Computer design of anticancer drugs. A new enediyne warhead

Seven criteria are developed and discussed that lead to the design of a new enediyne anticancer drug, which should have low toxicity but high biologic al selectivity and activity when attacking the DNA of tumor cells. These cr iteria concern (among others) the thermodynamic and kinetic stability of th e species involved in the reaction of an enediyne, the biradical character and H-abstraction ability of the intermediate biradical generated in a Berg man reaction of the enediyne, and the basicity of the enediyne and its asso ciated biradical. Thirteen different heteroenediynes were investigated with the help of B3LYP/6-31G(d,p) calculations to find a suitable candidate for a new enediyne anticancer drug, which fulfills the seven criteria. These c alculations included the determination of reaction profiles for Bergman and retro-Bergman reactions, the calculation of singlet-tripler splittings of biradicals formed from enediynes, and the prediction of pK(a) values. Resul ts were tested by using a larger basis set (6-311+G(3df,3pd)), another func tional (BLYP), and coupled cluster methods such as CCSD(T) and the Brueckne r orbitals-based BD(T) method. The best candidate for a new enediyne antica ncer drug is an N,C-dialkynyl aldimine incorporated into a cyclodecaene rin g.