ON THE SIGNIFICANCE OF THE TRIGGER REACTION IN THE ACTION OF THE CALICHEAMICIN GAMMA(I)(1) ANTICANCER DRUG

The significance of the so-called trigger reaction in the reaction mec hanism of the calicheamicin gamma(1)(l) anti-cancer drug has been stud ied with ab initio quantum chemical methods. The structures of four fr agments of calicheamicin gamma(1)(l), consisting of either 39 or 41 at oms, have been fully optimized using the Becke-Perdew86 density functi onal method and the 6-31G basis sets. The four structures constitute members of an isodesmic for which the reaction energy is a direct of t he change in activation energy of the Bergman reaction, caused by the structural rearrangements of the preceding trigger reaction. This diff erence in activation energy has been calculated with density functiona l theory, using the exchange-correlation functional mentioned above, a nd with second-order Moller-Plesset perturbation theory (MP2), employi ng an ANO-type basis set. In both cases a value of 12 kcal/mol is obta ined. The study firmly supports the hypothesis that the significance o f 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 imp lementation of an integral-direct, distributed-data, parallel MP2 algo rithm.