Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites.
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.
Bae
Suyeal
S
Organic Chemistry Laboratory, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 136-791, Korea.
Mah
Heduck
H
Chaturvedi
Surendrakumar
S
Jeknic
Tamara Musafia
TM
Baird
William M
WM
Katz
Amy K
AK
Carrell
H L
HL
Glusker
Jenny P
JP
Okazaki
Takao
T
Laali
Kenneth K
KK
Zajc
Barbara
B
Lakshman
Mahesh K
MK
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010616:Phenanthrenes / Q000737:chemistry* / Q000378:metabolism*
D018736:DNA Adducts; D004273:DNA, Neoplasm; D004852:Epoxy Compounds; D006845:Hydrocarbons, Fluorinated; D010616:Phenanthrenes