Claude Richard

Free radical scavenging and cytotoxic properties in the ellipticine series

In the series of cytotoxic intercalating compounds derived from ellipticine, we tried to correlate free radical scavenging properties with cytotoxic activities. Scavenging properties were determined in vitro on two experimental models: a) antioxidant activity of the drugs during the autoxidation of methyl linolenate induced by azo-bis-isobutyronitrile; this activity was measured either by the initial rate ratios in the presence and in the absence of the drug or by the length of the inhibition period of the reaction in the presence of the drug and b) ability to reduce DPPH free radicals. Cytotoxic properties were expressed by ID50 the dose which reduces by 50% the L 1210 cell growth rate as compared to controls after 48 h. It appears that antioxidant activity and reduction of DPPH both require the presence of a free OH group on the ellipticine ring. A good correlation is observed between cytotoxicity and antioxidant activity of the hydroxylated derivatives; minor structural modifications which result in a loss of cytotoxic activity also result in a loss of antioxidant properties. No such correlation is observed with DPPH reducing properties of ellipticine derivatives.

Kinetics of bimolecular decay of α‐tocopheroxyl free radicals studied by ESR

The kinetics of bimolecular decay of α‐tocopheroxyl free radicals (T.) was studied by ESR mainly in ethanol and heptanol solvents. A second‐order kinetic law was observed during the whole course of reaction (‐d[T.]d t = 2 k[T.]2) and the following rate constants were determined with good accuracy in the temperature range 281–321 K: ethanol: log(2 k) = 8.2 ± 0.5 — (6.6±0.7 kcal/mol)/(2.3 RT) M−1·s−1; heptanol: log(2 k)=6.1±0.4‐(4.3±0.6 kcal/mol)/(2.3 RT) M−1.s−1. The global rate constant clearly increases with solvent polarity.

Correlation between the OH bond dissociation energies of ellipticine hydroxylated derivatives and their cytotoxic properties

The O−H bond dissociation energies (BDEs) of ellipticine‐derived hydroxylated compounds have been evaluated by a kinetic method and are shown to correlate with the cytotoxic activity of these derivatives.