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系統識別號 U0007-0108201106331100
論文名稱(中文) 建立快速篩選天然物抗氧化活性成分之分析平台
論文名稱(英文) Establishment of Analytical Platform for Rapid Screening the Antioxidative Constituents in Natural Products
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(博士班)
系所名稱(英) Pharmacy (PhD)
學年度 99
學期 2
出版年 100
研究生(中文) 陳靜慧
研究生(英文) Chin-Hui Chen
學號 D301094003
學位類別 博士
語文別 中文
口試日期 2011-07-14
論文頁數 184頁
口試委員 指導教授-李慶國
委員-吳天賞
委員-郭曜豪
委員-呂廷璋
委員-李宗徽
中文關鍵字 酪胺酸酶  黃嘌呤氧化酶  脂質氧化酶  微孔盤分析  高壓液相層析串聯質譜儀 
英文關鍵字 tyrosinase  lipoxygenase  xanthine oxidase  microplate analysis  liquid chromatography-mass spectrometry 
學科別分類
中文摘要 由天然物複雜成分體系中快速篩選出具有生物活性成分並鑑定化學結構,是開發新藥的關鍵步驟。若以傳統的天然物分離與純化技術是一個相當冗煩與費時的過程,常常千辛萬苦得到純化合物,卻遭遇到的問題是量太少不足以測試多種生物活性或是根本無藥理活性,這對於天然物的新藥開發是一瓶頸。因此建立快速篩選天然物活性成分之分析平台,是值得探討的課題。本研究旨在開發以生物活性為前提之下,再以化學分析方法偵測出具有活性的成分,如此一來將可避免浪費無謂的時間與人力,而且只針對有活性成分選擇適當的分析方法是尋找有效的藥物候選重要的課題之一,如此可加速新藥的研發階段,具有實質的醫藥開發價值。
有鑑於傳統篩選活性成分技術的瓶頸,故本論文目的擬提出一個簡單有效的篩選技術,主要的分析步驟是將微孔盤分析酵素活性條件
,經過簡單修飾過程可立即應用到高壓液相層析儀分析,再利用分離或串聯技術鑑定出有效成分。首先一百一十種植物萃取物為實例進行對於黃嘌呤氧化酶、脂質氧化酶與酪胺酸酶的活性抑制試驗,有效的萃取物接著以高壓液相層析儀與光二極體陣列偵測器分析天然萃取物中抗氧化活性成分。本論文將以台灣欒樹、紅景天、茶、山櫻桃與酪梨萃取物為例,探討這些植物萃取物對於黃嘌呤氧化酶、脂質氧化酶與酪胺酸酶三種酵素及清除自由基 (2, 2 - 聯苯基 - 1 - 苦基肼基) 作用之抗氧化活性成分的篩選模式,再以分離與高壓液相層析串聯質譜儀以及核磁共振等方法鑑定化合物結構式。
最後試圖建立出一個簡單的數學估算模式,推算出以高壓液相層析方法分析活性成分時,應該使用酵素的最適化篩選劑量。因此,本論文的研究將生物活性與化學分析方法作一整合,縮短活性成分分析時間與簡化繁雜的分析工作,進而建立快速篩選天然物活性成分之分析平台。
英文摘要 Screening bioactive ingredients from the complex components of natural products and identifying their chemical structures are the key steps for drug development of natural products. Traditional separation and purification techniques are cumbersome and time-consuming. Oftentimes, the painstakingly obtained pure compounds present issues such as the amounts isolated are too small to test for multiple types of biological activity or they even have an absence of any pharmacological activity. These issues hinder the development of new medicines from natural products. Therefore, developing an analysis platform for quick screening of active ingredients in natural products is worthy of pursuit. The objective of this study, with biological activity as a prerequisite, was to develop a form of chemical analysis that can detect active ingredients. Selecting suitable analytic methods for the identification of herbs that possess active ingredients is important for the obtaining of effective drug candidates. In this way the research and development stage for new medicine can be accelerated preventing the waste of unnecessary time and human resources. This would be of substantial value in pharmaceutical development.
In view of the bottleneck of traditional techniques for screening of bio-active ingredients, this study proposed a screening technique primarily applying ELISA microplate analysis to high-performance liquid chromatography (HPLC). To start with inhibition tests for xanthine oxidase, lipoxygenase, and tyrosinase on 110 species of plant extracts were analyzed by using microplate analysis. The peak shifts of the active ingredients in the plant extracts were then analyzed to screen the antioxidant components by HPLC-DAD. Using Koelreuteria henryi Dummer Rhodiola rosea L.、Camellia sinensis L.、 Prunus campanulata Maxim and Persea americana Mill as examples, the inhibitory components of this plant towards xanthine oxidase, lipoxygenase, and tyrosinase were investigated as well as their DPPH (2,2-Diphenyl-1-picrylhydrazyl) - scavenging effects, followed by identification of the compound structure with isolation and liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) methods.
Finally, a simple mathematical estimation model would be established to estimate the optimum amount of screening enzyme for HPLC analysis of active ingredients. As a result, this study integrated bio-active and chemical analytic methods using a series of chemical techniques that can quickly detect active ingredients followed by efficient separation, purification, and identification of the compound structure. This method further shortened the time required for analytic work and simplified the process, establishing an analysis platform for fast screening of active ingredients in natural products.
論文目次 目 錄
謝誌------------------------------------------------------I
中文摘要-------------------------------------------------II
英文摘要-------------------------------------------------IV
目錄------------------------------------------------------V
表目錄 -------------------------------------------------XII
圖目錄------------------------------------------------ XIII
第一章 緒論-----------------------------------------------1
第一節 研究背景 ------------------------------------------ 1
1-1-1 天然物化學研究發展的階段--------------------------1
1-1-2 天然物活性成分開發的重要性------------------------7
1-1-3 植物新藥開發平台--------------------------------- 14
1-1-3.1 以生物活性為開發平台 ------------------------15
1-1-3.2 以化學分析技術為開發平台---------------------18
1-1-3.3 以生物活性分析與化學方法結合為開發平台-------19
第二節 藥物篩選模式之文獻回顧----------------------------22
1-2-1活性篩選平台之回顧 ------------------------------22
1-2-2串聯技術篩選平台 ---------------------------------36
第三節 研究動機 -----------------------------------------38
第二章 以酵素分析方法篩選植物萃取物中抗氧化活性成分-----41
第一節 前言 ---------------------------------------------41
2-1-1 篩選植物的種類----------------------------------43
2-1-2 抗氧化活性的意義--------------------------------45
2-1-3 酵素簡介----------------------------------------53
2-1-3.1酪胺酸酶的簡介 ------------------------------55
2-1-3.2脂質過氧化酶的簡介---------------------------57
2-1-3.3黃嘌呤氧化酶的簡介-------------------------- 59
第二節 篩選抗氧化活性成分的方法-------------------------62
2-2-1酪胺酸酶活性測試法------------------------------63
2-2-2脂質氧化酶活性測試法----------------------------64
2-2-3黃嘌呤氧化酶活性測試法--------------------------65
第三節 結果與討論-------------------------------------- 66
2-3-1 植物萃取物對酪胺酸酶活性抑制作用的探討----------74
2-3-2 植物萃取物對脂質氧化酶活性抑制作用的探討--------75
2-3-3 植物萃取物對黃嘌呤氧化酶活性抑制作用的探討------76
第三章 酵素分析與高壓液相層析方法的結合之可行性探討------77
第一節 前言----------------------------------------------77
第二節 研究動機------------------------------------------79
第三節 酵素篩選劑量的實例探討----------------------------82
3-3-1台灣欒樹-----------------------------------------82
3-3-1.1台灣欒樹萃取物與酪胺酸酶作用後的
HPLC-DAD分析方法與結果-----------------------82
3-3-1.2台灣欒樹與脂質氧化酶作用後的HPLC-DAD分析方法與結果----------------------85
3-3-1.3台灣欒樹與黃嘌呤氧化酶作用後的HPLC-DAD分析方法與結果----------------------88
3-3-2紅景天-------------------------------------------92
3-3-2.1紅景天萃取物與酪胺酸酶作用後的HPLC-DAD分析方法與結果----------------------92
3-3-2.2紅景天與脂質氧化酶作用後的HPLC-DAD分析方法與結果----------------------95
3-3-2.3紅景天與黃嘌呤氧化酶作用後的HPLC-DAD分析方法與結果----------------------98
3-3-3茶葉--------------------------------------------102
3-3-3.1茶葉萃取物與酪胺酸酶作用後的HPLC-DAD分析方法與結果---------------------102
3-3-3.2茶葉與脂質氧化酶作用後的HPLC-DAD分析方法與結果---------------------105
3-3-4山櫻桃------------------------------------------108
3-3-4.1山櫻桃與黃嘌呤氧化酶作用後的HPLC-DAD分析方法與結果---------------------108
第四節 酵素分析與高壓液相層析方法之結合的估算情形-------112
3-4-1前言--------------------------------------------112
3-4-2 由酵素動力論估算酵素分析劑量--------------------112
3-4-3 酵素篩選劑量的估算結果--------------------------114
第四章 台灣欒樹的抗氧化活性成分之結構分析---------------118
第一節 前言---------------------------------------------118
4-1-1 液相層析質譜儀簡介------------------------------119
4-1-1.1 電灑游離法簡介------------------------------122
4-1-1.2 四極柱質譜儀簡介----------------------------123
4-1-1.3 自由基簡介----------------------------------125
第二節 研究目的----------------------------------------128
第三節 研究方法---------------------------------------130
4-3-1 台灣欒樹萃取與分離-----------------------------130
4-3-2 DPPH 自由基清除效果的分析方法------------------131
4-3-3 台灣欒樹與DPPH作用後之HPLC-DAD分析方法-------132
第四節 結果與討論--------------------------------------134
4-4-1 抗氧化活性成分分析結果---------------------------134
4-4-2 以 LC-MS 方法分析活性成分------------------------137
4-4-3 1,3,4,5 -tetra-O-galloylquinic acid
之DPPH與Xanthine oxidase活性追縱試驗-----------142
第五章 結合微孔盤活性分析與高壓液相層析方法之探討------144
第一節 前言--------------------------------------------144
第二節 以酪梨 (Persea americana Mill)為例--------------148
5-2-1 酪梨簡介---------------------------------------148
5-2-2 酪梨分析結果與討論-----------------------------148
第三節 以captopril為例--------------------------------150
5-3-1 captopril 簡介---------------------------------150
5-3-2 captopril 分析結果與討論-----------------------150
第四節 實例應用之探討-----------------------------------155
5-4-1 紅景天分析--------------------------------------155
5-4-2 普洱茶葉分析------------------------------------155
第六章 結論 ---------------------------------------------159
第七章 實驗部分-----------------------------------------161
第一節 實驗儀器及藥品-----------------------------------161
第二節 實驗步驟-----------------------------------------164
第三節 光譜數據-----------------------------------------167
第八章 參考文獻-----------------------------------------174
發表文章------------------------------------------------185
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