title: 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.affiliation: Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de@
authors.forename: S
authors.initials: S
authors.lastname: Mahboobi
authors.forename: H
authors.initials: H
authors.lastname: Pongratz
authors.forename: H
authors.initials: H
authors.lastname: Hufsky
authors.forename: J
authors.initials: J
authors.lastname: Hockemeyer
authors.forename: M
authors.initials: M
authors.lastname: Frieser
authors.forename: A
authors.initials: A
authors.lastname: Lyssenko
authors.forename: D H
authors.initials: DH
authors.lastname: Paper
authors.forename: J
authors.initials: J
authors.lastname: Bürgermeister
authors.forename: F D
authors.initials: FD
authors.lastname: Böhmer
authors.forename: H H
authors.initials: HH
authors.lastname: Fiebig
authors.forename: A M
authors.initials: AM
authors.lastname: Burger
authors.forename: S
authors.initials: S
authors.lastname: Baasner
authors.forename: T
authors.initials: T
authors.lastname: Beckers
mesh_terms: D000482:Allantois / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002417:Cattle; D002823:Chorion / Q000098:blood supply; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001704:Biopolymers; D007211:Indoles; D014404:Tubulin; D020558:GTP Phosphohydrolases