1. Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents.
- Author
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Mahboobi S, Pongratz H, Hufsky H, Hockemeyer J, Frieser M, Lyssenko A, Paper DH, Bürgermeister J, Böhmer FD, Fiebig HH, Burger AM, Baasner S, and Beckers T
- Subjects
- Allantois blood supply, Angiogenesis Inhibitors chemical synthesis, Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Biopolymers, Cattle, Chorion blood supply, Drug Screening Assays, Antitumor, G2 Phase drug effects, GTP Phosphohydrolases chemistry, Humans, In Vitro Techniques, Indoles chemistry, Indoles pharmacology, Melanoma drug therapy, Mice, Mice, Nude, Mitosis drug effects, Structure-Activity Relationship, Transplantation, Heterologous, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis, Tubulin chemistry
- 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
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