| 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 (Rcum2), cumulative cross-validated (Qcum2) and root mean square error of estimation for the training set (RMSEE) are Rcum2 =0.840 and 0.939, Qcum2 =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 (Rcum2), cumulative cross-validated (Qcum2) and root mean square error of estimation for the training set (RMSEE) of 13C and 15N NMR are Rcum2 =0.929 and 0.987, Qcum2 =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... |
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