磺酰胺基取代的嘧啶联苯类杂环衍生物作为潜在的变构激酶抑制剂的设计与合成
发布时间：2018-07-18 21:48
【摘要】：癌症是影响人类健康的重大疾病之一，20世纪人类治疗癌症主要以化疗、放疗及外科手术为主，这些治疗方式都产生严重的副作用。而靶向治疗不但可以减少毒副反应，降低用药剂量，并且能够提高治疗效果，正成为癌症治疗的新趋势。 许多肿瘤细胞中都存在信号转导途径的异常，这些转导途径中的受体过表达引起细胞过度繁殖而导致肿瘤发生。而蛋白激酶在这些信号通路中发挥着关键作用，因此其成为抗肿瘤药物最重要的“新靶点”。 本论文主要包括两个章节，第一章主要讲述了蛋白激酶的研究现状，作用方式，并通过对比阐述了研究变构激酶抑制剂的意义。人类早在1954年就发现了激酶的活性，迄今为止，蛋白激酶抑制剂的研究已经取得长足的进步。如率先上市的伊马替尼，以及舒尼替尼，厄洛替尼，吉非替尼等等。 根据与底物络合方式的不同，我们把激酶抑制剂分为四种类型：Ⅰ型激酶抑制剂与激酶铰链区形成1-3个氢键从而占据激酶的活性区域，也称为三磷酸腺苷竞争性抑制剂；Ⅱ型抑制剂占据ATP结合口袋附近的活化环（DFG）翻转所暴露出的疏水区域，也被称为变构抑制剂；Ⅲ型变构抑制剂可同时占据上述两个结合区域，这类抑制剂第一个上市的药物为伊马替尼，其通过这种作用方式来抑制Bcr/Abl激酶。此类抑制剂不仅具备Ⅱ型抑制剂选择性高的特点，也具有高效性的特点；Ⅳ型激酶抑制剂与激酶的结合位置离ATP较远，虽然有一定的选择性，但由于其没有规律性，目前研究的较少。通过对上述几类抑制剂的对比研究，我们决定开发一类新颖的Ⅲ型变构抑制剂。 第二部分主要讲述了磺酰胺基取代的嘧啶联苯类激酶变构抑制剂的设计、合成，并研究其生物活性。首先我们通过查阅大量文献，研究已上市激酶变构抑制剂伊马替尼以及其他变构抑制剂的共晶结构，并通过理论计算，设计了嘧啶联苯母核。其次，在侧链衍生化方面，母核嘧啶环部分我们选择了药物化学中常用药效团磺酰胺基；在苯环部分我们尝试了多种芳香杂环和脂肪环，脂肪链通过取代，偶联及成脲的方式进行衍生化，并通过活性测试发现5个化合物的IC50在10μM以下。此外，我们发现在母核中引入具有多个氢键受体的嘧啶环能够提高生物活性，所以我们对所得中间体再次进行衍生化，经过细胞活性测试，，发现9个化合物的IC50在10μM以下，其中，活性最好的化合物2-15-2d的IC50值为113nM。 通过路线设计，大量的衍生化及优化工作，我们共合成了49个终产物，建立了一个以嘧啶联苯为母核的化合物库，并进行了生物活性筛选，得到了一系列活性较好的化合物，通过初步分析，为本课题后续研究提供参考和方向。
[Abstract]:Cancer is one of the major diseases affecting human health. In the 20th century, chemotherapy, radiotherapy and surgery were the main treatments for cancer. Targeted therapy can not only reduce side effects, reduce drug dosage, but also improve the therapeutic effect, which is becoming a new trend of cancer treatment. Signal transduction pathways are abnormal in many tumor cells. Overexpression of receptors in these transduction pathways leads to over-proliferation and tumorigenesis. Protein kinase plays a key role in these signaling pathways, so it becomes the most important new target of anti-tumor drugs. This paper mainly includes two chapters. The first chapter mainly describes the research status of protein kinase, the action of protein kinase, and the significance of studying isokinase inhibitors by comparison. Kinase activity was discovered as early as 1954, and so far, great progress has been made in the study of protein kinase inhibitors. Such as the first listed Imatinib, as well as Schunitinib, erlotinib, Gifitinib and so on. According to the different way of complexing with substrate, kinase inhibitors can be classified into four types: type I kinase inhibitors form 1-3 hydrogen bonds with kinase hinge to occupy the active region of kinase, also known as competitive inhibitor of adenosine triphosphate; Type 鈪
本文编号：2132876
[Abstract]:Cancer is one of the major diseases affecting human health. In the 20th century, chemotherapy, radiotherapy and surgery were the main treatments for cancer. Targeted therapy can not only reduce side effects, reduce drug dosage, but also improve the therapeutic effect, which is becoming a new trend of cancer treatment. Signal transduction pathways are abnormal in many tumor cells. Overexpression of receptors in these transduction pathways leads to over-proliferation and tumorigenesis. Protein kinase plays a key role in these signaling pathways, so it becomes the most important new target of anti-tumor drugs. This paper mainly includes two chapters. The first chapter mainly describes the research status of protein kinase, the action of protein kinase, and the significance of studying isokinase inhibitors by comparison. Kinase activity was discovered as early as 1954, and so far, great progress has been made in the study of protein kinase inhibitors. Such as the first listed Imatinib, as well as Schunitinib, erlotinib, Gifitinib and so on. According to the different way of complexing with substrate, kinase inhibitors can be classified into four types: type I kinase inhibitors form 1-3 hydrogen bonds with kinase hinge to occupy the active region of kinase, also known as competitive inhibitor of adenosine triphosphate; Type 鈪
本文编号：2132876
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