1,4-
Difluorobenzo[c]phenanthrene (1,4-DFBcPh) and its putative metabolites, the
dihydrodiol and diol
epoxides, have been synthesized and structurally characterized, and the extent of
DNA binding by the metabolites has been assessed. 1,4-DFBcPh and 1,4-difluoro-10-methoxybenzo[c]
phenanthrene were prepared by photochemical cyclization of appropriate naphthylphenylethylenes. The
dihydrodiol was synthesized from 1,4-difluoro-10-methoxybenzo[c]
phenanthrene, and the diol
epoxides were diastereoselectively synthesized from the
dihydrodiol. Interesting differences were noted in 1H NMR spectra of the series 1 (syn) diol
epoxides of
benzo[c]phenanthrene (BcPh) and 1,4-DFBcPh; the BcPh diol
epoxide displays a quasi-diequatorial orientation of the
hydroxyl groups, but in the 1,4-DFBcPh case these are diaxially disposed. This difference probably stems from the presence of the fjord-region
fluorine atom in 1,4-DFBcPh. A through-space, fjord-region H-F coupling has also been observed for 1,4-DFBcPh and its derivatives. Comparative X-ray crystallographic analyses of BcPh and 1,4-DFBcPh and their dihydrodiols show that introduction of
fluorine increases the molecular distortion by about 6-7 degrees . As a guide to estimating the molecular distortion and its effects, and for comparison with the X-ray structures in known cases, optimized structures of BcPh, 1,4-DFBcPh, and 1,4-DMBcPh (the dimethyl analogue) as well as their dihydrodiols and diol
epoxides were computed. Relative aromaticities of these compounds were assessed by nucleus-independent chemical shift calculations, and 13C NMR chemical shifts were computed by gauge-inducing atomic orbital calculations. 1,4-DFBcPh and its
dihydrodiol were subjected to metabolism, and the amount of
DNA binding in human
breast cancer MCF-7 cells was assessed. The extent of
DNA binding was then compared with that for BcPh and its
dihydrodiol and the potent
carcinogen benzo[a]pyrene. The 1,4-DFBcPh series 2 (anti) diol
epoxide-derived
DNA adducts were also compared with those arising from intracellular oxidation of the
dihydrodiol with subsequent
DNA binding. These experiments showed that increased molecular distortion decreased metabolic activation to the terminal metabolites but that diol
epoxide metabolites that are formed are the
DNA-damaging species.