抗白血病药物高三尖杉酯碱的结构改造与修饰

白血病是一类造血干细胞恶性克隆性疾病，是一种血液系统的恶性肿瘤，在骨髓和其他造血器官中，白血病细胞大量积累增生，使正常的造血系统功能受到抑制并且浸润其他器官组织。慢性髓系白血病是白血病的其中一种，其发病率高，占成人白血病比例的 15—20%，我国每年新增病例高达 30000 多例。  以高三尖杉酯碱为代表的三尖杉碱类化合物对不同类型的白血病细胞具有高度抑制活性。然而，天然三尖杉碱类生物碱的结构复杂性使得对其结构改造和修饰有了很大的挑战。在这项研究中，侧链手性丁二酸衍生物被引入到三尖杉碱的母核中，而新侧链的引入提高了新型三尖杉碱类化合物的抗白血病细胞的活性。

我们首先开发了一种高对映选择性的方法，用于β-取代衣康酸单酯与手性催化剂 Ru[DTBM-SegPhos](OAc)₂的不对称氢化反应，为新型手性丁二酸酯侧链的合成提供了一条简单便捷的途径。采用该方法合成了 22 个高对映选择性的三尖杉碱类化合物，用 K562、U937 和 HL60 三种白血病细胞对新化合物进行抗白血病活性筛选，对这一系列衍生物的构效关系进行了详细的讨论。活性结果表明，化合物 YYJ-17 在 K562、HL60 和 U937 三种白血病细胞中显示出广泛的抗白血病活性，其将作为候选化合物进行后续的研究。Docking 实验结果预测 YYJ-17 能够维持高三尖杉酯碱和蛋白之间的大部分关键相互作用，具有抑制蛋白质翻译的潜力。Western Blot 实验结果表明 YYJ-17 以剂量依赖的方式有效下调 Bcr-Abl、Myc 和 Mcl-1 三种癌蛋白的表达，从而抑制白血病细胞的增殖。在研究 YYJ-17 对源自不同组织的 12 个细胞系的抗增殖活性中，结果表明其对多种肿瘤细胞系具有广谱的细胞毒性。各种研究结果表明 YYJ-17 有希望成为下一个治疗慢性髓系白血病的三尖杉碱类药物，且 YYJ-17 与其他 Bcr-Abl 抑制剂的联合用药也可以成为未来的研究方向。

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