本文關鍵詞： 抗腫瘤 血管內(nèi)皮生長因子 血管內(nèi)皮生長因子受體-2 抑制劑 嘧啶萘甲酰胺 吲唑萘甲酰胺 糖尿病 葡萄糖激酶 葡萄糖激酶激動劑 7-氮雜吲哚　出處：《南昌大學》2014年碩士論文　論文類型：學位論文

【摘要】：本論文在傳統(tǒng)藥物化學設計理論以及現(xiàn)代有機合成技術(shù)的基礎上，綜合運用基于靶點以及結(jié)構(gòu)的藥物設計手段，設計、合成了一些含氮雜環(huán)類化合物，并分別對它們的抗腫瘤以及抗糖尿病的生物活性進行了研究探討。 論文的第一部分是關于嘧啶/吲唑萘甲酰胺類VEGFR-2抑制劑的設計、合成及生物活性研究。 血管內(nèi)皮生長因子（VEGF）是刺激新血管生成的重要因子之一，VEGF信號通路對于腫瘤血管新生具有關鍵性的調(diào)節(jié)作用。因而可以通過抑制VEGF的主要受體VEGFR-2來抑制腫瘤的生長。 課題組前期的工作研究中發(fā)現(xiàn)了一類萘甲酰胺類小分子對VEGFR-2具有較好的抑制活性，其中以苯胺嘧啶萘酰胺為母核的化合物DW10051和DW10111以及以吲唑萘酰胺為母核的化合物DW10066對VEGFR-2的IC50小于2nM。以這些化合物為先導，進行結(jié)構(gòu)改造，以期獲得活性更好的化合物。合成的31個衍生物中，大部分衍生物對VEGFR-2的IC50都小于10nM，其中化合物1-B-3以及1-C-1對VEGFR-2的IC50小于1nM。 論文的第二部分是關于氮雜吲哚類葡萄糖激酶激動劑的設計、合成及生物活性研究。 葡萄糖激酶（GK）是糖代謝途徑中的關鍵酶，促進葡萄糖代謝和胰島素分泌，有效控制體內(nèi)的血糖平衡。葡萄糖激酶已成為治療2型糖尿病的一個重要靶標。葡萄糖激酶激動劑（GKAs）作用于葡萄糖激酶的變構(gòu)位點，提高激酶的生物活性，，從而達到調(diào)控血糖的作用。 通過對葡萄糖激酶上激動劑的結(jié)合口袋以及目前報道的葡萄糖激酶激動劑的結(jié)構(gòu)的研究發(fā)現(xiàn)：這些小分子激動劑都具有1個核心結(jié)構(gòu)以及3個分支。2個疏水側(cè)鏈鑲嵌到葡萄糖激酶的疏水空腔中，1個含氮雜環(huán)類結(jié)構(gòu)，同時作為氫鍵的給體和受體與Arg63形成氫鍵作用，構(gòu)成產(chǎn)生GK活性的主體部分�；谝陨习l(fā)現(xiàn)，我們設計并合成了一系列以吡啶環(huán)為核心，以7-氮雜吲哚環(huán)為活性片段的小分子葡萄糖激酶激動劑。測試了所合成的這16個化合物在分子水平上的葡萄糖激酶活性，實驗結(jié)果表明，有11個化合物具有激酶激動活性，其中化合物2-A-1、2-A-4、2-A-5、2-B-1對于葡萄糖激酶的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.
【學位授予單位】：南昌大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914.5;R96

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相關期刊論文 前1條

1 陳軍;盛春泉;鄭燦輝;李耀武;呂加國;張萬年;周有駿;朱駒;;VEGFR2活性腔性質(zhì)以及與抑制劑的結(jié)合模式研究[J];化學學報;2007年06期

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