PHOTOELECTRON AND ABINITIO MOLECULAR-ORBITAL INVESTIGATIONS OF GENOTOXIC BENZ[A]ANTHRACENE METABOLITES - ELECTRONIC INFLUENCES ON DNA-BINDING

Gas-phase He(I) UV photoelectron (PE) spectra have been measured for nine benz[a]anthracene (BA) and alkyl-BA metabolites. Among the metabolites examined are the diols, (+/-)-trans-3,4-dihydroxy-3,4-dihydro-BA (BAD); the 7-methyl (MBAD), 7-ethyl (EBAD) and 7,12-dimethyl (DMBAD) derivatives of BAD; and cis-5,6-dihydroxy-5,6-dihydro-BA. Also investigated were the bay-region diol epoxides, (+/-)-trans-3,4-dihydroxy-anti- 1,2-epoxy- 1,2,3,4-tetrahydro-BA (BADE); the 7-methyl (MBADE) and 7-ethyl (EBADE) derivatives of BADE; and the K-region epoxide, BA-5,6-oxide (BAO). Of these metabolites, the diols, BAD, MBAD, and DMBAD, are potent proximate carcinogens, which in vivo are enzymatically activated to the ultimate carcinogens, BADE, MBADE, and the corresponding 7,12-dimethyl-BA epoxide. Current evidence indicates that the covalent binding, and possibly the reversible physical binding, of hydrocarbon epoxides to DNA influence the genotoxic activities of these molecules. Photoelectron spectra have been assigned by comparison with results from semiempirical HAM/3 and ab initio SCF molecular orbital calculations employing the 4-31G basis set. A comparison of DNA association constants and IP's for seven hydrocarbons with the naphthalene or anthracene pi systems and for the BA diols examined here demonstrates that, as the IP's of structurally similar unhindered hydrocarbons and BA diols decrease, the association constants increase. For structurally similar hydrocarbons and BA metabolites, average polarizabilities, calculated at the 4-31G level, also increase as the pi ionization potentials decrease. A relationship between polarizability and reversible binding to DNA is suggested by a comparison of polarization energy maps calculated, at the 4-3 IG level, for anthracene and 9,10-dimethylanthracene (9,10-DMA). In calculations using a 0.5 eu positive probe charge, the map calculated for 9,10-DMA has contours that over large regions, are 1.0-1.5 kcal/mol more attractive than corresponding contours in the map for anthracene. The present results indicating that the first IP's of the epoxides decrease in the order BAO (7.58 eV) > BADE (7.37 eV) > MBADE (7.28 eV) almost-equal-to EBADE (7.27 eV) are consistent with previously reported observations that alkylation of BADE in the 7- and 12-positions enhances reactivity and that bay-region diol epoxides are more reactive than K-region epoxides. The greater reactivity of bay-region diol epoxides versus K-region epoxides is also reflected in the electron distributions of the highest occupied molecular orbitals (HOMO's). For BADE, but not BAO, the HOMO has large electron density in a region that aids stabilization of transition states occurring in reactions with DNA.