A number of acetoxy-substituted dibenzo[a,g]quinolizin-8-ones were
synthesized by the reaction of 1-oxoisoquinolines with substituted homophthalic acid
anhydride. All of the derivatives with acetoxy groups in positions 3 and 10 bind to the
estrogen receptor. Relative binding affinities (RBA) ranged from 1.8 to 5.6 (estradiol:
RBA = 100) when the substituent at C-6 was a short alkyl group. Introduction of
additional oxygen functions in the 2- and/or 11-position decreased binding affinities.
Analyses of the enantiomers of 6-methyl (6b) and 6-ethyl (6c) derivatives revealed that
the receptor binding is mainly due to one optical isomer (e.g. (-)-6b, 9.9; (+)-6b, 0.6).
In hormone-sensitive human MCF-7 breast cancer cells, compounds with one acetoxy
group in each aromatic ring strongly inhibited cellular growth. Despite marked differences
in receptor affinity, the enantiomers displayed similar activities in this cell
culture. In hormone-independent MDA-MB 231 mammary tumor cells, only a weak
cytostatic effect was recorded at 10-5 M. In the immature mouse uterine weight test,
minimal estrogenic activity was observed. At higher doses, a significant anti-estrogenic
effect became evident. It is assumed that the estrogen antagonism is responsible for
the specific cytostatic effect in MCF-7 breast cancer cells.