Dibenzo[a,f]quinolizines: syntheses and cytostatic activity in estrogen-sensitive tumor cells.

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.