四氢咔啉类纺锤体驱动蛋白抑制剂的合成和抗肿瘤活性研究

Synthesis and antitumor activity of novel tetrahydro-β-carboline derivatives as KSP inhibitors

摘要:
纺锤体驱动蛋白 (kinesin spindle protein, KSP) 的功能被抑制将导致细胞周期停滞和细胞编程性细胞死亡, 因而可成为潜在的肿瘤治疗靶点。本文合成了10个新的β-四氢咔啉衍生物, 化合物结构经元素分析、IR、¹H NMR和质谱确证。生物活性测试结果表明目标化合物具有一定的KSP抑制活性, 体外抗肿瘤活性测试结果显示, 化合物8和9对肿瘤细胞Lung/A549的GI₅₀/IC₅₀分别为1.07/1.62和1.46/3.27 μmol·L⁻¹, 对Stomach/AGS的GI₅₀/IC₅₀分别为1.09/>10和1.22/6.33 μmol·L⁻¹, 抗增殖活性优于阳性对照物CK0106023。

Abstract:
Inhibitors of kinesin spindle protein (KSP) are a promising class of anticancer agents that cause mitotic arrest and induce apoptosis of tumor cells. A series of novel tetrahydro-β-carboline derivatives were synthesized as kinesin spindle protein inhibitor and evaluated as potential antitumor agents. All compounds showed promising KSP inhibitiory activity. Compounds 8 and 9 exhibited better antitumor activity (Lung/A549, Stomach/AGS) than CK0106023 with GI₅₀/IC₅₀ values (1.07/1.62 and 1.46/3.27 μmol·L⁻¹, 1.09/>10 and 1.22/6.33 μmol·L⁻¹, respectively).