A number of methoxy-substituted 7,11b,12,13-tetrahydro-6H-dibenzo-[a,f]
quinolizines with short alkyl groups in position 6 or 12 were synthesized by the Bischler-Napieralski reaction using the appropriate starting material followed by a second ring closure reaction involving a base-generated
benzyne intermediate. The methoxy functions in positions 2 or 3 and 9 were cleaved with BBr3 and the free hydroxy groups converted into the
acetates. The enantiomers of two of these derivatives were separated by liquid chromatography on
triacetylcellulose. Compounds with alkyl substituents bind strongly to the
estrogen receptor except those with a cis-orientation at the central ring connection. The RBA values ranged from 2.2-10.8 (
17 beta-estradiol: RBA = 100). There was no major difference in binding between the (+) and (-)-enantiomers. The 3,9-diacetoxy-6-alkyl derivatives also showed binding affinity for the
progesterone receptor (RBA: 1.2-3.1). The 2,9-diacetoxydibenzoquinolizines trans-61 and -6m with ethyl and propyl respectively in position 12 strongly inhibited the growth of
hormone-sensitive MCF-7
breast cancer cells at concentrations of 10(-6) M and higher but were inactive in
hormone-independent MDA-MB 231
breast cancer cells. Preliminary tests with
hormone-dependent MXT mouse mammary
tumors as model showed that these compounds have also
antineoplastic activity in vivo. Derivative trans-61 at a dose of 20 mg/kg
body weight, administered 3 times/week, inhibited the growth of these
tumors by 78% (
tamoxifen: 76% inhibition). Studies on the estrogenic and antiestrogenic properties of these agents in mice revealed that they are mixed agonists/antagonists with strong antiestrogenic activity at low doses but significant
estrogenic effects at higher doses.