以密閉式藻類毒性試驗研究鹵素取代酯類之定量結構－活性關係

Abstract

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□上之硫醇基之反應性）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).