【作者】 王娇娜；

【导师】 李志良； 陈小勇；

【作者基本信息】 重庆大学 ， 药物化学， 2006， 硕士

【摘要】 培美曲塞（Pemetrexed）,商品名Alimta,化学名N-（4-[2-（2-氨基-4（3H）-4-氧代-7-氢-吡咯并[2,3-d]嘧啶-5基-）乙基]苯甲酰基）-L-谷氨酸二钠,是多靶点作用于叶酸依赖途径的抗肿瘤新药。由于美国专利合成与提纯方法过于复杂且产率较低,本学位论文对培美曲塞的合成及精制尝试了多种改进方法,简化了反应条件与提纯方法并提高了产率。在此基础上,本论文对培美曲塞的活性与核磁共振谱进行了模拟与预测,均取得了良好的效果,对培美曲塞的结构优化与核磁共振谱的研究提供了一些参考。因此本论文的研究内容主要由以下三部分构成:（1）抗癌药物培美曲塞的合成与分析;（2）抗癌药物与抗艾滋病药物的定量构效关系（QSAR）研究;（3）培美曲塞与嘌呤类化合物¹³C与¹⁵N NMR化学位移的定量构谱关系（QSSR）研究。培美曲塞属细胞周期特异性抗代谢药物。临床研究表明,其单药对多种肿瘤有效,其中主要是非小细胞肺癌、恶性胸膜间皮瘤,其它还有头颈部肿瘤、胃癌、膀胱癌、宫颈癌以及胰腺癌等。本论文在专利文献的基础上对培美曲塞的合成方法进行了显著的改进,以烯丙醇与4-碘代苯甲酸乙酯为起始原料,经过Herk反应、醛加成反应、消去、加成、水解环合、酰胺化、水解共7步反应得到目标产物,总收率达19.9%,大幅降低了生产成本,具有一定的经济效益与应用价值。通过HPLC内标法检测其含量达99.7%,并对其化学结构进行了初步分析和归属确认。定量构效关系,是一个重要的现代药学与化学基础理论研究与开发应用领域,其核心内容是考察和分析基本分子结构特征与物化性质或生物活性之间的定量相关关系。本文利用实验室新提出的一种全新的3D分子结构描述——三维原子场全息作用矢量（3D-HoVAIF）对培美曲塞及38个抗癌药物与35个HETP类抗艾滋病药物进行了QSAR研究。两个模型的复相关系数(R_cum²)、交互校验的复相关系数(Q_cum²)和模型的标准偏差（RMSEE）分别为R_cum²=0.840和0.939, Q_cum²=0.792和0.906, RMSEE=0.769和0.433,其中对培美曲塞活性预测值为5.41与报道的5.70非常接近。这对培美曲塞结构优化提供了一种参考方法。定量构谱关系,是一种研究化合物分子结构与波谱关系的统计方法,本文利用原子电性作用矢量（AEIV）和原子杂化状态指数（AHSI）及γ效应校正表征培美曲塞及嘌呤类化合物66个C微环境,51个N微环境及其自身杂化状态,应用多元线性回归（MLR）建立QSSP模型,两个模型的复相关系数(R_cum²)、交互校验的复相关系数(Q_cum²)和模型的标准偏差（RMSEE）分别为R_cum²=0.929和0.987, Q_cum²=0.896和0.966, RMSEE=5.848和7.222。所建模型不仅在一定程度上阐明了以上化合物NMR谱化学位移与其分子结构信息间关系,同时也为培美曲塞15N NMR谱研究提供了参考。关键词:抗癌药物培美曲塞,合成,分析,定量构效相关,定量构谱相关更多还原

【Abstract】 The main contents of this thesis include three parts: 1) synthesis and analysis of pemetrexed as an anti-cancer drug. 2) Quantitative structure-activity relationship （QSAR） studies of anti-cancer drugs and anti-HIV drugs using three-dimensional holographic vector of atomic interaction field （3D-HoVAIF）. 3) Quantitative structure-spectroscopy relationship （QSSR） studies on 13C NMR and 15N NMR Chemical Shifts of pemetrexed -related purine derivatives.A new anti-cancer drug pemetrexed, commercially named alimta, chemically called N-[4-{2-（2-amino-4 （3H）-oxo-7H-pyrrolo [2,3-d] pyrimidin-5-yl） ethyl} benzoyl] -L-glutamate sodium, can restrain the synthesis of DNA by restrain the synthesis of purine and pyridine. It is proved by clinical studies that pemetrexed can treat many tumors, including both non-cellule lung cancer and malignant pleural mesothelioma, together with cervix tumor, tummy, bladder, matrix and pancreas. Synthesis of pemetrexed was done according to newly developed pathways based on many patents. Target compound was synthesized using allyl alcohol and ethyl 4-iodobenzoate as starting materials. By seven steps, as Herk, aldehyde, elimination, addition, hydrolyze and ring closure, amidation and hydrolyze, total yield arises from 14.9% to 19.9% and purity reaches 99.7% detected by high performance liquid chromatography （HPLC）. Finally the target molecular structure is in perfect agreement with those of the reference standards by HPLC, ultraviolet and visible spectrophotometry （UV-VIS）, infrared spectroscopy （IR）, mass spectroscopy （MS）, nuclear magnetic resonance spectroscopy （NMR）, and so on.QSAR, which investigates the quantitative relationship between the molecular structure and biological activities or dependent functions, is one of the most important fundamental fields in pure and applied chemistry and pharmacy. A three-dimensional holographic vector of atomic interaction field （3D-HoVAIF）, newly developed by our laboratory, was used to describe the chemical structures of 39 anti-cancer and 35 anti-HIV drugs. The cumulative multiple correlation coefficient (R_cum²), cumulative cross-validated (Q_cum²) and root mean square error of estimation for the training set （RMSEE） are R_cum² =0.840 and 0.939, Q_cum² =0.792 and 0.906, RMSEE=0.769 and 0.433 respectively. The predictive value of pemetrexed is 5.41, which is approximate to the reported value 5.70. QSAR models have favorable estimation stability and good prediction capabilities. So it provides a correlative method for optimizing the structure of pemetrexed.QSSR investigates the quantitative relationship between the spectrum and molecular structure. Atomic electro-negativity interaction vector （AEIV）, atomic heterocyclic state index （AHSI） andγcalibration are employed here for QSSR model establishment of 13C and 15N NMR chemical shift of pemetrexed-related purine compounds with satisfactory results of good description and high selectivity. The cumulative multiple correlation coefficient (R_cum²), cumulative cross-validated (Q_cum²) and root mean square error of estimation for the training set （RMSEE） of 13C and 15N NMR are R_cum² =0.929 and 0.987, Q_cum² =0.896 and 0.966, RMSEE=5.848 and 7.222 respectively. It is proved that the new method for QSSR, AEIV, AHSI descriptors andγcalibration should provide some reference for 15N NMR study of pemetrexed. Keywords: Anti-cancer pemetrexed, Total structurural synthesis, Structurural analysis, Quantitative structure-activity relationship, Quantitative structure-spectroscopy relationship更多还原