutic dose. The anticancerous activity of this compound was reported in a preliminary communication (11).…”

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confidence: 86%

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 title compound ( Fig. la) possesses pharmacological properties similar to those of its direct derivative 9-hydroxy-2-methylellipticinium (celiptium) (Le Pecq, Gosse, Dat-Xuong & Paoletti, 1975), the structure of which is described in the preceding paper (Salahou, CourseiUe & Tsai, 1988). The methylation of nitrogen in position 6 gives a threefold increase of DNA affinity (Paoletti, 0108-2701/88/122126-03503.00…”

mentioning

confidence: 90%

Nucleic acid intercalating drug. The structure of 9-hydroxy-2,5,6,11-tetramethylpyrido[4,3-b]carbazolium (9-hydroxy-2,6-dimethylellipticinium) chloride monohydrate

Salahou¹,

Courseille²,

Tsai³

1988

Acta Crystallogr C

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“…1) which displays a high affinity for DNA has been thoroughly investigated [6]. This compound is very active against L1210 mice lymphoid leukemia [7].…”

Section: Introductionmentioning

confidence: 99%

Effects of 9‐hydroxyellipticine on growth and macromolecular synthesis in Escherichia coli

1976

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Interest of Quantum Mechanical Calculations for the Design of Anticancerous Drugs in the Series of Ellipticines

Cited by 18 publications

References 17 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

Nucleic acid intercalating drug. The structure of 9-hydroxy-2,5,6,11-tetramethylpyrido[4,3-b]carbazolium (9-hydroxy-2,6-dimethylellipticinium) chloride monohydrate

Effects of 9‐hydroxyellipticine on growth and macromolecular synthesis in Escherichia coli

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