本文選題：有機(jī)磷化合物 + 乙酰膽堿酯酶��； 參考：《哈爾濱工業(yè)大學(xué)》2016年碩士論文

【摘要】：有機(jī)磷(Organophosphorus,OP)化合物主要通過(guò)抑制乙酰膽堿酯酶(acetylcholinesterase,AChE)的活性造成神經(jīng)系統(tǒng)功能紊亂,產(chǎn)生中毒現(xiàn)象。目前臨床上用于治療有機(jī)磷中毒的主要方法是通過(guò)肟類(oxime)化合物來(lái)重活化磷酰化的有機(jī)磷-乙酰膽堿酯酶(OP-AChE)加合物,從而恢復(fù)乙酰膽堿酯酶的活性。但是,在重活化反應(yīng)的同時(shí),磷�；腛P-AChE加合物還會(huì)發(fā)生一個(gè)競(jìng)爭(zhēng)性的不可逆轉(zhuǎn)的去烷基化反應(yīng),稱為“老化”反應(yīng),這導(dǎo)致了AChE的永久性失活。最近,Topczewski課題組設(shè)計(jì)并合成了一系列可用作甲基化試劑的N-甲基-2-甲氧基吡啶化合物,它能夠甲基化老化的OP-AChE加合物的最小模型,為實(shí)現(xiàn)老化反應(yīng)的可逆提供了參考。然而,目前還沒有類似的N-甲基-2-甲氧基吡啶化合物能夠甲基化真實(shí)老化OP-AChE加合物的報(bào)道�；诖�,本課題探究了N-甲基-2-甲氧基吡啶類化合物能甲基化老化的OP-ACh E加合物的最小模型(甲基甲烷磷酸單陰離子)的反應(yīng)機(jī)理,并預(yù)測(cè)了其甲基化真實(shí)老化的OP-AChE加合物的反應(yīng)能壘,通過(guò)比較兩個(gè)反應(yīng)在結(jié)構(gòu)以及機(jī)理方面的差異,闡明了影響甲基化反應(yīng)活化能的關(guān)鍵因素,為設(shè)計(jì)活性的更高甲基化試劑提供理論指導(dǎo)。通過(guò)密度泛函理論(DFT)計(jì)算方法和量子力學(xué)/分子力學(xué)(QM/MM)結(jié)合計(jì)算方法,本文選了9種取代基不同的N-甲基-2-甲氧基吡啶類化合物(編號(hào)分別為1-9),揭示了N-甲基-2-甲氧基吡啶分別甲基化甲基甲烷磷酸單陰離子、老化的Sarin-AChE化合物反應(yīng)的機(jī)理。結(jié)果表明:小分子模型反應(yīng)是一個(gè)典型的SN2反應(yīng),而不是一個(gè)多步進(jìn)攻反應(yīng),計(jì)算的自由能和實(shí)驗(yàn)值非常接近;而N-甲基-2-甲氧基吡啶甲基化老化的Sarin-AChE加合物反應(yīng)也是一個(gè)SN2反應(yīng),但是其反應(yīng)能壘要顯著高于小分子模型反應(yīng),以活性最高的化合物2(N-甲基-2-甲氧基-3-F-吡啶)為例,能壘值為30.4±3.5 kca/mol(算術(shù)平均自由能)或者26.6 kcal/mol(玻爾茲曼平均自由能),顯示這個(gè)反應(yīng)很難發(fā)生。通過(guò)結(jié)構(gòu)和機(jī)理分析,我們發(fā)現(xiàn)化合物2和AChE的W86殘基形成了一個(gè)π-π堆積作用,而這個(gè)作用使得化合物2本身不能像小分子模型反應(yīng)那樣接近Sarin來(lái)發(fā)動(dòng)甲基化反應(yīng),導(dǎo)致能壘升高。最后,根據(jù)計(jì)算結(jié)果,本文提出了幾種改進(jìn)吡啶類化合物甲基化反應(yīng)活性的策略,為實(shí)現(xiàn)老化的Sarin-AChE加合物的逆轉(zhuǎn)提供了理論指導(dǎo)。
[Abstract]:Organophosphorus organophosphorus (OPP) compounds cause nervous system dysfunction by inhibiting the activity of acetylcholinesterase acetylcholinesterase (acetylcholinesterase). At present, the main method for the treatment of organophosphorus poisoning is to reactivate the organophosphorus-acetylcholinesterase (OP-AChE) adducts through oxime compounds to restore the activity of acetylcholinesterase. However, at the same time of reactivation, the phosphorylated OP-AChE adducts will undergo a competitive and irreversible dealkylation reaction, called "aging" reaction, which leads to the permanent inactivation of AChE. Recently, Topczewski team designed and synthesized a series of N-methyl-2-methoxy pyridine compounds which can be used as methylating reagents. It can be used as the minimum model of OP-AChE adducts for methylation aging, which provides a reference for realizing the reversible aging reaction. However, there are no reports that N-methyl-2-methoxy pyridine compounds can methylate real aging OP-AChE adducts. Based on this, the reaction mechanism of N-methyl-2-methoxy pyridine compounds with methylated aging OP-ACh E adducts (methyl methane phosphate monoanion) was investigated. The reaction energy barrier of the methylated OP-AChE adducts was predicted. The key factors affecting the activation energy of the methylation reactions were discussed by comparing the differences in structure and mechanism between the two reactions. It provides theoretical guidance for the design of higher methylation reagents with high activity. By using density functional theory (DFT) and quantum / molecular mechanics (QM / MMM) method, Nine N-methyl-2-methoxy pyridine compounds with different substituents (numbered 1-9) were selected in this paper. The reaction mechanism of N-methyl-2-methoxy pyridine methylated methyl methane phosphate monoanion and aging Sarin-AChE compound was revealed. The results show that the small molecular model reaction is a typical SN2 reaction, not a multi-step attack reaction, and the calculated free energy is very close to the experimental value. The Sarin-AChE adduct of N-methyl-2-methoxypyridine methylation is also a SN2 reaction, but its energy barrier is significantly higher than that of the small-molecule model reaction. For example, the most active compound 2N- methyl-2-methoxy-3-F- pyridine is used as an example. The energy barrier of 30.4 鹵3.5 KCA / mol (arithmetic mean free energy) or 26.6 kcal / mol (Boltzmann mean free energy) shows that this reaction is difficult to occur. Based on the structure and mechanism analysis, we found that compound 2 and the W86 residue of AChE formed a 蟺-蟺 stacking effect, which made compound 2 itself not close to Sarin to initiate methylation as the small molecular model reaction. Cause the energy barrier to rise. Finally, based on the calculated results, several strategies to improve the methylation activity of pyridine compounds are proposed, which provide theoretical guidance for the reversal of aging Sarin-AChE adducts.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：O643.12

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