Goldbrunner, Michael and Loidl, Günther and Polossek, Thomas and Mannschreck, Albrecht and von Angerer, Erwin (1997) Inhibition of tubulin polymerization by 5,6-dihydroindolo[2,1-a]isoquinoline derivatives. JOURNAL OF MEDICINAL CHEMISTRY, 40 (22). pp. 3524-3533. ISSN 0022-2623, 1520-4804
Full text not available from this repository.Abstract
6-Alkyl-12-formyl-5,6-dihydroindolo[2,1-alpha]isoquinolines have been shown to inhibit the growth of human mammary carcinoma cells by an unknown mode of action. One of the possible molecular targets is the tubulin system which is involved in cell division. A number of 5,6-dihydroindolo[2, l-a]isoquinolines with methoxy or hydroxy groups in positions 3, 9, and/or 10 and various functional groups such as formyl, acetyl, cyano, alkylimino, and alkylamino in position 12 were synthesized and evaluated for both inhibition of tubulin polymerization and cytostatic activity in MDA-MB 231 and MCF-7 human breast cancer cells. In the tubulin polymerization assay, only hydroxy derivatives were active, whereas both the hydroxy derivatives and some of the methoxy compounds inhibited cell growth. In order to establish a correlation between the inhibition of tubulin polymerization and cytostatic activity in the hydroxy series, two of the most active racemates were separated into the enantiomers. In both assays, the relative potencies of the hydroxy derivatives were in a similar order. Highest activity was found for the (+)-isomers of 6-propyl-(6b) and 6-butyl-12-formyl-5,6-hydro-3,9-dihydroxyindolo[2,1-alpha]isoquinoline (6c) with IC50 values of 11 +/- 0.4 and 3.1 +/- 0.4 mu M, respectively, for the polymerization of tubulin at 37 degrees C (colchicine: 2.1 +/- 0.1 mu M). The active hydroxy derivatives displaced 40-70% of [H-3]colchicine from its binding site in the tubulin at concentrations 10-fold higher than that of colchicine. The data suggest that hydroxy-substituted indolo[2,1-alpha]isoquinolines bind to the colchicine-binding site and inhibit the polymerization of tubulin. This action can be assumed to be responsible for the cytostatic activity of the hydroxy derivatives and might also contribute to the antitumor effect of the corresponding methyl ethers.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ENDOGENOUS MAMMALIAN METABOLITE; COLCHICINE BINDING-SITE; PRODUCT CURACIN-A; ANTIMITOTIC AGENTS; ANTITUMOR AGENTS; BIOLOGICAL EVALUATION; ANTICANCER AGENTS; NATURAL-PRODUCTS; ANALOGS; 2-METHOXYESTRADIOL |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institut für Organische Chemie > Alumni or Retired Professors > Prof.Dr. Mannschreck |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Mar 2023 06:25 |
| Last Modified: | 28 Mar 2023 06:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/50468 |
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