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Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2001 Dec 20; Vol. 44 (26), pp. 4535-53. - Publication Year :
- 2001
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 44
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11741473
- Full Text :
- https://doi.org/10.1021/jm010940+