New C5-alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: Cytotoxic and antitumor activities

作者：Keller Laurent; Beaumont Stephane; Liu Jian Miao; Thoret Sylviane; Bignon Jerome S; Wdzieczak Bakala Joanna; Dauban Philippe^*; Dodd Robert H

来源：Journal of Medicinal Chemistry, 2008, 51(12): 3414-3421.

DOI：10.1021/jm701466p

A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate alpha-alkylbenzylamino o-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC(50) values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC(50)'s of 1-2 mu M. Compound 4f ((S)-5-ethyl) showed comparable antiproliferative activities (IC(50)'s of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.

• 出版日期2008-6-26