Mahboobi, Siavosh and Pongratz, Herwig and Hufsky, Harald and Hockemeyer, Jörg and Frieser, Markus and Lyssenko, Alexei and Paper, Dietrich H. and Buergermeister, Jutta and Boehmer, Frank-D. and Fiebig, Heinz-Herbert and Burger, Angelika M. and Baasner, Silke and Beckers, Thomas (2001) Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents. JOURNAL OF MEDICINAL CHEMISTRY, 44 (26). pp. 4535-4553. ISSN 0022-2623
Full text not available from this repository. (Request a copy)Abstract
A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered. (5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and 3-methoxyphenyl (3) derivatives displayed high cytotoxicity Of IC50 = 20 to 75 nM against the human HeLa/KB cervical, SK-OV-3 ovarian, and U373 astrocytoma carcinoma cell lines. The inhibition of proliferation correlated with the arrest in the G2/M phase of the cell cycle. In in vitro assays with tubulin isolated from bovine brain, in general antiproliferative activity correlated with inhibition of tubulin polymerization. Thus, the antimitotic activity of 2-aroylindoles is explained by interference with the mitotic spindle apparatus and destabilization of microtubules. In contrast to colchicine, vincristine, nocodazole, or taxol, I did not significantly affect the GTPase activity of beta -tubulin. Interestingly, selected compounds inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. In xenograft experiments, 1 was highly active after oral administration at 200 mg/kg against the human amelanocytic melanoma MEXF 989 in athymic nude mice. We conclude, that 2-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MICROTUBULE POLYMERIZATION DYNAMICS; TUMOR-CELL LINES; HYDROLYSIS; ANALOGS; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Nov 2021 06:28 |
| Last Modified: | 23 Nov 2021 06:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/40863 |
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