Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents.

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.

• Authors: S Mahboobi, H Pongratz, H Hufsky, J Hockemeyer, M Frieser, A Lyssenko, D H Paper, J Bürgermeister, F D Böhmer, H H Fiebig, A M Burger, S Baasner, T Beckers
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 26 Pg. 4535-53 (Dec 20 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11741473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Biopolymers
• Indoles
• Tubulin
• GTP Phosphohydrolases

Topics

• Allantois (blood supply)
• Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biopolymers
• Cattle
• Chorion (blood supply)
• Drug Screening Assays, Antitumor
• G2 Phase (drug effects)
• GTP Phosphohydrolases (chemistry)
• Humans
• In Vitro Techniques
• Indoles (chemical synthesis, chemistry, pharmacology)
• Melanoma (drug therapy)
• Mice
• Mice, Nude
• Mitosis (drug effects)
• Structure-Activity Relationship
• Transplantation, Heterologous
• Tubulin (chemistry)
• Tumor Cells, Cultured