Bay region distortions in cyclopenta[a]phenanthrenes.

Abstract

Two newly synthesized cyclopenta[a]phenanthrenes, namely the 1-methyl (VIII) and 7,11-dimethyl (VII) derivatives of the parent ketone 15,16-dihydrocyclopenta[a]phenanthren-17-one (I), have been tested for their capacity to produce skin tumors in mice. The former (VIII) is essentially inactive, whereas the latter (VII) is very potent in both repeated application and two-stage tests. X-ray crystallographic structure analyses have been carried out on seven derivatives of (I), namely its 11-methyl (II), 11,12-dimethyl (III), 11-methoxy (V), 11-ethyl (VI) and 7,11-dimethyl (VII) analogues (carcinogens), the 1-methyl derivative (VIII), and 11,12,15,16-tetrahydro-11-methyl-17-oxocyclopenta[a]phenanthrene (IV) (both non-carcinogens). The detailed molecular structures resulting from these studies have shown the effects of steric interactions and substitutions on the bay-region geometry. The methyl group on C(11) causes distortions of the molecule in the bay region. Out-of-plane distortions in the bay regions of the 11-methyl derivatives (II, III, VII) are greater than for the 11-methoxy or the 11-ethyl derivatives (V, VI). Molecules (except for III and IV) are packed in the crystals with interactions that include C = O...H interactions; this packing is in layers that are nearly parallel to each other. A hydrogen atom of the 11-methyl group appears, from computer modeling, to interact sterically with the hydrogen atom of the bay-region expoxide group in the activated diol-epoxide; this steric interaction may force one conformer of the diol-epoxide to be the predominant form, thereby accounting for the importance of a bay-region methyl group. Further computer modeling has been used to analyze possible modes of interaction of the diol-epoxides of cyclopenta[a]phenanthrenes with DNA.

• Authors: S Kashino, D E Zacharias, R M Peck, J P Glusker, T S Bhatt, M M Coombs
• Journal: Cancer research (Cancer Res) Vol. 46 Issue 4 Pt 1 Pg. 1817-29 (Apr 1986) ISSN: 0008-5472 [Print] United States
• PMID: 3948165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Gonanes

Topics

• Animals
• Carcinogens
• Female
• Gonanes (toxicity)
• Male
• Mice
• Models, Molecular
• Molecular Conformation
• Skin Neoplasms (chemically induced)
• Structure-Activity Relationship
• X-Ray Diffraction