jo071145s_si_018.pdf (4 MB)
Synthetic, Crystallographic, Computational, and Biological Studies of 1,4-Difluorobenzo[c]phenanthrene and Its Metabolites
journal contribution
posted on 2007-09-28, 00:00 authored by Suyeal Bae, Heduck Mah, Surendrakumar Chaturvedi, Tamara Musafia Jeknic, William M. Baird, Amy K. Katz, H. L. Carrell, Jenny P. Glusker, Takao Okazaki, Kenneth K. Laali, Barbara Zajc, Mahesh K. Lakshman1,4-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°. 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.