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

Abstract

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...

Interactions between Ellipticine and Phospholipids. Effect of Ellipticine and 9‐Methoxyellipticine on the Phase Behaviour of Phosphatidylglycerols

“…In the mixed films, both lipids would exist in a very similar and rather condensed state, intermediate between the liquidexpanded and gel states in which these two lipids can respectively exist on pure water. The possibility of membranes being one of the sites of action of ellipticines is discussed.Ellipticine and some of its derivatives constitute an interesting class of substances displaying an antitumoral activity against both experimental and human tumors, as well as other pharmacological propertiesThe mechanism of the cytotoxic action of these drugs is supposedly related to their interactions with DNA for which they exhibit a very high affinity and in which they intercalate [2,3].However, it can be observed in Fig. 1 that ellipticine and its 9-methoxy analogue have a net amphipathic character, a structural feature which endows these substances with the ability to interact with membrane components, especially with phospholipids.…”

“…The mechanism of the cytotoxic action of these drugs is supposedly related to their interactions with DNA for which they exhibit a very high affinity and in which they intercalate [2,3].…”

Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

“…This suggests that the magnitude of uncoupling depends on the concentration of the neutral form released in the matrix after accumulation of the protonated form. Based on membrane potential measurements, it appears that the protonable molecules (1, 3-6) induce a depolarization of the mitochondrial inner membrane much more efficiently than the permanent cation ellipticinium does (2). This comparison suggests that the protonable molecules are able to carry more cationic charges into mitochondria than ellipticinium.…”

“…A large number of ellipticine derivatives have been synthesized (2) to investigate its mode of action. It has been shown that this molecule is able to intercalate between DNA base pairs (3), and some authors have shown a good in vitro correlation between cytotoxicity and induced dichroic spectra of drug-DNA complexes (4).…”

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

“…In this series, 9-hydroxyellipticine ( fig. 1) which displays a high affinity for DNA has been thoroughly investigated [6]. This compound is very active against L1210 mice lymphoid leukemia [7].…”