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Singular Value Decompositions for Single-Curl Operators in Three-Dimensional Maxwell's Equations for Complex Media
No full textCalcium Sensor STIM1 in the Progression of Oral Cancer : Focusing on Metastasis
No full text自初級腫瘤位置離開，轉移癌細胞需要擁有透過鈣離子調控的細胞骨架重組及局部黏著斑（focal adhesion）動態所驅動的侵入及移動能力。為了維持生理動態平衡，細胞質內鈣離子的濃度受鈣池調控鈣離子進入（store-operated calcium entry，SOCE）之緊密調控，當內質網中鈣離子耗盡，基質交互分子（stromal interaction molecule，STIM）因此活化，進而活化細胞膜上的鈣離子選擇性通道ORAI，以胞外鈣離子補充內質網的不足。許多研究顯示在子宮頸癌與大腸癌中STIM1表現量異常，然而是否因為STIM1表現量異常影響SOCE活性或者是其他訊息傳遞路徑以致於誘發癌細胞的移動或侵入仍然不清楚。我們先前研究指出STIM1和口腔癌的進展有關。本研究因此欲探討失調的STIM1所調控的口腔癌細胞移動之假說。我們在此報導於試管及體內中，STIM1負向調控口腔癌細胞移動。在口腔鱗狀細胞癌（oral squamous cell carcinoma，OSCC）細胞中，利用shRNA對抗STIM1及ORAI1以致於SOCE活性下降，或者透過小分子SOCE抑制劑，皆可見癌細胞移動增加。相反的，過度表現YFP所標記的STIM1之細胞則阻礙其移動。我們也利用異種移植老鼠模型解釋STIM1在癌症轉移上所扮演之負向角色。和控制組的細胞相較之下，利用STIM1靜默之OSCC細胞進行原位移植老鼠，其在轉移速度、轉移數量及轉移位置的腫瘤大小上皆增加。因此，我們的結果證明在癌細胞移動及轉移的能力上，STIM1扮演抑制者的角色。更進一步的探討將著重於了解STIM1所調節的SOCE是如何影響細胞移動與癌症進展之機制。To escape from the primary tumor site, metastatic cancer cells acquire the abilities to invade and migrate partially through Ca2+ signaling-regulated cytoskeleton rearrangement and focal adhesion dynamics. To maintain physiological homeostasis, intracellular Ca2+ pool is tightly controlled via store-operated calcium entry (SOCE), which includes the activation of stromal interaction molecules (STIM) upon Ca2+ depletion within the endoplasmic reticulum, followed by the activation of Ca2+-selective channel ORAI on the plasma membrane to replenish Ca2+ from extracellular space. Several studies have revealed aberrant levels of STIM1 in human cancers such as cervical cancer and colorectal cancer, but whether STIM1 aberrancy affects SOCE activities or other signaling pathways to induce cancer cell migration or invasion were still unclear. Our preliminary results indicated that expression levels of STIM1 were associated with the progression of oral cancer. The present study is therefore aimed to test the hypothesis that dysregulated STIM1 could modulate the migration of oral cancer cells. We report here that STIM1 negatively regulated oral cancer cell migration in-vitro and in-vivo. Reduction of SOCE activities targeting STIM1 or ORAI1 by shRNA in oral squamous cell carcinoma (OSCC) cells, or by small-molecule SOCE inhibitor, increased cancer cell migration. In contrast, cells over-expressing YFP-tagged STIM1 had impeded cell motility. We also examined the negative role of STIM1 on cancer metastasis using xenograft mouse models. The metastatic rate, metastatic number and tumor size at metastatic sites were increased in mice orthotopically implanted with STIM1 silenced OSCC cells, compared to those implanted with control cells. Hence, our data demonstrated a suppressor role of STIM1 in OSCC cell migration and metastasis. Further explorations will aim at understanding the mechanism how STIM1-mediated SOCE contributes to OSCC cell migration and cancer progression
Characterization and Preparation of Microporous Non-crystalline Silica Low-k Films
No full text本實驗室過去已發展出使用短時間水熱製做非結晶二氧化矽沸石前驅液，製備介電常數小於2之中孔型高機械強度低介電薄膜。然而未來介電薄膜孔洞需在微孔範圍，故本研究目標為研發微孔型高機械強度低介電薄膜。 本研究利用蒸發及刮除法從鍍膜液中收集粉末樣品，以氬氣吸脫附與非局部密度泛函理論模擬，量測薄膜孔洞大小與體積。鍍膜液由沸石顆粒加界面活性劑組成，沸石顆粒由四丙基氫氧化銨(TPAOH)做為MFI微孔結構導向試劑，經水熱程序合成。界面活性劑能使薄膜均勻，但若聚集成微胞，鍛燒後會形成中孔。當薄膜孔隙度提高，藉由空氣之低介電常數(κ=1)，可降低薄膜κ值。 為了增加微孔洞，增加TPAOH之比例，發現TPAOH/Si比例增加無法增加7Å下之微孔體積，但過多TPAOH(鹼)會改變合成結果，孔洞分析顯示，當TPAOH比例提高達0.36，顆粒已不具MFI之結構。另外，界面活性劑會與沸石顆粒作用，改變微孔、破壞MFI結構後，聚集形成中孔。顆粒或界面活性劑之親水性上升可縮小聚集之中孔，故本研究嘗試縮短水熱時間(少於24 h)期望合成親水性更高之沸石顆粒，但研究結果發現過短的水熱時間(6小時)可能會保留矽源TEOS(tetraethyl orthosilicate)與水反應之散亂二氧化矽結構，無法增加親水性。 12小時水熱顆粒做為前驅液，減少四倍界面活性劑，可製備最大孔洞在17.3Å之微孔型低介電薄膜。減少的薄膜孔洞由分子量200，親水性較高之聚乙二醇(PEG200)做為成孔劑，增加孔隙度。為更精確得到薄膜孔洞分佈，改用刮除法收集粉末，經量測可得最大孔洞17.3Å，孔隙度0.31或0.32(PEG200濃度決定)之微孔薄膜。然而這些薄膜κ值大於2，未達未來工業需求，原因可能來自鍍膜的異質性或HMDS無法修飾。 本研究另外發現，加入成孔劑減少界面活性劑會造成薄膜不均勻，但當滴上鍍膜液後等待五秒，可塗佈出均勻薄膜。12小時水熱顆粒親水性高，但會造成界面活性劑形成大微胞，使薄膜產生不均勻條紋。使用短時間水熱時，TEOS的新舊會改變水熱顆粒性質，造成孔洞分佈及孔洞體積的改變。In our previous study, coating solution containing non-crystalline silica for preparing mesoporous low k film with k value below 2 and high mechanical strength has been made. However, microporous low k films is necessary for future needs. Therefore, the goal of this research is to make microporous low k film with high mechanical strength. In this research, pore size distribution (PSD) and pore volume of powders made from coating solution by evaporation method or scraping method were measured by argon adsorption/desorption and analyzed by non local density functional theory (NLDFT) simulation. Coating solution consist of synthesized silica, tetrapropylammonium hydroxide (TPAOH) and surfactant. TPAOH was used as a structure directing agent to synthesis MFIlike microporous silica during hydrothermal process. Surfactant added in the solution can form pores between silica particles after the calcination. As the porosity increases, dielectric constant of the film should decrease. In order to increase the micropore volume, the molar ratio of TPAOH to TEOS (tetraethyl orthosilicate) was increased from 0.15 to 0.36. Nevertheless, the micropore volume was not successfully increased. Instead, the surfactant interacted with silica strongly, resulting in destroying micropores of MFI structure. On the other hand, because increasing hydrophilicities of silica and surfactant (or porogen) can increase the interaction between these two, decrease the formation of micelles and mesopores, and resulting more micropores, shortening hydrothermal period (less than 24 hours) was adopted to manufacture more hydrophilic silica. It was found that micropore volume was increased and mesopore volume was decreased successfully. However, that from too short hydrothermal period (i.e., 6 hours) was not, may be because synthesized silica would maintain amorphous structure from incomplete reaction between TEOS and water. In this research, the low k film with the largest micropore size of 13.6Å has been produced from the coating solution containing silica (synthesized from 12 hours hydrothermal process) and the surfactant with a reduced amount (i.e., ratio of surfactant to TEOS decreases from 0.41 to 0.1). In order to increase the micropore volume, poly(ethylene glycol) with molecular weight 200 (PEG200) acting as hydrophilic porogen was added to coating solution. It was found that the largest micropore increased to 17.3Å and the porosity increased to 0.31 or 0.32, which is close for making low-k value less than 2. Nevertheless, the measured k values are all well above 2, which are not suit for the future needs of IC industry. One of the reasons may be because of the non-uniform coating. Although it can be solved by waiting 5 seconds after dispersing coating solution to wafer before the spinning, the k values are still unexpectedly large
Design and Synthesis of Stimuli-Responsive Supramolecular Gels via Metal-Coordination and Host-Guest Association
No full textIn supramolecular chemistry, using noncovalent interactions to form the stimuli-responsive supramolecular gels has become a popular research topic. External controls of a self-assembling system also interest the chemists. Common stimuli used to trigger the sol-gel transition of supramolecular gels can be generally separated into physical stimuli, such as temperature, light, and mechanics, and chemical stimuli, like pH, redox, ions, competitive molecules, and solvents. Metal-ligand coordination and host-guest association are two kinds of noncovalent interactions with high binding affinity that have been widely employed in supramolecular systems to enhance mechanical properties of supramolecular gels. These two noncovalent interactions were introduced in our system to build up supramolecular gels, which could be responsive to multiple external stimuli. Terpyridine-ZnII complexation and host-guest chemistry of β-cyclodextrin were successfully utilized for constructing a series of novel supramolecular gels that could response to several stimuli, for instance, ions, competitive molecules, and oxidants. The synthesis and characterization of the supramolecular cross-linkers and polymers with pendant β-cyclodextrin as well as their gelation and response tests were discussed, and also an application of metallomacrocycles for serving as supramolecular glue was demonstrated through a series of adhesion tests
Design, Synthesis and Investigation of Small-Molecule Materials for Organic Solar Cells
No full text在各式各樣的再生能源之中，具有較低廉的建置成本、輕量化的元件、材料多樣性以及可撓曲等優點的有機太陽能電池 (OSCs) 是很受到矚目的新科技，致使許多研究團隊致力於開發新型元件架構與新穎的有機材料，近年來在高分子有機太陽能電池以及小分子有機太陽能電池上都有不錯的元件效率表現。 在本論文中敘述了我在設計與合成AADAA和DAA架構的小分子有機太陽能電池染料的成果，研究分子結構、物理性質以及元件效率表現之間的關係。論文架構如下，第一章介紹有機太陽能電池原理、分子設計策略以及至今最先進應用於有機太陽能電池的小分子和高分子電子予體材料；第二章中我們為了濕製程太陽能電池合成出以雙噻吩并噻咯、雙噻吩并環戊二烯與雙噻吩并苯為中心之AADAA架構的染料，其中CPDT-T1染料達到了0.80%效率。在第三章中，我們增強AADAA染料的拉電子基，合成出了八個AADAA結構的染料，將HOMO與LUMO能階一併拉低的過程中，提升了蒸鍍製成元件的效率表現，其中CPDTBFC可以達到4.94%。在第四章中敘述具有推電子性質的二芳胺接上強拉電子基團thiazolidenemalononitrile，合成了一系列DAA架構的染料，而這些分子的電洞傳導率與分子間作用力息息相關，而在不具有純donor層的PMHJ元件架構下，DPPT效率可以達到3.52%。Among the various solar energy resources, organic solar cells (OSCs) are attracted attention of new technology owing to their advantageous features such as, cheaper manufacturing cost, light-weight, material diversity and mechanical flexibility, that render the interest of many research groups to develop such novel organic materials to design new device configurations. Recently, organic polymer solar cell and small-molecule organic solar cell both show fruitful device performance. This dissertation describes my research effort in the design and synthesis of small-molecule materials with DAA and AADAA molecular configuration for OSCs followed by investigation of molecular structure to evaluate structure-property relationships, physical properties and device performance. The thesis is divided into four chapters and is organized as follow. Chapter 1 provides an introduction of basic principle of organic solar cell, the strategy of molecular design, and a short summary of state-of-the-art of small-molecule and polymer electronic donor materials for OSCs. In chapter 2, we synthesized silolo [3,2-b:4,5-b''] dithiophene, cyclopenta[1,2-b:5,4-b'']dithiophene, and benzo [1,2-b:4,5-b''] dithiophene-based AADAA structure organic dyes for solution process solar cell, and CPDT-T1 exhibited 0.80% efficiency. In chapter 3, we synthesized eight organic dyes with AADAA structure having variable electron withdrawing ability. The lowering of both HOMO and LUMO energy level cause enhanced device performance of vacuum-deposited organic solar cells, and thus CPDTBFC yielded 4.94% efficiency. In chapter 4, we synthesized a series of electron withdrawing thiazolidenemalononitrile-based DAA structure dyes with different diarylamine functionalities. Hole mobility of these compounds is found to be strongly dependent on the various intermolecular interactions. DPPT-based device has 3.52% efficiency of a PMHJ device without the thin donor layer
The Fairness Behind Veil of Ignorance –Behavior Experiment on Formosan Macaque
No full text公平一直是人類決策研究中一個重要議題。在過去研究中，影響最深遠的理論就是由美國哲學家John Rawls所提出無知之幕的概念(Rawls.1971)。在無知之幕後方的社會分配者，不知道自己在無知之幕揭開後，會是社會上的哪一個階層，所以決策者必須考量到所有階層狀況，此時決策者所做的分配就是該決策者的“公平概念”。 經濟學研究發現，在兩個期望值相同但風險不同的選項中，如果人類決策者只考慮自己的報酬時，通常會選擇風險較小的選項。但如果決策者的決定會影響他人時，決策者多會選擇利他的選項，顯示人類有正向的社會偏好。如果人類在無知之幕後方的選擇只考量報酬，不在乎其他人，則無知之幕後方的選擇就會等同風險偏好。Schildberg-Hörisch (2010)在人類身上重現無知之幕的實驗，分別測量受試者在風險情境、社會情境、還有無知之幕後方情境的決策行為，結果發現在無知之幕後方的受試者，選擇風險的比例顯著的少於在風險情境下選擇風險的比例，而女性減少的比例又大於男性。 本實驗使用台灣獼猴（Macaca cyclopis）當受試者，分別測試獼猴在社會情境、風險情境、無知之幕情境中的決策偏好。我們比較這三個情境的關聯性及差異，同時透過行為記錄確認動物彼此之間的社會關係，以及其對決策的影響。結果我們發現獼猴的決策與人類不同，猴子都是風險愛好者。但即使是風險愛好者，無知之幕後方選擇風險(不平等選項)的比例也明顯低於風險情境中選擇風險(不平等選項)的比例。這些結果顯示另外一隻猴子的存在，會降低選擇不平等選項的比例。The veil of ignorance (VOI), behind which people allocate resource prior to learning their social positions, was introduced by John Rawls (1971). In a world of two, a prince and a beggar, an equal distribution yields an even share of resource to them, whereas an unequal distribution gives the prince the majority and leaves little for the beggar, preference over distributions may depend on a decision maker’s roles as a prince or a beggar. Decisions made before learning his roles are immune from being affected by his respective social position, and hence reflect what truly constitutes a just distribution. These are termed as preferences behind VOI, and they are therefore divided into two parts: the decision maker’s inequity aversion and their risk preference. In other words, when making decisions behind VOI, they balance between the desired distribution and the risk of not obtaining the desired role. We study the behavior of non-human primate, Formosan Rock Macaque (Macaca cyclopis), in the face of food decision problems. We conduct a class of modified dictator games in which a proposer chooses between two food allocations, and measure subjects’ preferences, including risk preference, inequity aversion, and preference behind VOI. Our data shows that subjects are strongly risk-loving and exhibit inequity aversion. Also, social context did affect choice in hierarchy system
Dysphoric Mood and Modes of Rumination on Emotion Regulation and Implicit Future Thinking
No full text情緒調節向來是憂鬱症研究者所關注的主題，研究者發現憂鬱患者較傾向於使用不具適應性的情緒調節策略，尤其是常使用憂鬱反芻作為情緒調節策略。Lyubomirsky、Caldwell 與 Nolen-Hoeksema（1998）主張「自我專注」於情緒調節歷程中扮演重要角色，憂鬱反芻會使負向認知之可得性增加，因而增加情緒一致效果。而Watkins與Teasdale（2001）根據互動式認知子系統（interacting cognitive subsystems, ICS）模式進一步提出兩種反芻式自我專注型式，即分析評價式反芻與經驗感受式反芻，它們分別會損害或提昇個體情緒調節與認知表現，另外，過去的研究也缺乏探討不同的情緒調節策略對於內隱未來思考的影響。因此，本研究擬探討在負向情緒脈絡下，個體的憂鬱傾向與不同反芻型式的情緒調節策略，對憂鬱情緒與內隱未來思考的影響。本研究先對190名參與者實施負向情緒誘發作業與未來思考關聯評估測驗前測，然後將參與者隨機分派至分析評價式反芻組或經驗感受式反芻組，最後進行未來思考關聯評估測驗後測與實驗操弄檢核。貝克憂鬱量表得分大於等於14分或得分小於等於5分的參與者會被納入正式資料分析，分別有37人與32人，共69人。本研究以參與者在負向情緒誘發後與情緒調節操弄後的正負向情緒感受為依變項，進行2（高/低憂鬱）×2（分析評價/經驗感受）×5（時間：情緒誘發前（T1）/情緒誘發後（T2）/反芻操弄前（T3）/反芻操弄後（T4）/未來思考關聯評估測驗後測（T5））的重複測量變異數分析。並以參與者之四種未來思考指標（屬受試者內變項：預期詞價性×未來情境詞價性）的前後測分數為依變項，分別進行2（高/低憂鬱）×2（分析評價/經驗感受）×2（時間：前/後測）×2（預期詞價性：我預期/我不預期）×2（未來情境詞價性：正/負未來情境詞）的重複測量變異數分析或共變數分析。在被誘發負向情緒後，高憂鬱組會肯定「負向未來情境會發生」，而低憂鬱組則會否定「負向未來情境會發生」。但在肯定「正向未來情境會發生」與肯定「負向未來情境不會發生」的程度上，高低憂鬱組兩組並無顯著差異。在反芻型式操弄後，分析評價組的參與者相較於其前測，對於「正向未來情境不會發生」的否定程度會下降，且對於「負向未來情境會發生」的肯定程度會增加；但接受經驗感受式反芻的參與者，其未來思考傾向在前後測間則無顯著差異。另外，參與者在接受分析評價式反芻與經驗感受式反芻後，均未顯著降低其負向情緒感受，也未顯著提昇其正向情緒感受。在被誘發負向情緒後，相較於低憂鬱組，高憂鬱組的內隱未來思考較為悲觀（即會肯定「負向未來情境會發生」）。這顯示，高憂鬱組之內隱思考具憂鬱病理性（depressogenic），在負向情緒脈絡下，因認知反應性（cognitive reactivity）與缺乏情緒不一致效果而使其內隱未來思考具負向偏誤。經分析評價式反芻型式操弄後，無論高低憂鬱組，其內隱未來思考相較於前測皆會更具負向偏誤。而經經驗感受式反芻操弄後，無論高低憂鬱組，其內隱未來思考表現無顯著前後測差異，與研究假設不符。針對上述結果，本研究透過不同反芻型式對於認知功能與工作記憶的影響，說明反芻型式之認知機制。本研究是第一個由內隱未來思考的觀點探討經驗感受式反芻與分析評價式反芻兩種情緒調節策略在其中所扮演的角色。本研究並發現在負向情緒脈絡下，分析評價式反芻會造成情緒一致效果，具體而言，參與者對於「正向未來情境不會發生」的否定程度會下降，且對於「負向未來情境會發生」的肯定程度會增加。基於研究結果，本研究建議內隱認知作業未來或許可作為一個可能的臨床治療策略與療效評估作業。此外，由於當採取分析評價式反芻時，無論是高或低憂鬱組，其「正向未來情境不會發生」的否定程度會下降，且對於「負向未來情境會發生」的肯定程度會增加，這意味著無論高、低憂鬱組，只要持續採取不具適應性的情緒調節策略，就會增加個體陷入憂鬱情緒的可能性。Emotion regulation has been widely studied with major depression disorder, and previous studies showed that depressive individuals tended to use maladaptive emotion regulation strategies, especially rumination. Lyubomirsky, Caldwell, & Nolen-Hoeksema (1998) proposed that depressive rumination enhanced accessibility of negative cognition and increased mood congruent effect. Recently Watkins & Teasdale (2001) proposed distinct modes of rumination, namely, analytic rumination and experiential rumination, as maladaptive and adaptive effect regulation strategies. Compared to analytic rumination, experiential rumination would be a more adaptive emotion regulation strategy. However, there has been no study on how experiential and analytic rumination affected implicit future thinking. In this study, the authors investigated how dysphoric mood and modes of rumination affect emotion regulation and implicit future thinking under negative mood context. Firstly, 190 participants underwent negative mood induction and pre-tests, including implicit future thinking task. Then, they were randomly assigned to analytic rumination or experiential rumination. Finally, they completed post-tests and manipulation check. The authors chose BDI-II scores > 14 to be the dysphoric group and BDI-II < 5 to be the nondysphoric group. Using these criteria, we screened 69 participants for data analyses. A 2 (dysphoric/nondysphoric group) × 2 (analytic/experiential ) × 2 (pre-test/post-test) × 2 (I-expect/I-don’t-expect ) × 2 (positive/negative future) five way repeated measures ANOVA was conducted. The results showed that under negative mood induction, the dysphoric group confirmed “I-expect-negative (future)”, and the nondysphoric group denied “I-expect-negative (future)”. Compared to the pre-test, the analytic rumination group tended to be more confirming I-expect-negative (future)” and less denial of “I –don’t expect -positive (future)” in the post-test. However, there was no significant difference between the pre-test and the post-test for the experiential rumination group. Besides, both analytic rumination group and analytic rumination group showed no mood recovery after the rumination manipulation. We concluded that, compared to the nondysphoric group, the dysphoric group was more pessimistic to the future. We also concluded that under negative mood context, analytic rumination would have more maladaptive effect on implicit future thinking, indicating that analytic rumination enhanced negative-biased cognition. Taken together, the present study supported that analytic rumination was a maladaptive emotion regulation strategy, indicating that keeping adopting maladaptive emotion regulation strategy might increased the possibility of developing depression. Finally, according to our finding, in the future, implicit thinking task may be a possible clinical intervention or an assessment tool for treatment effect
The First Synthesis of disaccharide a-iminosugar
No full text鑒於日益嚴重的細菌抗藥性，設計新的抗生素已是刻不容緩的議題。其中，因細菌細胞壁轉醣酶（TGase）不存在於哺乳類生物體內，但易於進出細菌且又尚未發現任何抗藥性的特性，此議題被認為是個有潛力的藥物目標。然而，此轉醣酶的受質（lipid II）因自然存在量低及複雜的化學結構，在合成製備上極其不易。研究人員已開發了許多lipid II藥物，但多是以葡萄糖作為基底而成。本篇旨在研究合成新的lipid II基底。由於亞胺醣在生物中也有不錯的抑制性，但O-醣苷鍵亞胺醣極其不穩定，又須應用於lipid II，因此目標物需為較穩定之α-C-醣苷鍵亞胺醣。應用本實驗室前人開發的合成方法，使用wittig reaction形成開環雙鍵後，再以Swern oxidation及reductive amiation生成一級胺，最後進行分子內hydroamination後即可以得到理想α-C-醣苷鍵亞胺醣產物。Due to the increasing drug resistance, design and synthesis of potent antibiotics is urgent and critical to scientist. Bacterial TGase is considered as a potential target due to the lack of the eukaryotic counterpart, easy access and no resistance to current drugs. In order to design new antibiotics against TGase, the detail study in protein-substrate interaction and the establishment of TGase assay are required. However, preparation of the key component, TGase substrate-lipid II, is difficult due to the low natural abundance and complex structure. Researchers have developed various lipid II, most of which are based on glucose analogues. In this thesis, we are focus on the designing of new lipid II based on iminosugar analogues. According to the good resistance of the iminosugar analogues and the similarly structure of the glycosylation transition state , we can apply these compound to the study of lipid II. However, the synthesis study of the α-C-iminosugar is few and difficult. We have designed a series of steps, wittig reaction, Swern oxidation, reductive amiation and hydroamination, to afford the ideal iminosugar target
Development of Abiraterone-based Photoaffinity Probe and Evaluation of their Labeling Efficiency for CYP17A1
No full textAbiraterone 在2012年底經美國食品暨藥物管理局許可，成為治療閹割抗性前列腺癌的二線藥物。其機轉為抑制類固醇生合成路徑中的 CYP17A1 以減少雄性激素的產生。至今大多數的體外實驗或是臨床試驗，為觀測 Abiraterone 影響生合成相關蛋白表現量和上下游產物的分泌量，然而專門探尋未知結合蛋白，所產生的藥物機轉研究卻相對貧乏。在本論文中，我應用 ABPP (Activity-Based Protein Profiling)原理，發展以 Abiraterone 為主體的光親和性探針。此探針是由辨識端Abiraterone、Diazirine光反應性基團和 Biotin為標籤所組成。當辨識端成功與目標蛋白結合時，可藉由 365 nm 波長的光激發使 Diazirine 對目標蛋白產生共價性鍵結，再由 Biotin 標籤做後續的純化或免疫染色。在結構設計上，依據 Docking 實驗結果和已報導的 X-ray 晶體結構，我們選擇 Abiraterone 之 C7a 位置做探針衍生化，以減少與 CYP17A1 結合的干擾。接著我們以單元模組化的合成策略，成功地合成以 Abiraterone 為導引的光親和性探針 Ab-C7a-PB 和 Ab-C7a-P，並以 NMR 技術確認了 C7a 位置的位向。最後進行光親和性探針的功能性鑑定，以 H295 細胞株作為 CYP17A1 來源，in vitro 光標示結果顯示，利用不同的細胞裂解液成分，皆無法萃取出有結合能力的 CYP17A1，故無法成功進行光標示。但以 in vivo 的方式，在維持原始生化功能的細胞組織下，加入 Ab-C7a-PB 進行培養和照光，經後續西方墨漬法分析顯示可成功標示到 CYP17A1。故確認 Ab-C7a-PB 具辨識和光標示的功能性，可用於剖析細胞層級之蛋白質體學研究。Abiraterone, a drug approved by US Food and Drug Administration at the end of 2012 for Castration-Resistant Prostate Cancer, is an inhibitor of CYP17A1, which catalyzes the steroid biosynthesis to produce the androgen in adrenal cortex. Up to date, most in vitro tumor cell lines research or in vivo clinic trials focused on the evaluation of the abiraterone effects on relative protein up/down regulation or the level of specific sterols in the hormonal signal pathways. Research works involving the drug mechanism of action as well as ligand-based protein screening are relatively rare. In this study, I applied the Activity-Based Protein Profiling (ABPP) concept to develop abiraterone-based photoaffinity probes to profile abiraterone’s possible working targets. The probes are composed of abiraterone (ligand) as a recognition unit, daizirine moiety as a photoreactive group and a biotin tag as an output. The working hypothesis is that once the ligand recognized by the target protein, the daizirine could be brought to the vicinity of the target protein and subsequently forms a covalent bond with the target protein upon irradiation at 365 nm. After washing off the nonspecific binding proteins, the covalent-linked proteins can be further purified and characterized either by the tag purification or tag immunohistochemistry via biotin. Based on the molecular docking result and the reported X-ray structure of abiraterone-CYP17A1 ternary complex, abiraterone was derivatized at the C7 position with α configuration to minimize the structural perturbation to bind CYP17A1. The probes, denoted by Ab-C7α-PB and Ab-C7α-P, were successfully synthesized by assembling different functional modules via the designed connectivities. The configuration at C7 was confirmed to be α by several different NMR techniques. To exploit the utility of the probes, H295 cell line was used since it contains abiraterone binding protein-CYP17A1. In vitro photolabeling results showed that Ab-C7α-PB failed to label CYP17A1 by using many kinds of lysis buffers. On the other hand, if Ab-C7α-PB was incubated and photoactivated under native cellular environments in vivo, subsequent Western Blot showed that Ab-C7α-PB could successfully label CYP17A implicating that Ab-C7α-PB could function as an effective photoaffinity probe for labeling CYP17A1 and profiling the abiraterone regulating proteins