Keller Laurent, Beaumont Stéphane, Liu Jian-Miao, Thoret Sylviane, Bignon Jérôme S, Wdzieczak-Bakala Joanna, Dauban Philippe, Dodd Robert H
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
J Med Chem. 2008 Jun 26;51(12):3414-21. doi: 10.1021/jm701466p. Epub 2008 May 27.
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 IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 microM. Compound 4f (( S)-5-ethyl) showed comparable antiproliferative activities (IC50'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.
通过3-碘代吲哚-2-羧酸酯与适当的α-烷基苄基氨基邻硼酸之间的铃木偶联反应，随后环化形成内酰胺，合成了一系列5-烷基吲哚并苯并氮杂卓-7-酮。发现C5位具有直链烷基链的衍生物对KB细胞具有高度细胞毒性，IC50值在30-80 nM范围内。这些化合物还抑制微管蛋白的聚合，IC50为1-2 μM。化合物4f（(S)-5-乙基）在多种癌细胞系中表现出相当的抗增殖活性（IC50为30-70 nM），细胞生长停滞在G2/M期。化合物4f在三种不同的癌细胞系中以剂量依赖性方式诱导凋亡，并显示出以与其对微管蛋白聚合的抑制作用一致的方式影响细胞形态。使用移植在鸡胚绒毛尿囊膜上的胶质瘤实验模型，用化合物4f进行局部治疗可显著降低肿瘤进展。
