- 學位論文
1. 不對稱二亞胺鋅/銅化合物的密度泛函理論計算研究 2. 順鉑氫化合物中間體是否存在?結合實驗與密度泛函理論計算之研究
1.DFT calculation study on the asymmetrical β-Diketiminato Zinc/Copper Complexes 2. Does cisplatin hydride intermediate exist? A joint experimental and DFT calculation study
摘要
Part A 二亞胺 (β-diketimine) 配位基之所以值得研究，主要是因為二亞胺配位基易形成較擁擠的配位環境，可用來穩定金屬中心稀有的氧化態和不飽和的配位環境。而二亞胺配位基也可以扮演一個模擬生物體的配位基，與銅離子形成鍵結後可以執行模擬生物體的化學反應，像是含銅金屬酶。且二亞胺鋅錯合物在催化乳酸交酯的開環聚合中佔有一個很重要的角色。在先前的文獻中，焦點放在對稱型的二亞胺配位基，鮮少有不對稱型的二亞胺配位基。起初設計不對稱型的二亞胺配位基是為了擁有較好提供電子給金屬能力，且在有較大的立體障礙時，易形成單體錯合物，因此將二配位延伸至三配位的構形。但是實驗結果與預期不符，由實驗室先前研究成功的得到晶體結構證實，三配位錯合物仍會形成雙體的結構。 從晶體結構發現，相同配位基的不對稱二亞胺鋅/銅錯合物，其中Cu(I)與Zn(II)都為d10的電子組態，卻會形成不同的單/雙體產物。所以在本論文中，利用密度泛函理論(density functional theory)來研究影響不對稱二亞胺鋅/銅錯合物的晶體結構的因子。 最後發現主導晶體結構的因子除了要考慮到熱力學之外，動力學也是主要因子之一，其中還包含了中間體的穩定性和活化能的高低。 Part B Cisplatin是現代臨床癌變腫瘤最常見的用藥，已經成功的被應用在睪丸癌、卵巢癌、子宮頸癌等癌症的治療。而很早就有文獻研究顯示，當cisplatin溶於水後會先水解，將cisplatin鉑金屬上的兩個氯離子取代成兩個水分子進行形成水合體化合物〔Pt(H2O)2(NH3)2〕2+，此化合物會與DNA骨架上的guanine bases N7的位子做鍵結。使DNA無法再進行複製，導致細胞凋零。其中也有研究顯示，當cisplatin經由輻射照射後會出現協同效應，使得cisplatin在後期也常被拿來做為輻射治療合併化學治療的臨床用藥。其中在進行輻射治療時，因為水佔人體體重的70%，所以大多數接受到輻射線的分子並非cisplatin而是環環包住它的水分子，因而產生水合電子。 在本實驗室先前的密度泛函理論研究裡發現，當Cisplatin在擁有水合電子的水溶液環境時，其反應途徑與文獻上的水解反應不相同。水分子會直接與水合電子反應形成cisplatin的自由基，再藉由自由基去與DNA做反應 ，最後達到傷害腫瘤癌細胞DNA的效果。Cisplatin的自由基在與DNA的反應過程中，會將thymine或者是醣鏈上的氫拔除，最後產生HPt(NH3)2Cl (cisplatin hydride)副產物。如果能在實驗上能證實cisplatin hydride的存在，就更能支持先前研究的反應機制是正確的。
並列摘要
Part A The N,N′-substituted β-diketiminato ligands have been attracting increasing interest over the past several decades, mainly due to their suitability as sterically crowded spectator ligands to stabilize coordinatively unsaturated metal centers and unusual oxidation state. The N,N`-substituted β-diketiminato ligands can act as a biomimetic ligand to bind copper ion and perform chemical biomimetic reaction such as a metalloenzymes does. And the β-diketiminato Zn(II) complexes are important catalysts to the ring-opening polymerization of lactide (LA). Among these researches, most of catalysis design focus on the symmetric β-diketiminato ligand, however, there were less attention on the study of asymmetric β-diketiminato ligands. The beginning design of the asymmetric β-diketiminato ligand is to have a better ability to donate electron to metal, and at a bigger steric effect, easy to form a monomer complexes. That is why we extend bidentate ligand to tridentate′s one. But the experiment results do not match the expectations generated by our design, the tridentate metal complex can also form dimer structure which has been confirmed by the crystal structure. From the X-ray crystal result, we can get different structure by using same ligand and same electron configuration of metal ions. Therefore, in this thesis, we investigate the influence factor of the crystal structure of the asymmetric β-diketiminato zinc/copper complexes using density functional theory (DFT). Part B Cisplatin, Pt(NH3)2Cl2, is one of the most widely used anticancer drugs nowadays. It has been successfully applied to the treatment of various cancers such as testicular, ovarian and cervical cancer. In the early literature study shows, prior to binding with DNA, cisplatin has to undergo a hydrolysis reaction in which one or two chlorides are replaced by water molecules. It is generally accepted that the target of cisplatin is DNA: it prefers binding to the N7 sites of two consecutive guanines, leading to intrastrand cross links and the subsequent cell apoptosis. Essentially study related to the radiation of cisplatin in the course of treatment have been proved that the chemoradiation therapy has a synergistic effect. That is why cisplatin has been used in the clinical treatment for many years. During chemoradiation therapy, cisplatin isn’t the majority molecular that received radiation exposure but water. When the water has been excited by radiation , hydrated electrons are formed. The previously DFT research in our lab found that the behavior of cispaltin is different between the existence of hydrated electrons or not. If cisplatin solution contain hydrated electrons, it will get diffent reaction from the literature’s one. Hydrated electrons will make cisplatin become cisplatin radical, and cisplatin radical will react with DNA. It can abstract hydrogen atoms from the C–H bonds of the ribose moiety and the methyl group of thymine, which in turn leads to DNA strand breaks and cross-link lesions. HPt(NH3)2Cl (cisplatin hydride) will form being byproducts. If we can prove the existence of cisplatin hydride, we can support the previously research.