本文選題：定量構(gòu)效關(guān)系　切入點(diǎn)：前藥　出處：《山東大學(xué)》2014年博士論文　論文類型：學(xué)位論文

【摘要】：近二十年來,定量構(gòu)效關(guān)系的研究方法已廣泛應(yīng)用于藥物、農(nóng)藥、環(huán)境等領(lǐng)域的研究。具體研究?jī)?nèi)容已從傳統(tǒng)的藥物結(jié)構(gòu)與其生物活性的定量關(guān)系研究,擴(kuò)展到包括預(yù)測(cè)藥物的理化性質(zhì)、藥物動(dòng)力學(xué)釋放、藥物的色譜保留行為等許多方面。特別是近年來量子化學(xué)計(jì)算方法(如DFT,Hartree-Fock等方法)的引入,進(jìn)一步提高了定量構(gòu)效關(guān)系對(duì)化合物結(jié)構(gòu)特性預(yù)測(cè)的精確性。因此,結(jié)合藥物的結(jié)構(gòu)特性計(jì)算,運(yùn)用統(tǒng)計(jì)學(xué)定量分析方法,可幫助科研工作者深入分析藥物結(jié)構(gòu)中影響藥動(dòng)學(xué)因素的關(guān)鍵問題,以及藥物結(jié)構(gòu)改變與色譜保留時(shí)間、流出順序和手性分離的關(guān)鍵影響因素。本文第一部分研究工作是將量子化學(xué)計(jì)算方法DFT應(yīng)用于香豆素前藥釋放系統(tǒng)的定量構(gòu)效關(guān)系研究。該前藥系統(tǒng)最初由本課題組開發(fā),適于短肽在體內(nèi)釋放。它可被體內(nèi)酯酶降解,繼而引發(fā)分子內(nèi)的環(huán)合內(nèi)酯化反應(yīng),生成香豆素并釋放氨基酸或短肽。實(shí)驗(yàn)室在前期研究工作中,曾對(duì)香豆素前藥釋放系統(tǒng)進(jìn)行了大量結(jié)構(gòu)修飾,并發(fā)現(xiàn)結(jié)構(gòu)改變能夠顯著影響藥物的釋放速率。為了深入闡明這一現(xiàn)象,我們應(yīng)用Gaussian 03軟件的的量子化學(xué)計(jì)算方法(B3LYP/6-31+G(d,p)),獲得了本實(shí)驗(yàn)室前期合成27個(gè)香豆素類前藥的結(jié)構(gòu)參數(shù),然后分別應(yīng)用線性回歸和多項(xiàng)式神經(jīng)網(wǎng)絡(luò)等方法建立了 5個(gè)QSPR模型。其中兩個(gè)線性模型分別為SMLR線性模型(q2=0.427,r2=0.516)和PLS線性模型(q2=0.584,r2=0.663)。其它3個(gè)非線性QSPR模型由多項(xiàng)式神經(jīng)網(wǎng)絡(luò)(PNN)模擬法建立(q2=0.692,0.675,0.663;r2=0.700,0.688,0.672)。相關(guān)結(jié)果表明,基于量子化學(xué)DFT計(jì)算的QSPR模型,尤其是PNN模型,可成功用于香豆素前藥釋放動(dòng)力學(xué)的預(yù)測(cè),為開發(fā)新型香豆素類前藥候選物提供理論指導(dǎo)。本文第二部分的主要研究?jī)?nèi)容是3,5-二取代手性乙內(nèi)酰脲的新型合成方法及其在手性色譜保留的QSAR研究。乙內(nèi)酰脲作為一種重要的雜環(huán)化合物,已廣泛出現(xiàn)在許多藥物和天然產(chǎn)物結(jié)構(gòu)之中。近年來還發(fā)現(xiàn),3,5-二取代手性乙內(nèi)酰脲化合物可作為手性配體用于催化不對(duì)稱羥醛縮合和Mannich反應(yīng),具有廣泛的用途。我們?cè)趯?shí)驗(yàn)中發(fā)現(xiàn)了一種新型3,5-二取代手性乙內(nèi)酰脲化合物的合成方法。該方法以伯胺或芳胺為原料,先制得相應(yīng)異腈酸酯,然后與氨基酸甲酯鹽酸鹽反應(yīng)生成脲中間體,最后在不同堿催化下可以得到消旋或手性中心保持的3,5-二取代手性乙內(nèi)酰脲化合物。特別是當(dāng)應(yīng)用無水四氫呋喃為溶劑,在-20℃低溫和氫化鈉催化下可得到構(gòu)型保持的手性3,5-二取代乙內(nèi)酰脲化合物。該方法具有反應(yīng)步驟少、時(shí)間短、分離產(chǎn)率和ee%值高等特點(diǎn),不僅適用于常見的N3位烷基取代的手性乙內(nèi)酰脲化合物合成,還可用于N3位為芳基的相關(guān)衍生物合成,具有廣泛的適用范圍。在此基礎(chǔ)上,我們研究了上述合成的11個(gè)手性化合物在兩種多糖型手性固定相(ChiralpakIA柱和ChiralpakIC柱)的分離和保留規(guī)律。結(jié)果顯示,含有不同取代基的手性乙內(nèi)酰脲衍生物在手性色譜柱的保留行為有明顯差異。另一方面,多糖類的固定相Chiralpak IA柱較Chiralpak IC柱表現(xiàn)出更好的手性識(shí)別能力。例如20%乙醇作為流動(dòng)相改性劑時(shí),Chiralpak IA柱可實(shí)現(xiàn)所有11個(gè)3,5-二取代手性乙內(nèi)酰脲衍生物的手性拆分;而Chiralpak IC柱在常用的20%乙醇或20%異丙醇條件下,約有一半的目標(biāo)化合物未能實(shí)現(xiàn)基線分離。我們還發(fā)現(xiàn),3,5-二取代乙內(nèi)酰脲化合物的手性色譜行為不僅與手性固定相有關(guān),還受到極性改性劑和溫度的影響。例如,應(yīng)用不同的極性改性劑(如乙醇、丙醇、異丙醇和正丁醇)可導(dǎo)致同一個(gè)乙內(nèi)酰脲類手性化合物在Chiralpak IA柱的保留行為各有差異,但一般先流出的光學(xué)異構(gòu)體為S構(gòu)型。在Chiralpak IC柱時(shí),使用20%的乙醇為極性改性劑時(shí),多數(shù)化合物的R構(gòu)型先流出;而20%異丙醇為極性改性劑時(shí),多數(shù)化合物S構(gòu)型先流出。對(duì)于分離效果不好的化合物(如ChiralpakIA柱在20%異丙醇條件下,化合物4,6和9分離度不佳),降低極性改性劑濃度可改善部分化合物的手性分離效果。但應(yīng)用Chiralpak IC柱時(shí),部分分離效果不好的情況(如化合物7和11)即使在降低極性改性劑比例的情況下,仍未能實(shí)現(xiàn)基線分離�？紤]到van't Hoff方程中溫度對(duì)手性色譜柱的影響,我們推測(cè)部分化合物難以實(shí)現(xiàn)有效分離的原因,可能是由于在某種極性改性劑條件下,柱溫接近其等對(duì)映體選擇性溫度(Tiso)而處于溫度盲區(qū)。因此我們基于van't Hoff方程,測(cè)試了不同溫度條件的實(shí)驗(yàn)數(shù)據(jù),并計(jì)算出相應(yīng)化合物在特定手性固定相和極性改性劑條件下的Tiso。研究結(jié)果顯示,Chiralpak IA柱在20%異丙醇極性改性劑條件下,化合物6和9的Tiso分別為20.6℃和30.8℃,從而解釋了這兩個(gè)化合物在室溫下應(yīng)用20%異丙醇可出現(xiàn)對(duì)映異構(gòu)體同時(shí)流出的現(xiàn)象,因此無法實(shí)現(xiàn)手性分離。類似的情況在Chiralpak IC柱上也同樣存在。例如,化合物7在20%乙醇條件下的Tiso為20.3℃;化合物11在20%異丙醇條件下的Tiso為11.8℃。根據(jù)熱力學(xué)有關(guān)原理,當(dāng)化合物處于溫度盲區(qū)時(shí),通過改變溫度和降低極性改性劑兩種方法可以使手性分離條件遠(yuǎn)離盲區(qū)而實(shí)現(xiàn)基線分離,同時(shí)可以觀察到兩個(gè)光學(xué)異構(gòu)體流出順序反轉(zhuǎn)的情況。在我們的實(shí)驗(yàn)中,結(jié)合溫度改變和降低極性改性劑比例,不僅成功解決了部分化合物(Chiralpak IA柱化合物6和9;ChiralpakIC柱化合物7和11)在乙醇或異丙醇條件下的手性分離問題,而且首次報(bào)道了4個(gè)3,5-二取代手性乙內(nèi)酰脲衍生物所產(chǎn)生的流出順序反轉(zhuǎn)現(xiàn)象。上述研究也為深入探討多糖型手性固定相與手性乙內(nèi)酰脲衍生物的分離機(jī)制提供了新的研究思路。為進(jìn)一步探索3,5-二取代手性乙內(nèi)酰脲衍生物的色譜保留機(jī)制,我們運(yùn)用三維定量構(gòu)效關(guān)系研究的比較分子力場(chǎng)分析方法(CoMFA),考察該類化合物的三維立體結(jié)構(gòu)與其色譜保留因子之間的關(guān)系。通過選擇最優(yōu)參數(shù)進(jìn)行運(yùn)算,我們成功獲得了 3,5-二取代手性乙內(nèi)酰脲衍生物應(yīng)用Chiralpak IA柱和Chiralpak IC柱時(shí),以EtOH和IPA為流動(dòng)相時(shí)的CoMFA模型,交叉驗(yàn)證系數(shù)q20.528,非交叉驗(yàn)證系數(shù)r20.926,均具有較好的預(yù)測(cè)能力。該模型為深入研究該類手性化合物的色譜保留行為提供的理論基礎(chǔ)。
[Abstract]:In the past twenty years, the research method of quantitative structure-activity relationship has been widely used in medicine, pesticide, environment and other fields. The specific research contents from the traditional quantitative drug structure and biological activity studies, extended to include prediction of physicochemical properties of drugs, drug release kinetics, drug retention behavior many aspects. Especially in recent years, the quantum chemistry calculation method (such as DFT, Hartree-Fock and other methods) are introduced, further improve the accuracy of QSAR prediction on the structure of the compounds. Therefore, the characteristics of computing with drug nodes, using the method of quantitative analysis in statistics, can help researchers to deeply analyze the key issues affecting drug the dynamic factors of drug and drug structure, structure change and retention time, key factors influencing the elution order and chiral separation. In the first part of this research work The quantum chemistry calculation method DFT applied to quantitative coumarin prodrug delivery system of structure-activity relationship study. The prodrug system originally developed by our research group development, suitable for short peptides released in vivo. It can be esterase degradation, followed by esterification of intramolecular cyclization, formation of coumarin and release of amino acids or peptides laboratory. In previous study, the drug release system has coumarin before of the modified structure, and found that structural changes can significantly affect the release rate of the drug. In order to further elucidate this phenomenon, quantum chemistry calculation methods we used Gaussian 03 software (the B3LYP/6-31+G (D, P)), to obtain structural parameters the synthesis of 27 coumarin prodrugs in the laboratory, and then using linear regression and polynomial neural network method establishes 5 QSPR models. Two of them were SMLR linear model Linear model (q2=0.427, r2=0.516) and PLS linear model (q2=0.584, r2=0.663). The other 3 nonlinear QSPR model by polynomial neural network (PNN) simulation was established (q2=0.692,0.675,0.663; r2=0.700,0.688,0.672). The results show that the QSPR model based on DFT quantum chemical calculation, especially the PNN model can be successfully used for the prediction of coumarin before the drug release kinetics, to provide theoretical guidance for the development of novel coumarin prodrug candidates. The main research contents of the second part of this paper is a new method of synthesis of 3,5- two substituted chiral hydantoin and its QSAR in the study of chiral chromatographic retention. Hydantoin as an important heterocyclic compounds, have been widely found in many drugs and natural products. In recent years, also found that two 3,5- substituted chiral hydantoin compounds can be used as chiral ligands for catalytic asymmetric aldol condensation and anti Mannich We should, with a wide range of uses. We found a new synthesis method of 3,5- two substituted chiral hydantoin compounds in the experiment. The method of using primary amine or aromatic amine as raw materials, first prepared corresponding isocyanates, and amino acid methyl ester hydrochloride reacts urea intermediates, most in different base catalysis can get or keep the 3,5- racemic chiral center two substituted chiral hydantoin compounds. Especially when the application of anhydrous tetrahydrofuran as solvent, the catalytic -20 low temperature and sodium borohydride can be obtained under retention of configuration of chiral 3,5- two substituted hydantoin compounds. This method has less reaction steps, time is short, the separation efficiency and ee% value etc., not only applicable to common N3 chiral ethylene alkyl substituted hydantoin compounds, can also be used for the synthesis of N3 related derivatives for aryl, which has a wide application scope on the basis of this, We studied 11 chiral compounds in the synthesis of two kinds of polysaccharide based chiral stationary phase (ChiralpakIA column and ChiralpakIC column) separation and retention rules. The results showed that the chiral hydantoin derivatives with different substituents have obvious differences in the retention behavior of chiral column. On the other hand, polysaccharide fixed Chiralpak IA column Chiralpak IC column showed better chiral recognition ability. For example, 20% ethanol as mobile phase modifier, Chiralpak IA column can achieve all 11 3,5- two substituted chiral chiral hydantoin derivatives; and the Chiralpak IC column in isopropanol conditions of 20% ethanol or 20% commonly used under about half of the target compound, failed to achieve baseline separation. We also found that 3,5- two substituted chiral chromatographic behavior of hydantoin compounds not only with chiral stationary phase, but also by the polar modifier and temperature Impact. For example, the application of different polar modifiers (such as ethanol, propanol, and isopropanol butanol) can lead to the same kind of chiral hydantoin compounds have the difference in the retention behavior of Chiralpak IA column, but the optical isomers generally first out of the S configuration in the Chiralpak IC column. 20%, using ethanol as polar modifier, R configuration most compounds were first and 20% outflow; isopropanol as polar modifier, most compounds S configuration first outflow. The effect is not good for the separation of compounds (such as the ChiralpakIA column in 20% isopropanol conditions, compounds 4,6 and 9 degrees of separation poor), reduce the chiral separation of polar modifier can improve the concentration of some compounds. But the application of Chiralpak IC column, part of the separation effect is not good situation (such as compounds 7 and 11) even in the lower polar modifier of the proportion of cases failed to achieve baseline separation. Considering van't Effect of column temperature, the opponent in the Hoff equation, the reason we speculate that it is difficult to achieve effective separation of some compounds, probably due to some polar modifier conditions, the column temperature is close to the enantioselective temperature (Tiso) in the temperature zone. So we based on the van't Hoff equation, the experimental data at different temperatures the conditions of the test, and calculate the corresponding compounds in particular chiral stationary phase and polarity of the modified Tiso. results of agent under the condition of Chiralpak, IA in the 20% column of isopropanol modifier under the condition of Tiso 6 and 9 compounds were 20.6 degrees and 30.8 degrees, which can be explained to reflect at the same time, the phenomenon of outflow application of isomer 20% isopropanol these two compounds at room temperature, it is impossible to realize chiral separation at similar situation also exists in the Chiralpak IC column. For example, 7 compounds in 20% ethanol under the condition of Tis O is 20.3 DEG C; compound 11 in 20% isopropanol Tiso under the conditions of 11.8 DEG C. According to the principle of thermodynamics, the temperature when the compound is in the blind spot, by changing the temperature and reduce the polar modifier two ways to chiral separation conditions away from the blind area to achieve baseline separation, the same can be observed when the two optical reverse the order of outflow isomers. In our experiment, combining with the temperature change and reduce the polar modifier proportion, not only solved the compounds (compounds 6 and 9 Chiralpak IA column ChiralpakIC column; compounds 7 and 11) in the chiral separation of ethanol or isopropanol conditions, and reported for the first time. 4 3,5- two substituted chiral hydantoin derivatives produced by the elution order reversal phenomenon. The research is to further explore the separation mechanism of polysaccharide based chiral stationary phase and chiral hydantoin derivatives provide a new The ideas of the research. To further explore the 3,5- two substituted chiral hydantoin derivatives retention mechanism, we use comparative molecular three-dimensional quantitative structure-activity relationship field analysis method (CoMFA), the three-dimensional structure of this kind of compounds with retention factor between operations. By choosing the optimal parameters, we success of the 3,5- two substituted chiral hydantoin derivatives using Chiralpak IA column and Chiralpak IC column, with EtOH and IPA for the CoMFA model of mobile phase, the coefficient of cross validation q20.528, non cross validated coefficient r20.926 has good prediction ability. This model provides theoretical basis for further study of chromatographic retention behavior of the chiral compounds.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R917

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