Synthetic, Crystallographic, Computational, and Biological Studies of 1,4-Difluorobenzo[c]phenanthrene and Its Metabolites
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1,4-Difluorobenzo[c]phenanthrene (1,4-DFBcPh) and its putative metabolites, the dihydrodiol and diolepoxides, have been synthesized and structurally characterized, and the extent of DNA binding by themetabolites has been assessed. 1,4-DFBcPh and 1,4-difluoro-10-methoxybenzo[c]phenanthrene were preparedby photochemical cyclization of appropriate naphthylphenylethylenes. The dihydrodiol was synthesizedfrom 1,4-difluoro-10-methoxybenzo[c]phenanthrene, and the diol epoxides were diastereoselectivelysynthesized 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 aquasi-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. ComparativeX-ray crystallographic analyses of BcPh and 1,4-DFBcPh and their dihydrodiols show that introduction offluorine increases the molecular distortion by about 6-7. As a guide to estimating the molecular distortionand 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 epoxideswere computed. Relative aromaticities of these compounds were assessed by nucleus-independent chemicalshift 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 humanbreast cancer MCF-7 cells was assessed. The extent of DNA binding was then compared with that forBcPh and its dihydrodiol and the potent carcinogen benzo[a]pyrene. The 1,4-DFBcPh series 2 (anti) diolepoxide-derived DNA adducts were also compared with those arising from intracellular oxidation of thedihydrodiol with subsequent DNA binding. These experiments showed that increased molecular distortiondecreased metabolic activation to the terminal metabolites but that diol epoxide metabolites that are formedare the DNA-damaging species.

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