On the significance of the trigger reaction in the action of the calicheamicin γ1I anti-cancer drug

The significance of the so-called trigger reaction in the reaction mechanism of the calicheamicin γ₁ ^I anti-cancer drug has been studied with ab initio quantum chemical methods. The structures of four fragments of calicheamicin γ₁ ^I , 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 preceding 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 M?ller-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 vicinity 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. Received: 10 January 1997 / Accepted: 1 April 1997