Vogel Susanne, Kaufmann Doris, Pojarová Michaela, Müller Christine, Pfaller Tobias, Kühne Sybille, Bednarski Patrick J, von Angerer Erwin
Institut für Pharmazie, Universität Regensburg, D-93040 Regensburg, Germany.
Bioorg Med Chem. 2008 Jun 15;16(12):6436-47. doi: 10.1016/j.bmc.2008.04.071. Epub 2008 May 3.
Cell cycle arrest of malignant cells is an important option for cancer treatment. In this study, we modified the structure of antimitotic 2-phenylindole-3-carbaldehydes by condensation with hydrazides of various benzoic and pyridine carboxylic acids. The resulting hydrazones inhibited the growth of MDA-MB 231 and MCF-7 breast cancer cells with IC(50) values of 20-30 nM for the most potent derivatives. These 2-phenylindole derivatives also exerted an inhibitory effect on the growth of both proliferating and resting U-373 MG glioblastoma cells. Though the hydrazones exhibited similar structure-activity relationships as the aldehydes, they did not inhibit tubulin polymerization as the aldehydes but were capable of blocking the cell cycle in G(2)/M phase. The cell cycle arrest was accompanied by apoptosis as demonstrated by the activation of caspase-3. Since these 2-phenylindole-based hydrazones display no structural similarity with other antitumor drugs they are interesting candidates for further development.
恶性细胞的细胞周期阻滞是癌症治疗的一个重要选择。在本研究中，我们通过与各种苯甲酸和吡啶羧酸的酰肼缩合来修饰抗有丝分裂的2-苯基吲哚-3-甲醛的结构。所得到的腙抑制MDA-MB 231和MCF-7乳腺癌细胞的生长，对于最有效的衍生物，其IC(50)值为20 - 30 nM。这些2-苯基吲哚衍生物对增殖和静止的U-373 MG胶质母细胞瘤细胞的生长也具有抑制作用。尽管腙与醛表现出相似的构效关系，但它们不像醛那样抑制微管蛋白聚合，但能够在G(2)/M期阻断细胞周期。如通过半胱天冬酶-3的激活所证明的那样，细胞周期阻滞伴随着细胞凋亡。由于这些基于2-苯基吲哚的腙与其他抗肿瘤药物没有结构相似性，它们是进一步开发的有趣候选物。
