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© 1992 Oxford University Press

research-article

Modulation of carcinogenicity in 1,2,3,4-tetrahydro-7,12-dimethylbenz[{alpha}]anthracene (THDMBA) by fluorine substitution: crystal structures of the 5- and 6-fluoro regjoisomers

Shaun D. Black 1 2 3, Pradeep K. Sharma 1, Judith C. Gallucci 4, Anthony C. Blackburn 4, James W. Downs 5, Stephen J. Rinderle 1 and Donald T. Witiak 1 3

1Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy OH 43210-1291, USA
2Ohio State Biochemistry Program, The Ohio State University Columbus, OH 43210-1291, USA
3Comprehensive Cancer Center, The Ohio State University Columbus, OH 43210-1291, USA
4Department of Chemistry, The Ohio State University Columbus, OH 43210-1291, USA
5Department of Geological Sciences, The Ohio State University Columbus, OH 43210-1291, USA

l,2,3,4-Tetrahydro-7,12-dimethylbenz[{alpha}]anthracene (THDMBA) is an animal carcinogen which lacks an aromatic bay-region and shows promise as a model to investigate non-classical mechanisms of carcinogenesis. The fluorine-substituted derivatives at positions 5 and 6 on the B-ring exhibit a striking range of oncogenic potential wherein the 6F-THDMBA is twice as potent as the parent carcinogen, but the 5F-THDMBA is virtually inactive. To study structure -reactivity relationships for these fluorine regioisomers, we have determined the three-dimensional structures of the compounds by single-crystal X-ray diffraction. These crystal structures are the first such to be reported for any monofluoro anthracene (or pyrene) derivative. The partially-reduced A-ring exists in both enantiomeric half-chair conformers in the crystalline state, and the compounds have quasi-planar anthracene ring systems which exhibit a right-handed twist in the ‘ß’-conformer, with the expected opposite twist in the other. A complete analysis of bond lengths, bond angles and torsion angles is presented. Preliminary electrostatic potentials have been derived from the X-ray data sets, and the results indicate significant differences in potential between 5F- and 6F-THDMBA at positions near the partially reduced bay region. Such results are likely to be of importance in the understanding of metabolic activation to reactive intermediates capable of bonding covalently to DNA.


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