臺灣博碩士論文加值系統

在1973年學者發現到以往投予抗菌用途的磺胺類藥物會蓄積在腫瘤細胞內，於是興起了研發苯磺醯胺為主要結構的抗癌藥物，例如：ABT751 (1)。
ABT751 (1) 是透過和微小管上的秋水仙素結合位置產生口腔癌細胞的抑制作用，而且口服投予仍具有廣泛抗癌細胞活性的化合物，現正在美國進行人體臨床試驗第二期；於文獻上有發表的ABT751 (1) 對人類口腔表皮細胞株 (human oral epidermoid carcinoma KB cell line) 有抗癌活性 (IC50 = 251 nM)，由於口服投與藥品的用藥順服性相對於其他藥物投予路徑來得好，再加上其有頗好的抗癌活性，所以我們以此一化合物的結構為基礎，探討相關類緣物的抑制癌細胞的作用活性。
保留三號位的磺胺鍵上的取代基，先針對二號位上的取代基作改變，並且將其兩芳香環間的胺鍵除去直接連結在一起，因此我們以N-(2-bromopyridin-3-yl)-4-methoxybenzenesulfonamide (4) 為主要結構，在化合物的二號位以鈴木偶合反應作取代基的改變，並研究其不同的取代基對癌細胞的抑制作用的關聯性。
首先由起始物2-Bromo-3-nitro-pyridine做還原反應得到化合物3，在其結構上的胺基上形成磺胺鍵與4-methoxyphenylsulfonyl chloride結合，因此而得到化合物4為主要結構，另外，再使用不同取代基的硼酸衍生物和其吡啶環上的溴原子進行偶合作用而得到我們的最終產物 (2, 5-7, 12, 18-23)，此外，我們還在磺胺鍵上的胺基的位置作短鏈的烷化作用 (8-11, 13-17)，以便探討其與活性作用上的變化。
除此之外，我們還將indoline和ABT751 (1) 結合在一起，以indoline為主要的結構中心，並且在indoline七號位上苯胺支鏈對位的取代基作改變 (24, 28-32)，另外以短鏈的官能基來取代苯環支鏈 (33, 34)，而研究其與抑制口腔癌細胞的作用活性的相關性，而由部分的抗癌生物活性檢測數據顯示：化合物24, 28, 29, 33, 34均表現出相當理想的抗KB細胞株活性，其IC50數值各別為200, 50, 103, 238, 197 nM，都比ABT751 (1) 的抗癌細胞活性強。
此良好的結果激勵我們在未來能對此類衍生物作更多研究與探討。

In 1973, Sulfadiazine, an antibacterial sulfonamide, was reported to preferentially accumulate in sc-implanted murine tumors after ip administration. The lab in Japan undertook the synthesis and screening of a number of sulfonamides with widely differing chemical structure and hoped the sulfonamide compounds had new bioactivity to anticancer.
ABT-751 is an orally available antimitotic methoxybenzene sulfonamide agent that binds preferentially and competitively to the colchicine site of the ?? tubuline. In preclinical studies, it inhibited cellular proliferation of a broad range of human tumor cell lines, and it was in phase II of clinical trial.
Following the structure of the lead compound - ABT751; our lab designs two series analogs of it in order to improve the bioactivity to antitumor. At first, we link the pyridine and benzene rings substituting the amide bond and modify the hydroxyl- group on benzene ring to others (2, 5-7, 12, 18-23) with Suzuki coupling reaction. And then, we add different alkyl groups on sulfonamide bond (8-11, 13-17) because we hope they have more ability to occupy the colchicines domain.
The other series is that we put indoline into the structure which behaves main architecture in compounds. And following before idea of last series, we also change the functional group on benzene ring (24, 28-32). In the other way, we substituted the functional group on 7-amino group of indoline with short side chain (33, 34). On the basis of preliminary data of anti-proliferative activity, compound 24, 28, 29, 33,and 34 exhibited substantial activity stronger than ABT751 (251 nM). And their IC50 (KB cell line) are 200, 50, 103, 238, and 197 nM.
The result inspired us to further investigate and synthesize this series of analoges in the future.

目 錄
目錄----------------------------------------------------------------------I
附圖目錄--------------------------------------------------------------VI
附表目錄-------------------------------------------------------------VII
流程目錄------------------------------------------------------------VIII
附錄光譜圖目錄-----------------------------------------------------IX
中文摘要--------------------------------------------------------------XI
英文摘要-------------------------------------------------------------XII
壹、緒論
一、 前言-----------------------------------------------------------------------1
二、 化學治療藥物-----------------------------------------------------------3
三、 微小管在細胞週期-有絲分裂中的重要性-----------------------14
四、 作用於微小管的抗癌藥物------------------------------------------17
五、研究背景-----------------------------------------------------------------19
六、研究目的-----------------------------------------------------------------22
貳、結果及討論
一、2-Arylpyridine sulfonamide-----------------------------------------24
(一)化學結構設計-------------------------------------------------------24
(二)合成流程與方式----------------------------------------------------25
(三)化學合成結果與討論----------------------------------------------27
二、7-Aminoindoline sulfonamide
(一)化學結構設計-------------------------------------------------------30
(二)合成流程與方式----------------------------------------------------30
(三)抗癌細胞活性與結果----------------------------------------------35
(四)化學結構與抗癌活性的相關性----------------------------------35
参、結論---------------------------------------------------------------37
肆、實驗部分
一、實驗儀器-----------------------------------------------------------------38
二、試藥與試劑-------------------------------------------------------------38
三、合成步驟
2-Bromo-3-amino-pyridine(3)----------------------------------------42
N-(2-bromopyridin-3-yl)-4-methoxybenzenesulfonamide (4) ------------------------------------------------------------------------------43
N-(2-(4-hydroxyphenyl)pyridin-3-yl)-4-methoxybenzene-sulfonamide (2) -----------------------------------------------------------------44
4-methoxy-N-(2-phenylpyridin-3-yl)benzenesulfonamide (5) ------------------------------------------------------------------------------45
4-methoxy-N-(2-(4-methoxyphenyl)pyridin-3-yl)benzene-sulfonamide (6) -----------------------------------------------------------------46
N-(2-(4-cyanophenyl)pyridin-3-yl)-4-methoxybenzenesulfonamide (7) ----------------------------------------------------------------------47
N-(2-(4-cyanophenyl)pyridin-3-yl)-4-methoxy-N-methylbenzenesulfonamide (8) -------------------------------------------------------48
N-(2-(4-cyanophenyl)pyridin-3-yl)-N-ethyl-4-methoxybenzenesulfonamide (9) ----------------------------------------------------------49
N-(2-(4-cyanophenyl)pyridin-3-yl)-4-methoxy-N-propylbenzenesulfonamide (10) -------------------------------------------------------50
N-(2-(4-cyanophenyl)pyridin-3-yl)-N-isopropyl-4-methoxybenzenesulfonamide (11) ---------------------------------------------------51 N-(2-(4-fluorophenyl)pyridin-3-yl)-4-methoxybenzenesulfonamide (12) -------------------------------------------------------------------52 N-(2-(4-fluorophenyl)pyridin-3-yl)-4-methoxy-N-methylbenzenesulfonamide (13) ------------------------------------------------------53 N-ethyl-N-(2-(4-fluorophenyl)pyridin-3-yl)-4-methoxybenzenesulfonamide (14) --------------------------------------------------------54
N-(2-(4-fluorophenyl)pyridin-3-yl)-4-methoxy-N-propylbenzenesulfonamide (15) -------------------------------------------------------55
N-(2-(4-fluorophenyl)pyridin-3-yl)-N-isopropyl-4-methoxybenzenesulfonamide (16) ---------------------------------------------------56 N-(2-(4-fluorophenyl)pyridin-3-yl)-N-((4-methoxyphenyl)sulfonyl)acetamide (17) -------------------------------------------------------57 4-methoxy-N-(2-(4-nitrophenyl)pyridin-3-yl)benzenesulfonamide (18) --------------------------------------------------------------------58 4-methoxy-N-(2-(4-(trifluoromethyl)phenyl)pyridin-3-yl)benzenesulfonamide (19) ----------------------------------------------------59 N-(2-(4-chlorophenyl)pyridin-3-yl)-4-methoxybenzenesulfonamide (20) -------------------------------------------------------------------60
Ethyl 4-(3-((4-methoxyphenyl)amino)pyridin-2-yl)benzoate (21)-------------------------------------------------------------------------61
4-methoxy-N-(2-(3,4,5-trimethoxyphenyl)pyridin-3-yl)benzenesulfonamide (22) ---------------------------------------------------------62
N-([2,4''-bipyridin]-3-yl)-4-methoxybenzenesulfonamide (23)-------------------------------------------------------------------------63
5-Bromo-1-(4-methoxybenzenesulfonyl)-7-nitroindoline (25)-------------------------------------------------------------------------64
5-Bromo-1-(4-methoxybenzenesulfonyl)-7-aminoindoline (26)-------------------------------------------------------------------------65
1-(4-Methoxybenzensulfonyl)-7-aminoindoline (27) ------------66
4-((1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)amino)phenol (24)-------------------------------------------------------------------------67
4-((1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)amino)benzonitrile (28) ---------------------------------------------------------------------68
1-((4-methoxyphenyl)sulfonyl)-N-(4-nitrophenyl)indolin-7-amine (29) ----------------------------------------------------------------------69
N-(3,4-difluorophenyl)-1-((4-methoxyphenyl)sulfonyl)indolin-7-amine(30)-----------------------------------------------------------------70
Methyl-4-((1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)amino) benzoate (31) ------------------------------------------------------------71
4-((1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)amino)benzoic acid (32) ------------------------------------------------------------------72
N-(1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)cyanamide (33)-------------------------------------------------------------------------73
2-(dimethylamino)-N-(1-((4-methoxyphenyl)sulfonyl)indolin-7-yl)acetamide (34) -------------------------------------------------------74
四、抗癌細胞活性檢測材料及測試方法--------------------------------75
伍、參考資料----------------------------------------------------------76
附圖目錄 (Figure Contents)
圖一、全球人口死因統計數字及發展趨勢預測 (2002-2030)-----------2
圖二、民國九十五年臺灣地區主要死因死亡率趨勢圖------------------2
圖三、血管標靶藥物分類-----------------------------------------------------14
圖四、血管破壞劑造成腫瘤血管阻塞之機轉-----------------------------14
圖五、微管與微小管之構造圖-----------------------------------------------16
圖六、細胞週期圖--------------------------------------------------------------16
圖七、有絲分裂流程圖--------------------------------------------------------17
圖八、抗有絲分裂藥物與微小管的結合部位-----------------------------19
圖九、臨床目前使用之各種具磺胺結構之藥物--------------------------22
圖十、秋水仙素與ABT751結合位------------------------------------------23
圖十一、ABT751結合位------------------------------------------------------23
圖十二、流程一中c步驟的作用機轉---------------------------------------27
圖十三、化合物24合成機轉-------------------------------------------------28
圖十四、流程二中c步驟的合成機轉---------------------------------------34
圖十五、流程二中d步驟的合成機轉---------------------------------------34
圖十六、酪胺酸------------------------------------------------------------------36
附表目錄 (Table Contents)
表一、民國九十七年十大死因-------------------------------------------------3
表二、化合物2, 5-23化學合成產率-----------------------------------------27
表三、化合物1, 24-34之KB細胞活性檢測------------------------------35
流程目錄 (Scheme Contents)
流程一----------------------------------------------------------------------------26
流程二----------------------------------------------------------------------------31
流程三----------------------------------------------------------------------------33
附錄光譜圖目錄
圖一、化合物 3之氫核磁共振光譜圖-------------------------------------81
圖二、化合物 4之氫核磁共振光譜圖-------------------------------------82
圖三、化合物 2之氫核磁共振光譜圖-------------------------------------83
圖四、化合物 5之氫核磁共振光譜圖-------------------------------------84
圖五、化合物 6之氫核磁共振光譜圖--------------------------------------85
圖六、化合物 7之氫核磁共振光譜圖-------------------------------------86
圖七、化合物 8之氫核磁共振光譜圖-------------------------------------87
圖八、化合物 9之氫核磁共振光譜圖-------------------------------------88
圖九、化合物 10之氫核磁共振光譜圖-------------------------------------89
圖十、化合物 11之氫核磁共振光譜圖-------------------------------------90
圖十一、化合物 12之氫核磁共振光譜圖----------------------------------91
圖十二、化合物 13之氫核磁共振光譜圖---------------------------------92
圖十三、化合物 14之氫核磁共振光譜圖--------------------------------93
圖十四、化合物 15之氫核磁共振光譜圖--------------------------------94
圖十五、化合物 16之氫核磁共振光譜圖--------------------------------95
圖十六、化合物 17之氫核磁共振光譜圖--------------------------------96
圖十七、化合物 18之氫核磁共振光譜圖--------------------------------97
圖十八、化合物 19之氫核磁共振光譜圖--------------------------------98
圖十九、化合物 20之氫核磁共振光譜圖--------------------------------99
圖二十、化合物 21之氫核磁共振光譜圖-------------------------------100
圖二十一、化合物 22之氫核磁共振光譜圖------------------------------101
圖二十二、化合物 23之氫核磁共振光譜圖-----------------------------102
圖二十三、化合物 25之氫核磁共振光譜圖----------------------------103
圖二十四、化合物 26之氫核磁共振光譜圖----------------------------104
圖二十五、化合物 27之氫核磁共振光譜圖-----------------------------105
圖二十六、化合物 24之氫核磁共振光譜圖-----------------------------106
圖二十七、化合物 28之氫核磁共振光譜圖-----------------------------107
圖二十八、化合物 29之氫核磁共振光譜圖-----------------------------108
圖二十九、化合物 30之氫核磁共振光譜圖-----------------------------109
圖三十、化合物 31之氫核磁共振光譜圖--------------------------------110
圖三十一、化合物 32之氫核磁共振光譜圖-----------------------------111
圖三十二、化合物 33之氫核磁共振光譜圖-----------------------------112
圖三十三、化合物 34之氫核磁共振光譜圖-----------------------------113

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