title: Dibenzo[a,g]quinolizin-8-ones: synthesis, estrogen receptor affinities, and cytostatic activity.
abstract: 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.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, FRG.
authors.forename: S
authors.initials: S
authors.lastname: von Angerer
authors.forename: G
authors.initials: G
authors.lastname: Brandl
authors.forename: A
authors.initials: A
authors.lastname: Mannschreck
authors.forename: C
authors.initials: C
authors.lastname: Weimar
authors.forename: W
authors.initials: W
authors.lastname: Wiegrebe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002417:Cattle; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism*; D011807:Quinolizines / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011807:Quinolizines; D011960:Receptors, Estrogen