臺灣博碩士論文加值系統

本研究是以密閉式BOD瓶藻類毒性試驗，評估親電性物質－鹵素取代酯類之毒性，探討此類化合物以SN2親核性取代反應與生物分子作用進而對生物體造成毒性之機制，利用化合物與生物分子共價鍵結之反應性參數RC50值（榖胱甘?忖W之硫醇基之反應性）及親電性參數（ELUMO、與鹵素鍵結之碳之部分電荷、鹵素之部分電荷），建立預估毒性能力佳之QSAR模式，並探討反應性與生物體毒性之關係。
鹵素取代酯類之藻類毒性趨勢反比於鹵素電負度之大小。化學物Ethyl fluoroacetate和Methyl 3-bromopropionate之藻類毒性與SN2親核性取代反應無關，Ethyl fluoroacetate對於藻類生長的抑制應與檸檬酸循環之破壞有關，而Methyl 3-bromopropionate之毒理機制較偏向於麻醉性。
在QSAR分析方面，以反應性參數RC50值去掉不屬於SN2親核性取代反應的化學物和outlier - Ethyl tribromoacetate，可得到較好的相關性。當鹵素鍵結超過一個的化學物時，利用RC50值建立QSAR似乎並不適合。
本研究結果之outlier為Ethyl tribromoacetate，查詢文獻，推測可能的原因為空間立體障礙所造成之毒性下降，但是利用反應性參數RC50值來描述其毒性，過於理想的模擬情境似乎無法顯示於生物體內空間立體障礙對於化學物之毒性所造成的影響，可能是造成Ethyl tribromoacetate(13)為oulier的原因。
本次論文最重要之貢獻為-利用電性模擬軟體建立良好的鹵素取代酯類之藻類毒性之定量結構－活性關係，用以取代毒性試驗，減少實驗成本。

This study presents the toxicity data of various halogen-substituted aliphatic esters to Pseudokirchneriella subcapitata. using a closed algal toxicity testing technique with no headspace. Three different response endpoints, i.e., final yield, growth rate, and the dissolved oxygen production were used to evaluate the toxicity of halogen-substituted aliphatic esters. We also use abiotic thiol reactivity (RC50) to establish the QSAR models.
Halogen- substituted aliphatic esters toxicity mechanism are classified as electrophiles which are for a subgroup of the SN2 mechanistic domain. Between α-halo-carbonyl-containing compounds the order of reactivity is I>Br>Cl>F; but the toxicity of ethyl fluoroacetate (NO.1) is relatively high. The toxicity mechanism of ethyl fluoroacetate (NO.1) could be the inhibition of the Krebs cycle. Ethyl-2,3-di-bromopropionate(NO.14) with two halogens connect with two carbons which make the effect of the carbonyl group separated into a less pronounced overall electrophilicity as compared to ethyl bromoacetate(NO.3). Multi-halogenation at a single-carbon center (halogenated carbon) may sterically hinder their electrophilic reactivity which makes them less toxic than the chemical with only single bromine.
The quantitative structure-activity relationship of halogen-substituted aliphatic esters toxicity with reactivity respect two outliers- Methyl 3-bromopropionate (NO.6) and ethyl tribromoacetate (NO.13). Methyl 3-bromopropionate (NO.6) has relatively high reactivity but low toxicity which seems more like nonpolar narcosis. The steric hindrance of ethyl tribromoacetate (NO.13) could not be presented by the ideal test which using pure glutathione to represent the target in vivo (RC50).

摘要 I
目錄 III
表目錄 V
圖目錄 VI
符號說明 VII
第一章 前言 1
1.1研究緣起 1
1.2 研究目的 2
1.3 研究架構 3
第二章 文獻回顧 4
2.1 酯之介紹 4
2.1.1 基本特性 4
2.1.3 鹵素取代酯類之介紹 4
2.1.2 酯類的應用 5
2.2 定量結構－活性關係（QSAR） 8
2.2.1 起源 8
2.2.2 分類 8
2.2.3 二維定量構效關係 9
2.2.4 活性參數 9
2.2.5 結構參數 10
2.3 鹵素取代酯類之QSAR 11
2.3.1 親核試劑之介紹 11
2.3.2 SN2親核性取代反應之介紹 11
2.3.3 文獻之鹵素取代酯類之QSAR 13
2.4 藻類毒性試驗 16
2.4.1 月芽藻之介紹 16
2.4.2 藻類生長測定方法 16
2.4.3 藻類毒性試驗方法 17
2.4.4 試驗中之重要參數 19
第三章 基本原理 21
3.1 基本生長動力學 21
3.2 毒性物質之濃度反應關係模式 22
第四章 材料與方法 25
4.1 實驗設備與材料 25
4.2 實驗方法 27
4.3 儀器操作原理、步驟與設定條件 32
4.3.1 TOC (總有機碳分析法) 32
4.3.2 總有機碳分析之標準液配製流程 32
4.4 RC50反應性參數值實驗 33
4.5 實驗之品保及品管 (QA/QC) 34
4.5.1 確定藻類生長狀況 34
4.5.2 實驗條件之控制 34
4.5.3 儀器的保養 34
第五章 結果與討論 35
5.1 藻類實驗毒性數據 35
5.2 急慢毒性比（Acute-Chromic Toxicity Ratio ; ACR） 39
5.3 鹵素取代酯類與基線毒性之比較 41
5.4 密閉式BOD瓶藻類毒性試驗與其他物種試驗之比較 44
5.5 QSAR分析 47
5.5.1 毒性數據與傳統物化參數LogKow迴歸分析 47
5.5.2 毒性數據與反應性參數迴歸分析 48
5.5.3 藻類與纖毛蟲物種間關係 52
5.5.4 毒性數據與傳統電性參數回歸分析 53
5.6 文獻比較 64
5.6.1 Ethyl fluoroacetate之文獻毒理機制 64
5.6.2 其他同屬SN2親核性取代反應之化學物之文獻 65
第六章 結論與建議 67
6 .1 結論 67
6.2 建議 68
第七章 參考文獻 69
附錄一 原始數據 73
附錄二 其他迴歸 93
附錄三 統計方法 96
附錄四 參數計算軟體使用方法 102

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