1. Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents
- Author
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Heinz-Herbert Fiebig, Markus Frieser, Siavosh Mahboobi, Harald Hufsky, Thomas Beckers, D. H. Paper, Jutta Bürgermeister, Herwig Pongratz, Frank-D. Böhmer, Jörg Hockemeyer, Angelika M. Burger, Alexei Lyssenko, and Silke Baasner
- Subjects
G2 Phase ,Indoles ,Transplantation, Heterologous ,Mice, Nude ,Mitosis ,Angiogenesis Inhibitors ,Antineoplastic Agents ,In Vitro Techniques ,GTP Phosphohydrolases ,HeLa ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Biopolymers ,Microtubule ,Allantois ,Tubulin ,Drug Discovery ,Tumor Cells, Cultured ,Animals ,Humans ,Cytotoxicity ,Melanoma ,biology ,Chorion ,Cell cycle ,biology.organism_classification ,Nocodazole ,Biochemistry ,chemistry ,biology.protein ,Molecular Medicine ,Antimitotic Agent ,Cattle ,Drug Screening Assays, Antitumor - 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 IC(50) = 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, 1 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.
- Published
- 2001