POLOSSEK, T and AMBROS, R and VONANGERER, S and BRANDL, G and MANNSCHRECK, A and VONANGERER, E (1992) 6-ALKYL-12-FORMYLINDOLO[2,1-A]ISOQUINOLINES - SYNTHESES, ESTROGEN-RECEPTOR BINDING AFFINITIES, AND STEREOSPECIFIC CYTOSTATIC ACTIVITY. JOURNAL OF MEDICINAL CHEMISTRY, 35 (19). pp. 3537-3547. ISSN 0022-2623,
Full text not available from this repository.Abstract
A number of 6-alkyl-12-formyl-5,6-dihydroindolo[2,1-alpha]isoquinolines were synthesized by the Bischler-Napieralski reaction from the respective 1-alkyl-2-(3-methoxyphenyl)ethylamines and bromo-substituted (methoxyphenyl)acetic acid chlorides followed by a second ring closure reaction involving a base-generated benzyne intermediate. The methoxy functions in positions 3 and 9 or 10 were cleaved with BBr3 and the free hydroxy groups converted into the acetates. The enantiomers of the most potent derivatives were separated by liquid chromatography on tri-acetylcellulose. All of the compounds tested bind to the calf uterine estrogen receptor. The relative binding affinities (RBA) ranged from 0.5 to 3.9 (17-beta-estradiol: RBA = 100) and were dependent on the position of the oxygen function in the indole moiety. The 3,10-diacetoxy derivatives showed higher RBA values than the corresponding 3,9-substituted tetracycles. There was no major difference in binding affinity between (+)- and (-)-enantiomers. Computer-assisted molecular modeling studies showed that the chiral carbon atom 6 of the indoloisoquinoline is likely to mimic the C-11 atom of estradiol. In the mouse uterine weight test, only the 3,10-diacetoxy series exhibited weak estrogenic activity at higher doses. The antiestrogenic effects found with all the compounds varied considerably. Maximum inhibition of estrone-stimulated uterine growth was found for the ethyl derivative 7d (80% with 250-mu-g/animal per day). All derivatives strongly inhibited the growth of human breast cancer cells in vitro. There was no significant difference between hormone-sensitive MCF-7 cells and hormone-independent MDA-MB 231 cells. Cytostatic activity was higher for the 3,9-substituted indoloisoquinolines than for the 3,10-analogues and dependent on the length of the alkyl group at C-6. The maximum effect was found with the butyl derivative 7g. When the enantiomers of the ethyl (7c), propyl (7e), and butyl derivative were studied, a strong difference in activity was observed between the stereoisomers. The IC50 values of the (+)-forms were usually only a tenth of those of the levorotatory isomers. Maximum cytostatic activity was found with (+)-7g: 85% inhibition at 1 X 10(-7) M in MCF-7 cells and 94% inhibition at 2.5 X 10(-7) M in MDA-MB 231 cells. This stereospecificity indicates a selective action on a biochemical target. Since no interaction with DNA was observed, the precise mode of action still remains to be elucidated.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR INHIBITING ACTIVITY; POSITIVE MAMMARY-TUMORS; BIOLOGICAL-ACTIVITY; LIQUID-CHROMATOGRAPHY; MOLECULAR-STRUCTURES; SELECTIVE ACTION; DERIVATIVES; DIETHYLSTILBESTROL; TRIACETYLCELLULOSE; ANTIOESTROGENS; |
| Depositing User: | Dr. Gernot Deinzer |
| Last Modified: | 19 Oct 2022 08:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/54380 |
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