Quantum chemical and other theoretical studies of carcinogens, their metabolic activation and attack on DNA constituents.

We have carried out a variety of different types of studies on carcinogens: ab-initio quantum chemical, including generation of electrostatic molecular potential contour (EMPC) maps and graph theoretical generation of polycyclic aromatic hydrocarbon (PAH) structures and characterization of the "carcinogenic" bay regions. Polycyclic aromatic hydrocarbon (PAH) carcinogens are activated metabolically from precarcinogen (PAH's) through proximate carcinogens (PAH epoxides and dihydrodiols) to ultimate carcinogens (PAH dihydrodiolepoxides) which then attack DNA constituents. We carried out ab-initio MODPOT/VRDDO/MERGE calculations on a variety of these molecules using our own ab-initio programs which incorporate as options a number of desirable options for ab-initio calculation on large molecules. From these electronic wave functions, we generated electrostatic molecular potential contour (EMPC) maps around these molecules. These EMPC maps indicated predictively the positions at which epoxides would form and the propensity and geometrical preference to form dihydrodiols and dihydrodiolepoxides. We performed spin and symmetry analyses for attack of O adding across C = C bonds or inserting in C-H or N-H bonds. We also carried out ab-initio calculations for attack of ultimate carcinogens on DNA constituents. Using graph theory we generated all possible structures for any arbitrary numbers of aromatic rings and also set up a graph theoretical characterization of the "carcinogenic" bay region. Most recently, we have incorporated this into a computer program for global prediction of toxicity.