本文關鍵詞： 蛋白酪氨酸激酶抑制劑 定量構效關系 分子對接 2-吲哚酮 苯并咪唑　出處：《青島科技大學》2013年碩士論文　論文類型：學位論文

【摘要】：蛋白酪氨酸激酶(Protein tyrosine kinase, PTK)是一類催化ATP上γ-磷酸轉移到蛋白酪氨酸殘基上的激酶,能催化多種底物蛋白酪氨酸殘基磷酸化,在細胞生長、增殖、分化中具有重要作用。蛋白酪氨酸激酶是多種腫瘤最常見的生長因子受體,抑制其活性可破壞腫瘤細胞的信號傳導,抑制腫瘤細胞增殖和新生血管形成,而對正常細胞的影響較小,這與傳統(tǒng)的化學治療藥物相比是很大的優(yōu)勢,因此,蛋白酪氨酸激酶是當今腫瘤化學治療的熱門靶點,其抑制劑是抗腫瘤研究的重要方向。 本研究的目的是設計和合成新型的蛋白酪氨酸激酶抑制劑,通過篩選獲得具有一定活性和自主知識產(chǎn)權的化合物,用于進一步的活性研究。本文主要進行了以下方面的工作 1運用定量構效關系(QSAR)勺方法研究了2-吲哚酮類血管內(nèi)皮生長因子受體-2(VEGFR-2)蛋白酪氨酸激酶抑制劑的定量構效關系,以定量構效關系研究的結構為指導,結合已有的苯并咪唑類蛋白酪氨酸激酶抑制劑的構效關系研究結果,設計出了一系列結構新穎、未見報導的新型VEGFR-2蛋白酪氨酸激酶抑制劑,組建成虛擬化合物庫。 2將新型VEGFR-2蛋白酪氨酸激酶抑制劑分子用分子對接軟件DOCK6.0與人的VEGFR-2蛋白酪氨酸激酶進行分子對接研究。通過對接能量大小的比較,篩選出活性較高的10個小分子,分析了抑制劑分子與受體的結合位點的情況。 3以取代苯胺為原料,經(jīng)成肟、合環(huán)成靛紅、水合肼還原等反應合成了一系列2-吲哚酮衍生物,優(yōu)化了合成條件,積累了合成此類蛋白酪氨酸激酶抑制劑藥物的相關經(jīng)驗。 4以取代苯胺為原料,經(jīng)�；Ｗo氨基、硝化、還原、和乙醇酸反應、氧化等反應合成了一系列苯并咪唑-2-甲醛衍生物,探索了合成苯并咪唑醛衍生物的合成條件,為下面的合成工作提供了有效的借鑒。
[Abstract]:Protein tyrosine kinase protein tyrosine kinase (PTK) is a kind of kinase that catalyzes the transfer of 緯 -phosphoric acid from ATP to the protein tyrosine residue. It can catalyze the phosphorylation of tyrosine residues in many substrates and play an important role in cell growth proliferation and differentiation. Protein tyrosine kinase is the most common growth factor receptor in many kinds of tumors. Inhibition of its activity can destroy the signal transduction of tumor cells, inhibit tumor cell proliferation and angiogenesis, but have little effect on normal cells, which is a great advantage over traditional chemotherapeutic drugs. Protein tyrosine kinase (PKK) is a hot target of tumor chemotherapeutic therapy, and its inhibitor is an important direction of anti-tumor research. The aim of this study was to design and synthesize novel protein tyrosine kinase inhibitors and obtain compounds with certain activity and independent intellectual property rights by screening. The main work of this paper is as follows 1 the quantitative structure-activity relationship of 2-indole ketone receptor-2 VEGFR-2 protein tyrosine kinase inhibitor was studied by quantitative structure-activity relationship (QSAR). A series of novel structures were designed under the guidance of the structure of quantitative structure-activity relationship (QSAR) and the results of the existing studies of benzimidazole protein tyrosine kinase inhibitors. A novel inhibitor of VEGFR-2 protein tyrosine kinase has been constructed into a virtual compound library. (2) the molecular docking of novel VEGFR-2 protein tyrosine kinase inhibitor (DOCK6.0) with human VEGFR-2 protein tyrosine kinase was studied by means of docking energy. A comparison of size. Ten small molecules with high activity were screened and the binding sites of inhibitor molecules to receptors were analyzed. 3 A series of 2-indoleone derivatives were synthesized from substituted aniline by oxime, cyclization into indirubin and reduction of hydrazine hydrate. The synthesis conditions were optimized. Accumulated experience in the synthesis of such protein tyrosine kinase inhibitors. A series of benzimidazole-2-formaldehyde derivatives were synthesized from substituted aniline by acylation of protected amino groups, nitration, reduction, reaction with glycolic acid and oxidation. The synthetic conditions of benzimidazolaldehyde derivatives were explored, which provided an effective reference for the following synthesis work.
【學位授予單位】：青島科技大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R914.5

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