臺灣博碩士論文加值系統

近年來活性雙羰基化合物 (Reactive dicarbonyl species，RCS) 越來越受重視，已有研究指出此化合物在人體內累積會造成細胞傷害，長時間在體內中會使蛋白質糖化，形成不可逆的糖化終產物 (Advanced glycation end product，AGE) ，人體內的 AGE 濃度高低，已被證實與許多疾病的標記因子成正比，如糖尿病患者，其血漿中之雙羰基化合物高於正常人。因此本實驗目的為找尋可以有效減少甲基乙二醛 (Methylglyoxal，MG) 化合物的物質，可以將體內及體外的 MG 清除，避免細胞傷害及 AGE 的生成。在此實驗中，是以 21 種酚類化合物及 aminoguanidine 、黑加崙、荔枝殼萃取物 (oligonol) 做為主要探討的原料。並利用 CS ChemDraw Ultra 11.0.1 software (CSCDU) 軟體計算 21 種酚類化合物的化學結構式中苯環碳上的電荷分佈，探討可用此軟體初步判定捕捉 MG 之能力，結果顯示電荷密度負值越大者可能具有捕捉 MG 能力，故此軟體是可有效推測捕捉 MG 的一個很好工具。
在進行 MG 捕捉能力測定中，是在模擬生理的條件下所進行，以 37 ℃ ， Phosphate buffered saline、 pH 7.4 下反應，而 MG 分子小具揮發性，在紫外光/可見光波長下無吸收。本實驗以 o-Phenylenediamine 與 MG 進行縮合反應形成 2-Methylquinoxaline (2MQ) 衍生物，以 HPLC 進行分析，則可在 313 nm 下被偵測出。
結果顯示黑加崙萃取物與荔枝殼萃取物 (oligonol) 分別減少 MG 百分比為 36.11 ± 7.19 % 、 47.68 ± 0.66 % ，兩者都能有效減少 MG 含量，並以黑加崙萃取物做以下實驗，藉由分離純化黑加崙萃取物中的主要花青素，探討 MG 減少百分比及花青素與 MG 有無形成加成反應。黑加崙萃取物先經 Sephadex LH-20 chromatography 管柱層析，此分離物經 LC-ESIMS 分析可得黑加崙的主要花青素為 Delphinidin-3-O-rutinoside (D3R) 及 Cyanidin 3-O-rutinoside (C3R) 。將此片段的樣品再經一次逆相管柱層析，分別收集主要兩個片段並減壓濃縮後冷凍乾燥，即可得到純化的花青素粉末。將收集到的 D3R 與 C3R 分別在 37 ℃ 水浴下反應及 D3R 、 C3R 與 MG 於 37 ℃ 水浴反應，探討 D3R 、 C3R 對熱的穩定性及與 MG 之反應變化，結果顯示在 37 ℃ 水浴下， D3R 、 C3R 減少的百分比分別為 28.60 ± 2.30 % 、 21.26 ± 1.07 % ，在37 ℃水浴下與 MG 反應， D3R 、 C3R 減少的百分比分別為 96.52 ± 0.21 %、 97.67 ± 0.08 %，表示花青素對熱很不穩定，在與 MG 反應中，除了熱不穩定而大量裂解外，花青素與 MG 的反應也導致花青素含量減少。 MG 減少百分比， D3R 、 C3R 分別為 46.72 ± 0.76 %、 49.80 ± 0.56 %，顯示 C3R 反應效果較好，除了解釋 D3R 在B環中多了羥基，導致捕捉 MG 能力不同，經 LC-ESIMS 分析發現， D3R 、 C3R 可分別接上一個 MG ，表示有加成反應的進行。

Reactive dicarbonyl species have drawn much attention in recent decades, it has been demonstrated that reactive dicarbonyl species irreversibly modified proteins over time and yielded the advanced glycation endproducts (AGEs). AGEs in the body were confirmed to be proportional to many diseases』 markers. For example, blood levels of dicarbonyl were found higher in diabetic patients than in healthy individuals. The aim of the present study is to find the substances that can reduce methylglyoxal (MG) in vivo or in vitro, in order to prevent cell injury and the AGE production. Twenty-one simple phenols, extracts of black currant, and oligonol have been evaluated for MG trapping ability. The relationships between reaction activity and physical and chemical properties of phenolic compounds were discussed further. Computer software, CS ChemDraw Ultra 11.0.1 (Copyright c 1986-2007 by Cambridge Soft Corporation (CS)) was used for the calculation of electron charges.
MG trapping was done under simulated physiological conditions (pH 7.4 and 37 °C). MG molecule is small and volatile, therefore no absorption in UV/Vis. The quantification of MG was based on the detection of its derivative compound, 2-methylquinoxaline (2MQ), at 313 nm in HPLC analysis.
The results showed that after reacting with black currant extract and oligonol, MG reduction rates are 36.11 ± 7.19 % and 47.68 ± 0.66 %, respectively. Both showed effective MG trapping ability. Black currant extract was then further separated and purified to obtain the main anthocyanidins within to investigate the MG trapping percentages and the addition reaction between individual anthocyanidin and MG. Black currant extract was first separated using Sephadex LH-20 chromatography. After analysis by LC-ESIMS, Delphinidin-3-O-rutinoside (D3R) and Cyanidin 3-O-rutinoside (C3R) were identified as main anthocyanidins. This particular fraction then passed through HPLC sorbents octadecyl (C18) 15-40μm chromatography again for collection of D3R and C3R. In order to study the stability of D3R and C3R under heat, both were set in 37 ℃, reaction for 1 hour. The reduction rates of D3R and C3R were 28.60 ± 2.30 % and 21.26 ± 1.07 %, respectively. D3R and C3R also reacted with MG in 37 ℃ for 1 hour. The reduction rate of D3R and C3R were 96.52 ± 0.21 % and 97.67 ± 0.08 %, respectively. Therefore, D3R and C3R were not heat-stable and reacted with MG. The MG trapping ability of D3R and C3R were 46.72 ± 0.76 % and 49.80 ± 0.56 %. C3R showed better ability than D3R did. This illustrated that one extra OH existed on B ring of D3R caused the difference in MG trapping ability. It was also found that after reaction, D3R and C3R appeared to have one MG addition when analyzed by LC-ESIMS.

致謝 I
摘要 II
Abstract IV
簡寫表 VI
目錄 VII
表目錄 XI
圖目錄 XII
壹、前言 1
貳、文獻回顧 3
一、活性雙羰基化合物 3
(一) 來源 3
(二) 與 AGE 的關係 4
(三) 雙羰基化合物與糖化終產物對生物體之影響 8
(四) 抑制 AGE 生成物質 9
二、酚類化合物簡介 12
(一) 21 種酚類化合物 13
(二) 花青素 14
(三) 花青素之構造變化 15
(四) 原花青素 17
三、化學結構式中苯環碳上的電荷分佈 17
四、實驗材料簡介 19
(一) 21 種酚類化合物 19
(二) 黑加崙 (black currant) 19
(三) 荔枝殼之萃取物 (oligonol) 19
參、研究目的與實驗架構 21
一、研究目的 21
二、實驗架構 22
肆、實驗材料與方法 24
一、實驗材料 24
(一) 21種酚纇化合物 24
(二) 黑加崙萃取物 24
(三) 荔枝殼萃取物 (oligonol) 24
二、化學藥品與溶劑 24
(一) 試藥 24
(二) 溶劑 26
三、儀器設備 26
(一) 一般儀器設備 26
(二) 化學分析相關儀器設備 27
四、實驗方法 29
(一) 簡單酚類化合物和兒茶素及 aminoguanidine 對 MG 捕捉能力測定 29
(二)以 LC-ESIMS 分析 2,4,6-trihydroxybenzoic acid 與 MG 之結合能力 29
(三) CS ChemDraw Ultra 11.0.1 software (CSCDU) 軟體計算化學結構式中苯環碳上的電荷分佈 30
(四) 多酚類化合物對 MG 捕捉能力測定 30
(五) 分離及純化黑加崙萃取物 32
(六) D3R 與 C3R 對 MG 捕捉能力測定 34
伍、結果與討論 37
一、以 HPLC 定量 Methylglyoxal (MG) 之方法 37
二、20 種簡單酚類化合物在苯環上的電荷密度及 22 種化合物與 MG 反應後剩餘之含量百分比 39
(一) 21 種酚類化合物及 aminoguanidine 與 MG 反應剩下含量百分比 39
(二) 以 LC-ESIMS 分析 2,4,6-trihydroxybenzoic acid 與 MG 之結合能力 41
(三) 20 種簡單酚類化合物苯環上碳的電荷分佈 43
(四) (-)-Epicatechin (EC) 的電荷密度 44
(五) 黑加崙中的主要花青素的電荷密度 45
三、黑加崙和荔枝殼萃取物 (oligonol) 之 MG 捕捉能力測定 46
四、分離純化花青素 49
(一) Sephadex LH-20 chromatography 49
(二) HPLC sorbents octadecyl (C18) 15-40 μm chromatography 純化片段Ⅳ當中的主要花青素 61
五、D3R 及 C3R 與 MG 反應 63
(一) D3R 及 C3R 在 37 ℃ 下之熱穩定性 64
(二) D3R 及 C3R 在37 ℃ 下與 MG 反應其 D3R 及 C3R之減少百分比 65
六、D3R 及 C3R 與 MG 反應後 MG 減少百分比 66
(一) MG 減少百分比 66
(二) 單因子變異數分析 68
七、D3R 及 C3R 與 MG 的結合能力 69
八、D3R 及 C3R 與 MG 結合的化合物以 LC-MSMS 分析 76
陸、結論與後續研究與建議 81
一、結論 81
二、後續研究與建議 82
柒、參考文獻 83

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