Synthetic, Crystallographic, Computational, and Biological Studies of 1,4-Difluorobenzo[c]phenanthrene and Its Metabolites

Abstract

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.

Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia–Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape

“…To date, various methods have been used for the introduction of fluorine into polycyclic aromatic systems, such as diazotization-fluorination, 11 direct electrophilic substitution, 12 bromine-fluorine exchange, 13 and cyclizations of smaller fluorinated building blocks. 14 Photocyclizations of stilbene like derivatives with appropriate fluorine atom-substituted and often commercially available aryl moieties are known, 10,15 and recently photodehydrofluorination approach to polyfluorinated polycyclic aromatic hydrocarbons has been reported. 15e Although stilbene can be cyclized readily to phenanthrene, it has been reported that α-fluorostilbene could not be cyclized to the fluoro analogue.…”

Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives

“…Both quinones showed characteristic fjord-region quinonoid proton resonances (d, J = 10.5 Hz), which corresponded well with other quinones of B c Ph and its derivatives. 32e,33,34 …”

“…This difference between the two hydrocarbons is likely due to the extreme out-of-plane distortion of DFB c Ph. 34 The series 1 diol epoxide of benzo[ ghi ]fluoranthene (B[ ghi ]F), a compound that is expected to be more planar than both B c Ph and DFB c Ph, surprisingly, also shows a much smaller coupling constant between its carbinol protons ( J = 2.1 Hz), 49 identical to that observed with DFB c Ph. By contrast, the hydroxyl group conformation in the series 1 diol epoxides of both 5-MB c Ph [(±)- 26 )] and H 2 B[ l ]A [(±)- 27 )] are comparable to that in B c Ph.…”

“…32–34 Introduction of methoxy substituents into the angular ring then allows for the conversion of the hydrocarbons to their oxidized metabolites, the dihydrodiols and diol epoxides, via the ortho -quinones. 33–36 Despite the convenience of the photochemical approach, availability of starting materials can be a limitation.…”

A Computational Study of the Ozonolysis of Phenanthrene

“…Furthermore, Huh reported a successful method for the ozonolysis of phenanthrene adsorbed on powdered polyethylene, that can be applied for a large-scale preparation of ozonides [28]. Bae et al [29] explored the impact of the genetic material 1,4-difluorobenzo[c]phenanthrene (1,4-DFBcPh) on the DNA and its distortions. This study has covered the crystallographic, computational, and biological investigations of the compound.…”