一些含氮杂环类化合物的设计、合成及其生物活性研究

发布时间：2018-02-28 10:06

本文关键词： 抗肿瘤血管内皮生长因子血管内皮生长因子受体-2 抑制剂嘧啶萘甲酰胺吲唑萘甲酰胺糖尿病葡萄糖激酶葡萄糖激酶激动剂 7-氮杂吲哚　出处：《南昌大学》2014年硕士论文　论文类型：学位论文

【摘要】：本论文在传统药物化学设计理论以及现代有机合成技术的基础上，综合运用基于靶点以及结构的药物设计手段，设计、合成了一些含氮杂环类化合物，并分别对它们的抗肿瘤以及抗糖尿病的生物活性进行了研究探讨。论文的第一部分是关于嘧啶/吲唑萘甲酰胺类VEGFR-2抑制剂的设计、合成及生物活性研究。血管内皮生长因子（VEGF）是刺激新血管生成的重要因子之一，VEGF信号通路对于肿瘤血管新生具有关键性的调节作用。因而可以通过抑制VEGF的主要受体VEGFR-2来抑制肿瘤的生长。课题组前期的工作研究中发现了一类萘甲酰胺类小分子对VEGFR-2具有较好的抑制活性，其中以苯胺嘧啶萘酰胺为母核的化合物DW10051和DW10111以及以吲唑萘酰胺为母核的化合物DW10066对VEGFR-2的IC50小于2nM。以这些化合物为先导，进行结构改造，以期获得活性更好的化合物。合成的31个衍生物中，大部分衍生物对VEGFR-2的IC50都小于10nM，其中化合物1-B-3以及1-C-1对VEGFR-2的IC50小于1nM。论文的第二部分是关于氮杂吲哚类葡萄糖激酶激动剂的设计、合成及生物活性研究。葡萄糖激酶（GK）是糖代谢途径中的关键酶，促进葡萄糖代谢和胰岛素分泌，有效控制体内的血糖平衡。葡萄糖激酶已成为治疗2型糖尿病的一个重要靶标。葡萄糖激酶激动剂（GKAs）作用于葡萄糖激酶的变构位点，提高激酶的生物活性，，从而达到调控血糖的作用。通过对葡萄糖激酶上激动剂的结合口袋以及目前报道的葡萄糖激酶激动剂的结构的研究发现：这些小分子激动剂都具有1个核心结构以及3个分支。2个疏水侧链镶嵌到葡萄糖激酶的疏水空腔中，1个含氮杂环类结构，同时作为氢键的给体和受体与Arg63形成氢键作用，构成产生GK活性的主体部分。基于以上发现，我们设计并合成了一系列以吡啶环为核心，以7-氮杂吲哚环为活性片段的小分子葡萄糖激酶激动剂。测试了所合成的这16个化合物在分子水平上的葡萄糖激酶活性，实验结果表明，有11个化合物具有激酶激动活性，其中化合物2-A-1、2-A-4、2-A-5、2-B-1对于葡萄糖激酶的EC50小于1μM。
[Abstract]:Based on the traditional pharmacochemical design theory and modern organic synthesis technology, some nitrogen-containing heterocyclic compounds were designed and synthesized by using the drug design method based on target and structure. Their anti-tumor and anti-diabetic biological activities were studied. The first part is about the design, synthesis and bioactivity of pyrimidine / indazole naphthalamide VEGFR-2 inhibitors. Vascular endothelial growth factor (VEGF) is one of the important factors to stimulate new angiogenesis. VEGF signaling pathway plays a key role in the regulation of tumor angiogenesis, so it can inhibit tumor growth by inhibiting VEGFR-2, the main receptor of VEGF. In our previous work, we found that a class of small naphthyl formamide molecules have good inhibitory activity on VEGFR-2. The IC50 of VEGFR-2 was less than 2nMwith aniline naphthalamide as parent nucleus and DW10066 with indazolaphthalamide as parent nucleus. Among the 31 derivatives, the IC50 of most derivatives to VEGFR-2 is less than 10nM, and the IC50 of compounds 1-B-3 and 1-C-1 to VEGFR-2 is less than 1nM. The second part is about the design, synthesis and bioactivity of azaindole glucokinase agonists. Glucokinase (GK) is a key enzyme in the glucose metabolism pathway, which promotes glucose metabolism and insulin secretion. Glucokinase has become an important target in the treatment of type 2 diabetes mellitus. GK agonist GKAs) acts on the structural site of glucokinase and enhances its biological activity. In order to achieve the function of regulating blood sugar. Through the study of the binding pocket of the agonist on the glucokinase and the structure of the currently reported glucokinase agonist, it is found that these small molecular agonists all have one core structure and three branches, and two hydrophobic sides. The chain is embedded in the hydrophobic cavity of glucokinase, with a nitrogen-containing heterocyclic structure. At the same time, the donor and receptor of hydrogen bond form hydrogen bond with Arg63, forming the main part of producing GK activity. Based on the above findings, we have designed and synthesized a series of pyridine ring as the core. A small molecular glucokinase agonist with 7-azaazindole-ring as active fragment was used to test the glucokinase activity of these 16 compounds at the molecular level. The results showed that 11 compounds had kinase activation activity. The EC50 of compound 2-A-1H _ 2-A-4N _ 2-A-5N _ 2-B _ (-1) for glucokinase is less than 1 渭 M.
【学位授予单位】：南昌大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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