本文選題：基于藥效團(tuán)拼合原理的藥物設(shè)計(jì) + FXR配體��； 參考：《華東理工大學(xué)》2015年博士論文

【摘要】：本論文由兩個(gè)部分組成：第一部分是基于FXR配體的設(shè)計(jì)優(yōu)化及調(diào)控機(jī)制研究。FXR是核受體家族中的一員,主要在肝臟、腸、腎臟以及腎上腺等器官中表達(dá)。目前,FXR已經(jīng)明確能夠在多種代謝途徑中起到調(diào)節(jié)作用,包括膽固醇、膽汁酸、脂類(lèi)以及葡萄糖代謝。此外,FXR與膽汁淤積、動(dòng)脈粥樣硬化、膽結(jié)石、糖尿病和癌癥等多種疾病有著緊密的聯(lián)系。然而目前的研究表明甾體類(lèi)FXR配體在靶點(diǎn)選擇性和基因選擇性上均存在潛在的缺陷,設(shè)計(jì)非甾類(lèi)的FXR配體對(duì)于設(shè)計(jì)開(kāi)發(fā)以FXR為靶點(diǎn)的治療藥物具有重要意義。因此,我們探討了非甾類(lèi)FXR配體的設(shè)計(jì)優(yōu)化以及調(diào)控機(jī)制研究。在前期自主開(kāi)發(fā)的非甾類(lèi)FXR拮抗劑(18)與非甾類(lèi)FXR激動(dòng)劑GW4064(24)的基礎(chǔ)上,我們根據(jù)藥效團(tuán)拼合原理將GW4064(24)的疏水藥效團(tuán)與化合物18進(jìn)行了拼合。結(jié)合化合物的可合成性和結(jié)合活性,選取了化合物36作為FXR配體的先導(dǎo)結(jié)構(gòu)進(jìn)行優(yōu)化和探索,通過(guò)合理藥物設(shè)計(jì)和化學(xué)合成手段,進(jìn)行三輪結(jié)構(gòu)改造,得到45個(gè)化合物(36,A1-19,B1-25)。通過(guò)測(cè)試其分子水平及細(xì)胞水平活性,最終發(fā)現(xiàn)了三個(gè)FXR激動(dòng)劑(A10,B2和B3)和一個(gè)FXR拮抗劑(B25)。之后我們以FXR拮抗劑B25為配體,利用分子動(dòng)力學(xué)模擬探究配體對(duì)FXR的拮抗機(jī)制,拮抗劑B25的構(gòu)象變化引起了FXR激動(dòng)形式的H12構(gòu)象改變,阻礙共激活因子的招募。我們的分子模擬結(jié)果提出了FXR拮抗機(jī)制重要的分子基礎(chǔ),FXR結(jié)構(gòu)中H12螺旋上的氨基酸E467的構(gòu)象是FXR拮抗調(diào)控的關(guān)鍵,這與之前文獻(xiàn)中報(bào)道的機(jī)制一致。第二部分是兩種優(yōu)勢(shì)骨架的合成方法學(xué)研究。我們發(fā)展了以二苯基酮亞胺為關(guān)鍵底物的兩種3-取代-2-吲哚酮優(yōu)勢(shì)骨架合成方法,應(yīng)用這些方法可以快速構(gòu)建優(yōu)勢(shì)骨架分子,為藥物篩選研究提供快捷的合成方法以及較好的分子庫(kù)。其一,以各種取代靛紅(56)、甘氨酸叔丁酯鹽酸鹽(57)及二苯基酮亞胺(58)為原料,在溫和條件下經(jīng)一步三組分反應(yīng)和一步輔助基團(tuán)脫去,高效制得含3-羥基-2-吲哚酮類(lèi)優(yōu)勢(shì)骨架的非天然氨基酸,產(chǎn)率58-90%。其二,以二苯基酮亞胺(58)為氨基供體,在含碘添加劑與TBHP的氧化體系下,高效完成醛類(lèi)、二芳基甲烷類(lèi)以及3-取代-2-吲哚酮類(lèi)底物的氨基化反應(yīng),制得文獻(xiàn)中極少報(bào)道的伯胺產(chǎn)物,產(chǎn)率38-89%。綜上所述,基于藥效團(tuán)拼合原理,針對(duì)FXR這一與多種疾病密切相關(guān)的重要靶標(biāo),我們?cè)O(shè)計(jì)并合成了45個(gè)化合物(36,A1-19,B1-25),最終發(fā)現(xiàn)了該靶標(biāo)的三個(gè)激動(dòng)劑和一個(gè)拮抗劑,并首次利用自主研發(fā)的非甾類(lèi)FXR拮抗劑進(jìn)行了分子動(dòng)力學(xué)模擬以解釋FXR拮抗機(jī)制。另外,發(fā)展了以二苯基酮亞胺為關(guān)鍵底物的兩種優(yōu)勢(shì)骨架合成方法,快速構(gòu)建了兩類(lèi)3-取代-2-吲哚酮類(lèi)優(yōu)勢(shì)分子骨架。這些研究為我們開(kāi)發(fā)新藥奠定了基礎(chǔ)。
[Abstract]:This thesis consists of two parts: the first part is based on the design optimization and regulation mechanism of FXR ligand. FXR is a member of nuclear receptor family, mainly expressed in liver, intestine, kidney and adrenal gland. FXR has been identified to play a regulatory role in a variety of metabolic pathways, including cholesterol, bile acids, lipids, and glucose metabolism. In addition, FXR is closely associated with many diseases, such as cholestasis, atherosclerosis, gallstone, diabetes and cancer. However, current studies have shown that steroidal FXR ligands have potential defects in targeting selectivity and gene selectivity, and the design of non-steroidal FXR ligands is of great significance in the design and development of FXR targeted therapeutic drugs. Therefore, we discussed the design optimization and regulatory mechanism of nonsteroidal FXR ligands. On the basis of the previously developed non-steroidal FXR antagonist (C18) and the nonsteroidal FXR agonist (GW40644N24), the hydrophobic pharmacophore of GW406424) was combined with compound 18 according to the principle of pharmacophore assembly. Combined with the synthesis and binding activity of the compounds, compound 36 was selected as the leading structure of FXR ligands for optimization and exploration. Through rational drug design and chemical synthesis, 45 compounds were obtained by three-wheeled structural modification. Three FXR agonists, A10B _ 2 and B _ 3) and a FXR antagonist, B25, were found by measuring their molecular and cellular activity. Then we used FXR antagonist B25 as ligand to explore the antagonistic mechanism of ligand against FXR by molecular dynamics simulation. The conformation change of antagonist B25 caused the conformation change of FXR excited form H12, which hindered the recruitment of coactivator. Our molecular simulation results suggest that the conformation of the amino acid E467 on the H12 helix in the FXR structure is the key to the regulation of FXR antagonism, which is consistent with the previously reported mechanism. The second part is the synthesis methodology of two dominant skeletons. We have developed two methods for the synthesis of 3-substituted -2-indole ketone dominant skeleton using benzophenone imine as the key substrate, which can be used to construct the dominant skeleton molecule quickly. To provide a rapid synthetic method and a better molecular library for drug screening. First, with various substituted indirubin 56, glycine tert-butyl hydrochloride 57) and benzophenone imine 58) as raw materials, under mild conditions, they were removed by one step, three component reaction and one step auxiliary group. An unnatural amino acid containing 3-hydroxyl-2-indoleones was prepared in 58-90 yield. Secondly, the amino reactions of aldehydes, diaryl methane and 3-substituted -2-indole ketone substrates were efficiently completed in the oxidation system containing iodine and TBHP, using benzophenone iminimide 58) as the amino donor, and in the oxidation system containing iodine and TBHP, the amino reactions of aldehydes, diaryl methane and 3-substituted -2-indole ketones were efficiently completed. The primary amines, which are rarely reported in the literature, have been prepared in 38-89. To sum up, based on the principle of pharmacophore assembly, we designed and synthesized 45 compounds, C36A1-19OB1-25N, for FXR, an important target closely related to many diseases, and finally found three agonists and an antagonist for this target. The molecular dynamics simulation of non-steroidal FXR antagonist was carried out for the first time to explain the mechanism of FXR antagonism. In addition, two kinds of dominant skeleton synthesis methods with benzophenone imine as the key substrate were developed, and two kinds of 3-substituted -2-indole ketones dominant molecular skeletons were constructed rapidly. These studies have laid the foundation for the development of new drugs.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R914

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