本文選題：腫瘤血管生成抑制劑 + 來那度胺衍生物�。� 參考：《北京工業(yè)大學(xué)》2015年碩士論文

【摘要】：隨著分子生物學(xué)研究的不斷深入,惡性腫瘤的分子靶向治療已成為除手術(shù)、放療和化療之外的第四種治療方法,越來越多的用于臨床治療惡性腫瘤。血管生成與腫瘤的生長(zhǎng)、侵襲和轉(zhuǎn)移密切相關(guān),以抑制腫瘤血管生成為靶點(diǎn)治療腫瘤的方法已經(jīng)成為抗腫瘤新療法之一。來那度胺(Lenalidomide)是一種新型免疫調(diào)節(jié)劑,具有抗腫瘤作用活性,主要表現(xiàn)在抑制腫瘤血管生成作用。本文通過對(duì)來那度胺衍生物抑制腫瘤血管生成分子靶點(diǎn)的虛擬篩選研究,設(shè)計(jì)了一系列來那度胺衍生物的分子結(jié)構(gòu)。在優(yōu)化來那度胺合成工藝的基礎(chǔ)上,合成并得到一系列來那度胺衍生物,并對(duì)其進(jìn)行藥理活性研究,為來那度胺衍生物抗腫瘤作用機(jī)制的研究及其作為分子靶向腫瘤血管生成抑制劑的研發(fā)提供理論與實(shí)驗(yàn)基礎(chǔ)。首先,來那度胺抑制腫瘤血管生成分子靶點(diǎn)的篩選,及其抑制劑分子結(jié)構(gòu)的設(shè)計(jì)和虛擬篩選。采用反向?qū)臃椒?以來那度胺(化學(xué)名為3-(4-氨基-1,3-二氫-1-氧代-2H-異吲哚-2-基)-2,6-哌啶二酮)為初始結(jié)構(gòu),在AutoDock 4.0平臺(tái)上,選取六個(gè)血管生成促進(jìn)因子靶蛋白,即血管內(nèi)皮生長(zhǎng)因子受體(VEGFR-2)、表皮生長(zhǎng)因子受體(erbB-3)、成纖維細(xì)胞生長(zhǎng)因子受體(FGFR-4)、BCR-ABL酪氨酸激酶(ABL)、p38絲裂原活化蛋白酶(p38MAPK)和基質(zhì)金屬蛋白酶(MMP-3)進(jìn)行對(duì)接研究。通過分析對(duì)接結(jié)果,初步確定來那度胺抑制腫瘤血管生成的潛在靶點(diǎn)是FGFR-4。采用分子對(duì)接法,對(duì)設(shè)計(jì)的54個(gè)來那度胺衍生物與FGFR-4進(jìn)行對(duì)接研究,確定擬合成包括烷基化衍生物、酰基化衍生物和磺�；苌镌趦�(nèi)的30個(gè)目標(biāo)化合物結(jié)構(gòu)。其次,來那度胺及其衍生物的合成研究。通過對(duì)來那度胺及其中間體合成方法的綜述,確定來那度胺的合成路線。以來那度胺為原料,通過對(duì)其氨基的衍生化研究(烷基化、�；突酋；磻�(yīng)),合成出30個(gè)來那度胺衍生物。通過考察溶劑,溫度,催化劑,縮合劑和縛酸劑對(duì)合成過程中各步反應(yīng)的影響,確定了各步反應(yīng)的最佳反應(yīng)條件。所合成的目標(biāo)化合物均通過核磁共振氫譜、核磁共振碳譜和質(zhì)譜等技術(shù)進(jìn)行結(jié)構(gòu)表征,其中28個(gè)化合物未見報(bào)道。最后,來那度胺及其衍生物的體外抗腫瘤活性研究。采用CCK-8法,進(jìn)行來那度胺及其衍生物對(duì)食管癌細(xì)胞株EC9706的細(xì)胞毒性測(cè)試。結(jié)果表明,來那度胺及其衍生物均具有一定的抑制活性,來那度胺對(duì)EC9706的抑制活性IC50為340.3μg/m L(ΔG=-7.05 kcal/mol),而所選取的三個(gè)來那度胺衍生物對(duì)EC9706的抑制活性IC50分別為309.5μg/mL(ΔG=-7.19 kcal/mol),263.8μg/mL(ΔG=-7.68kcal/mol)和225.2μg/mL(ΔG=-8.40 kcal/mol),發(fā)現(xiàn)經(jīng)過修飾的烷基化,�；突酋；瘉砟嵌劝费苌锉葋砟嵌劝肪哂懈玫囊种苹钚�,其中磺酰化衍生物的抑制活性最為突出。此外,結(jié)果還表明來那度胺及其衍生物對(duì)EC9706的細(xì)胞毒性測(cè)試實(shí)驗(yàn)結(jié)果與分子對(duì)接結(jié)果相一致,說明將抑制腫瘤血管生成分子靶點(diǎn)作為來那度胺及其衍生物的研究方向是可行的,可進(jìn)一步確定FGFR-4就是來那度胺抗腫瘤血管生成的作用靶點(diǎn)。
[Abstract]:With the continuous development of molecular biology research, the molecular targeting therapy of malignant tumor has become the fourth treatment methods except surgery, radiotherapy and chemotherapy, and more and more clinical treatment of malignant tumors. Angiogenesis is closely related to tumor growth, invasion and metastasis, in order to inhibit tumor angiogenesis as a target for tumor treatment. The method has become one of the new antitumor therapies. Lenalidomide is a new immunomodulator with antitumor activity, which is mainly manifested in inhibiting tumor angiogenesis. In this paper, a series of amines were designed by the virtual screening study on the molecular targets of tumor angiogenesis inhibition by the ramification. The molecular structure of the derivatives. Based on the optimization of the synthesis of amines, a series of amines were synthesized and obtained, and their pharmacological activities were studied. The research on the anti-tumor mechanism of the amines derivatives and the theoretical and experimental basis for the development of molecular targeting tumor angiogenesis inhibitors were provided. The screening of the molecular targets of tumor angiogenesis by amido, and the design and virtual screening of the molecular structure of the inhibitors. Using the reverse docking method, the initial structure of the amine (chemical named 3- (4- amino -1,3- two hydrogen -1- -2H- isoindole -2- based) -2,6- piperidine two ketone) was the initial structure, and six angiogenesis was selected on the AutoDock 4 platform. Promoting factor target proteins, such as vascular endothelial growth factor receptor (VEGFR-2), epidermal growth factor receptor (erbB-3), fibroblast growth factor receptor (FGFR-4), BCR-ABL tyrosine kinase (ABL), p38 mitogen activated protease (p38MAPK) and matrix metalloproteinase (MMP-3), are studied. By analyzing the docking results, the initial determination is made. The potential target of diamine inhibition of tumor angiogenesis is that FGFR-4. uses molecular docking to dock the designed 54 amines with FGFR-4 and determine the synthesis of 30 target compounds, including alkylated derivatives, acyl derivatives and sulfonylated derivatives. Secondly, the combination of amines and its derivatives A synthetic route to the synthesis of amines and their intermediates was reviewed to determine the synthetic route of the amines. Since the amine was used as a raw material, 30 diamine derivatives were synthesized by the study of its amino derivatives (alkylation, acylation and sulfonylation). Through the investigation of solvent, temperature, catalyst, condensation agent, and acid binding agent, The optimum reaction conditions for each step reaction were determined in the process of synthesis. The synthesized target compounds were characterized by nuclear magnetic resonance spectroscopy, nuclear magnetic resonance carbon spectroscopy and mass spectrometry, and 28 compounds were not reported. Finally, the antitumor activity of the amine and its derivatives in vitro was studied by CCK-8. The cytotoxicity test of the amines and their derivatives on the esophageal cancer cell line EC9706 showed that both amines and their derivatives had certain inhibitory activity, and the inhibitory activity of amines to EC9706 was 340.3 u g/m L (delta G=-7.05 kcal/mol), and the inhibitory activity of the three amino derivatives on EC9706 was selected. IC50 is 309.5 mu g/mL (delta G=-7.19 kcal/mol), 263.8 g/mL (delta G=-7.68kcal/mol) and 225.2 mu g/mL (delta G=-8.40 kcal/mol). It is found that the modified alkylation, acylation and sulfonylation of amines have better inhibitory activity than lauryl amine, and the inhibitory activity of sulfonylated derivatives is most prominent. The results of the cytotoxicity test of amidodiamine and its derivatives to EC9706 are in agreement with the molecular docking results, indicating that it is feasible to inhibit the molecular target of tumor angiogenesis as the direction of the amines and its derivatives. It can be further determined that FGFR-4 is the target of antitumor angiogenesis of amido.

【學(xué)位授予單位】：北京工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R91;R914.5
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本文編號(hào)：1867828