臺灣博碩士論文加值系統

目前具有發展性的抗癌藥物是antimitotic agents；例如 taxanes 和 vinca alkaloids。但是以上化合物具有生理毒性、複雜合成、抗藥性以及繁複的分離方式問題，所以科學家想發展新的 antimitotic agents 來克服以上問題。根據文獻，Combretastatin A-4 [ cis-1-(3,4,5-trimethoxyphenyl)-2-(3-hydroxy-4-methoxyphenyl) ethane; CA4] 是目前最有發展性的物質。它主要是結合至colchicine binding domain，它主要作用是可以快速使微管束快速depolymerization，因此改變血管內皮細胞形狀，封閉已存在的腫瘤血管，最後促使癌細胞缺乏氧和養份而死亡。
Combretastatin A-4P(CA4P, ZYBRESTATTM)是目前發展快速的VDA。因此很多藥化學家模仿它的形狀，創造許多的新的相似物。因此，在設計活性分子的結構，同樣基於 bioisosterism 的概念，將 A ring 改變，來進行研發具有活性的分子。我們以五環的方式，在空間上形成與 CA4 相似的結構，形成5,6,7-trimethoxyindoles和5,6,7-trimethoxy-2-oxoindoles系列，以期待具有生物活性。針對這兩個主結構，進行修飾。
在主結構5,6,7-trimethoxyindole上，我們以各種aryl, aroyl, arylthio, benzyl, arylsufone等修飾3位，形成化合物1-8；另外以各種substituted benzyl/heterocyclic group等修飾1位，形成化合物9-15。在主結構5,6,7-trimethoxy-2-oxoindole上，我們將之接上各種substituted benzyl/heterocyclic aldehyde等修飾主結構，形成化合物16-23。以上化合物等來進行人類口腔癌細胞的抑制活性測試(IC50)。
從活性結果從顯示在以5,6,7-trimethoxy-2-oxoindole為主體的化合物，不論接上何種基團活性都大於10 μM。而在5,6,7-trimethoxyindole骨架的3號位置做修飾，活性約在IC50 > 2,5 μM. 其indole環上1號位置以aryl 官能基做修飾，其活性是在這三個系列中，活性較佳的。例如以化合物11和13，其抑制口腔癌細胞生長之為31nM和17nM。

One of currently useful chemotherapy drugs in oncology is represented by antimitotic agents, for example, taxanes and vinca alkaloids. However, the issues of high systemic toxicity, complex syntheses, drug resistance, and isolation procedures have encouraged scientists to develop new antimitotic agents. Recent literatures reported that the antitubulin agents targeting at the colchicine-binding domain, rapidly depolymerize microtubules of vasculatures changing morphology in the endothelial cells of tumor’s vessels to block the blood supply to tumors, can act as vascular-disrupting agents, for example, compound combretastatin A-4P (CA4P) and ZD-6126. The encouraging antivascular and antitumor prolife of CA4P has stimulated pronounced interest in design and synthesis of variety of derivatives or analogues. Here we report our attempt to explore the 5,6,7-trimethoxyindoles or 5,6,7-trimethoxy-2-oxoindoles core coupled with the various aryl, arylthio, arylsulfone, and aroyl groups as anticancer agents. The structure-activity relationship studies of series of 5,6,7-trimethoxyindoles led to discovery of N1-heteroaryl-5,6,7-trimethoxy-indoles as novel potent anticancer agents, for example, compound 11 and 13, showing antiproliferative activity with IC50 values of 11 and 17 nM, respectively.

目錄………………………………………………………………Ⅰ
附圖目錄…………………………………………………………Ⅲ
附錄實驗部份目錄…………………..……………………………..Ⅳ
附錄附圖部份目錄……………………………………………………Ⅵ
中文摘要.......................................... 1
英文摘要...........................................2
研究背景........................................... 3
研究目的與設計.................................... 10
結果及討論.......................................... 13
一、5,6,7-trimethoxyindoles…………………………………………….13
1. 化學結構設計…………………………………………………13
2. 合成流程及方式……………………………..………………..13
3. 抗癌細胞活性試驗結果………………………………...17
4. 化學結構與抗癌活性的關係…………………………………18
二、5,6,7- trimethoxy-2-oxoindole………………………………19
1. 化學結構設計……………………………………………………..19
2. 合成流程及方式……………………………………………………19
3. 抗癌細胞活性試驗結果……………………………………………23
4. 化學結構與抗癌活性的關係………………………………………24
生物活性實驗方法.................................... 25
結論……………………………………………………26
實驗儀器........................................... 27
試藥與試劑......................................... 28
參考資料............................................... 31
實驗附份………………………………………………………33
附圖部份……………………………………………71

1.Attard, G.; Greystoke, A.; Kaye, S.; Bono, J. D. Update on tubulin-binding agents. Pathologie Biologie 2006, 54, 72-84.
2.Gaya, A. M.; Rustin, G. J. S. Vascular Disrupting Agents: A New Class of Drug in Cancer Therapy Clinical Oncology 2005, 17, 277-290.
3.Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Tubulin as a Target for Anticancer Drugs: Agents Which Interact with the Mitotic Spindle. Medicinal research reviews 1998, 18, 259-296.
4.Lippert, J. W. Vascular disrupting agents. Biological & Medicinal Chemistry 2007, 15, 605-615.
5.Tozer, G. M.; Kanthou, C.; Baguley, B. C. Distrupting Tumour Blood Vessels. Nature Reviews. Cancer. 2005, 5, 423-435.
6.Liou, J.-P.; Chang, Y.-L.; Kuo, F.-M.; Chang, C.-W.; Tseng, H.-Y.; Wang, C.-C.; Yang, Y.-N.; Chang, J.-Y.; Lee, S.-J.; Hsieh, H.-P. Concise Synthesis and Structure−Activity Relationships of Combretastatin A-4 Analogues, 1-Aroylindoles and 3-Aroylindoles, as Novel Classes of Potent Antitubulin Agents. Journal of Medicinal Chemistry 2004, 47, 4247-4257.
7.Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Rainey, T. J.; Westlund, N.; Lynch, V. Synthesis of the Kopsia alkaloids (±)-pauciflorine B, (±)-lahadinine B, (±)-kopsidasine, (±)-kopsidasine-N-oxide, (±)-kopsijasminilam and (±)-11-methoxykopsilongine. Tetrahedron 2002, 17, 3423-3443.
8.De Martino, G.; La Regina, G.; Coluccia, A.; Edler, M. C.; Barbera, M. C.; Brancale, A.; Wilcox, E.; Hamel, E.; Artico, M.; Silvestri, R. Arylthioindoles, potent inhibitors of tubulin polymerization. Journal of Medicinal Chemistry ,2004, 47, 6120-6123.
9.Benington, F.; Morin, R. D.; Clark, L. C.; Jr. Mesclin analogs. VIII. Subtituted 5-methoxy- and 5,6,7-timethoxyindoles. Journal of Medicinal Chemistry 1958, 23, 19-23.
10.N, K.; K, J.; S, D.; PW, B.; RT, C.; S, T.; DH, T.; Jr, K. J.; C, N.-N.; A, S.; R, Y.-S.; Q., W. Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists. Jounal of Medicinal Chemistry 2007 , 50, 21-39
11.Crestini, C.; Saladino, R. A new efficient and mild syntheisis of 2-oxindoles by one-pot Wolff-kishner like reduction of isatin derivatives. synthetic communications 1994, 24, 2835-2841.
12.OLgen, S.; GOTZ, C.; Jose, J. Synthesis and biological evaluation of 3-(substituted-benzylidene)-1,3-dihydro-indolin Derivatives as Human Protein Kinase CK2 and p60c-Sre tyrosine kinase inhibitors. Biological & Parmaceutical Bulletin, 2007, 30, 715-718.