2-Phenylindenes: development of a new mammary tumor inhibiting antiestrogen by combination of estrogenic side effect...

A new antiestrogenic, mammary tumor inhibiting 2-phenylindene was developed by the use of structural elements that we have shown to decrease estrogenic side effects but to increase antiestrogenic activity and retain the antitumor effect of certain stilbenes. The new 2-phenylindenes were synthesized from their corresponding methoxy-substituted 3,4-diphenylhexane-3,4-diols by cyclization with acetyl chloride and acetic anhydride and subsequent ether cleavage and acetylation. In this series, the 2-phenylindene derivative (compound 13) with a 5,6,3',4'-tetraacetoxy and a 1-methyl-3-ethyl substitution had the highest affinity for the estrogen receptor, the strongest antiestrogenic effect, and the lowest estrogenic effect. This compound was superior to the 2-phenylindenes with 5,3'-diacetoxy substitution or 1,1-dimethyl and 3-isopropyl moieties, respectively. Compound 13 exhibited a strong, significant inhibiting effect on the growth of the hormone-dependent MXT mouse mammary tumor without estrogenic side effects.