Calicheamicin

Drugs involving an enediyne moiety has found much use in cancer therapy, e.g. calicheamicin. We have studied how the reaction of these drugs is triggered [23]. Evidently, the saturation of a double bound, causing a relaxation of the structure, is more important for the trigger than the decrease in the distance between the two acetylenic carbon atoms in the drug.

On the significance of the trigger reaction in the action of the calicheamicin anti-cancer drug.

Roland Lindh, Ulf Ryde & Martin. Schütz

Theor. Chem. Acc. 97 (1997) 203-210.

Abstract
The significance of the so-called trigger reaction in the reaction mechanism of the calicheamicin anti-cancer drug has been studied with ab initio quantum chemical methods. The structures of four fragments of calicheamicin, consisting of either 39 or 41 atoms, have been fully optimized using the Becke-Perdew86 density functional method and the 6-31G* basis sets. The four structures constitute members of an isodesmic reaction for which the reaction energy is a direct measure of the change in activation energy of the Bergman reaction, caused by the structural rearrangements of the preceeding trigger reaction. This difference in activation energy has been calculated with density functional theory, using the exchange-correlation functional mentioned above, and with second-order Moeller-Plesset perturbation theory (MP2), employing an ANO-type basis set. In both cases a value of 12 kcal/mol is obtained.The study firmly supports the hypothesis that the significance of the trigger reaction is to saturate a double bond in the vincinity of the enediyne group, which counteracts the formation of the biradical state of the drug. The MP2 computations became feasible by a novel implementation of an integral-direct, distributed-data, parallel MP2 algorithm.