NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)發炎體是NLRP3被病原體或損害相關訊號活化形成的蛋白質複合體，NLRP3發炎體的活化導致促發炎細胞因子IL-1β、IL-18釋放進而導致發炎反應及細胞焦亡 (pyroptosis)。研究顯示此發炎途徑和許多發炎疾病具有密切相關性，而NLRP3發炎體可能是這些發炎疾病的潛在藥物標靶。近期多種小分子被發現抑制NLRP3發炎途徑並減輕相關疾病的病理症狀，幾個非類固醇抗發炎藥物也包含在其中。芬布芬是一種非類固醇抗發炎藥物，主要用於骨關節炎及類風溼性關節炎等發炎疾病的治療，因此本論文以芬布芬作為骨架並改變苯環上的官能基，嘗試篩選出具有抑制效果的結構，應用於NLRP3發炎途徑的抑制。
本研究是以芬布芬側鏈片段構築所需之4-溴苯為起始物，先與丁二酸酐Friedle-Craft acylation並將酸基酯化，再將溴基以硼頻那醇取代後以過碘酸鈉去除頻那醇保護基，可得到帶有硼酸基團的單苯環芬布芬側鏈，之後再和市售之各種溴苯類似物進行Suzuki coupling後將酯基保護去除，即可以總產率10 ~ 16%得到芬布芬類似物6a ~ 6o。路徑二嘗試在芬布芬上建構磺醯胺基團，磺醯胺基團在許多小分子抑制劑中被認為是影響活性的關鍵，因此選用帶有胺基但酯基保護未去除的芬布芬5o，將其胺基以對甲苯磺酸基團保護後再以氫氧化鋰配合氫離子交換樹酯移除酯基保護，便可得帶有磺醯胺基團之芬步芬8，總產率為5%。
將濃度為50 μM的芬布芬、本實驗室先前合成的芬布芬類似物9 ~ 13及本研究中合成的化合物6a ~ 6o和化合物8進行NLRP3發炎途徑抑制實驗，並以現行最有效的小分子抑制劑MCC950 (1 μM)作為對照組。實驗使用小鼠J774A.1細胞並以LPS/ATP活化NLRP3發炎體，透過觀測NLRP3發炎反應下游產物IL-1β的濃度來判斷化合物的抑制效果。結果顯示作為類似物骨架的芬布芬降低10% IL-1β的濃度，效果較佳的化合物13、6c、6d、6f、6j、6o及化合物8則降低20 ~ 30%的IL-1β濃度。
本研究製備了16種芬布芬類似物，雖然改善了芬布芬對NLRP3發炎途徑的抑制活性，但仍跟MCC950有極大的差距，未來研究方向或許可保留部分幾個活性較佳的化合物的苯環區結構，透過對酸基的修飾進一步提升對NLRP3發炎途徑的抑制效果。

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a protein complex formed by activation of NLRP3 by pathogens or damage-associated signals. The activation of NLRP3 inflammasomes lead to the release of proinflammatory cytokines IL-1β and IL-18, thus inducing inflammatory and cells pyroptosis. Numbers studies have shown that this inflammation pathway is closely related to a number of inflammatory diseases, and the NLRP3 inflammasome may be a potential drug target for these diseases. Several small molecules have recently been identified to target the NLRP3 inflammasome pathway and alleviate related disease pathology. Fenbufen is a kind of non-steroidal anti-inflammatory drugs, mainly used for the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. Therefore, this thesis uses fenbufen as the template and changes the functional groups on the aromatic ring to screen out useful structure to inhibit NLRP3 inflammation pathway.
In this study, 4-bromobenzene, which is required for the construction of fenbufen side chain, was used as the starting material. Starting from 4-bromobenzene, via Friedle-Craft acylation with succinic anhydride, acid group esterification, Miyaura borylation and then removed pinacol protecting group via sodium periodate to provide (4-(4-methoxy-4-oxobutanoyl)phenyl)boronic acid 4. After coupling with commercial bromobenzene analogs and removal of ester protector, fenbufen analogs were obtained over six steps synthesis and total yield is 10 ~ 16%. In scheme 2, as a key functional group in inhibiting NLRP3, sulfonamide group is introduced on ester protected fenbufen 5o. After all, ester protecting group was removed via LiOH/H+ resin and fenbufen 8 was obtained with 5% total yield over 7 steps.
The NLRP3 inhibition test was carried out for fenbufen, compound 9-13, 6a-6o at a concentration of 50 μM and the most effective small molecular inhibitor MCC950 (1 μM) served as control group. The experiment used mouse J774A.1 cells and activated NLRP3 inflammasome with LPS/ATP, and assessed the inhibitory effect of the compound by observing the concentration of the NLRP3 inflammasome downstream product IL-1β. The results show that fenbufen, template of these analogs, reduces the concentration of IL-1β by 10%. The more effective compound 13, 6c, 6d, 6f, 6j, 6o and compound 8 reduce the concentration of IL-1β by 20-30%.
In this study, sixteen fenbufen analogs were prepared. Although the inhibitory activity of fenbufen on the NLRP3 inflammation pathway was improved, but still far from MCC950. The future works may retain the aromatic structure of several compounds with better activity, and further improve the inhibition on NLRP3 inflammation pathway through modification of acid groups

摘要--------1
Abstract-------2
誌謝-------4
全名縮寫對照表-------5
目錄-------7
1. 緒論-------9
1.1 發炎反應-----9
1.2 NLRP3發炎體 (NLRP3 inflammasome)-----9
1.2.1 NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-----9
1.2.2 NLRP3發炎體之活化機構-----10
1.2.3 NLRP3作為發炎疾病之治療標靶-----12
1.3 針對NLRP3發炎體途徑的小分子抑制劑-----13
1.3.1 MCC950-----13
1.3.2 Glyburide-----14
1.3.3 JC121類似物-----15
1.3.4 INF4E類似物-----16
1.3.5 NBCs-----17
1.3.6 OLT1177-----18
1.3.7 非類固醇類抗發炎藥物 (Non-Steroidal Anti-Inflammatory Drugs, NSAIDs)-----18
1.4 研究動機-----19
2. 結果與討論-----20
2.1 芬布芬衍生物之化學製備-----20
2.1.1 以路徑一製備芬布芬衍生物-----20
2.1.2 以路徑二製備化合物8-----28
2.2 芬布芬衍生物之活性分析-----28
3. 實驗-----31
3.1 儀器設備、溶劑與試藥之一般處理-----31
3.2 實驗步驟與光譜數據-----33
3.2.1 化學實驗-----33
3.2.2 NLRP3抑制活性實驗-----66
4. 結論-----67
5. 附錄-----68
5.1 化合物光譜、質譜與HPLC圖譜-----68
6. 參考文獻-----178

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