6-Alkyl-12-formylindolo[2,1-a]isoquinolines. Syntheses, estrogen receptor binding affinities, and stereospecific cytostatic activity

Abstract

A number of 6-alkyl-12-formyl-5,6-dihydroindolol[2,1-a]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 triacetylcellulose. 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 micrograms/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.

Inhibition of Tubulin Polymerization by 5,6-Dihydroindolo[2,1-a]isoquinoline Derivatives

“…In a previous paper we reported on the cytostatic activities and endocrine properties of a series of acetoxy-substituted 6-alkyl-12-formyl-5,6-dihydroindolo[2,1- a ]isoquinolines . Although these compounds bind to the estrogen receptor (ER), they did not show a preference for ER-positive cells when tested for cytostatic activity.…”

Antiestrogenic Activities of 3,8-Dihydroxy-6,11-dihydrobenzo[a]carbazoles with Sulfur-Containing Side Chains

“…As in previous studies [12] , we used the calf uterine cytosol as a convenient source of estrogen receptors. The RBA values of the new compounds ranged from 0.1 to 4.2 ( Table 1).…”

Synthesis of Dihydroindoloisoquinolines through Copper‐Catalyzed Cross‐Dehydrogenative Coupling of Tetrahydroisoquinolines and Nitroalkanes

“…In this regard, studies on the biological activity of 5,6‐dihydroindolo[2,1‐ a ]isoquinolines have revealed promising results to advance in the treatment of manifold diseases. For instance, compounds 1 a and 1 b strongly inhibit tubulin polymerization and the growth of human breast cancer cells in vitro,, whereas compound 1 c is a melatonin agonist (Figure ) . Modern synthetic methods towards the 5,6‐dihydroindolo[2,1‐ a ]isoquinoline skeleton rely on the intramolecular cyclization of N ‐aryl‐1,2,3,4‐tetrahydroisoquinolines .…”