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標題: 三-氮-取代基硫代氨基甲酸抑制盤尼西林酵素之動力學與此類化合物碳-氮部份雙鍵轉動動力核磁共振之構形分析
Enzyme Kinetics for Penicillinase Inhibition by 3-N-Substituted Thiocarbamylpropanols and Conformational Analysis of Rotation on Partial C-N Double Bonds of These Compounds by Dynamic Nmr
作者: 林家立
關鍵字: 化學類
quantitative structure activity relationship
enzyme kinetics
dynamic NMR
conformational analysis
摘要: 三-氮-取代基硫代氨基甲酸抑制盤尼西林酵素之動力學與此類化合物碳-氮部份雙鍵轉動動力核磁共振之構形分析本計畫我們設計合成三-氮-取代基硫代氨基甲酸(1)為盤尼西林酵素之抑制劑。因為盤尼西林酵素是一種絲氨酸水解酵素,這些抑制劑(1)可能像其他氨基甲酸化合物是此酵素之類受質抑制劑。這些抑制反應之抑制劑常數(Ki),氨基甲酸化常數(kc),及總抑制劑常數(ki = kc / Ki)將藉由最小平方差之非線性曲線逼近(nonlinearcurve fitting)計算其吸收值-時間圖而得。這些抑制反應之pKi,logkc,及logki 可能與抑制劑上取代基之哈密特氏常數(Hammett’s ),鐵夫氏立體常數(Taft’s Es),及漢司氏疏水常數(Hansch’s )存在著甲夫氏(Järv’s)方程式(pKi,logkc,或logk i= + Es + )之多重參數(multiple parameters)之線性自由能關係式。這些多重參數線性逼近圖形之斜率(逼近後求得之參數)可以分辨出上述效素抑制反應之機理。例如若哈密特氏反應常數(Hammett’s )大於零代表酵素活性位置之絲氨酸攻擊抑制劑之硫代氨基甲酸形成帶負電荷之酵素-抑制劑四面體中間物。另外一部份是研究化合物1 轉動碳-氮部份雙鍵的構形分析。轉動類-順式至類-反式化合物1 的活化能可利用動力核磁共振由兩位置氮上氫在變溫下交換原理求得。轉動碳-氮部份雙鍵的化合物1 之構形分析也可藉由MP4 (Gaussian 程式)理論計算求得上述活化能並印證之。
Enzyme Kinetics for Penicillinase Inhibition by 3-N-SubstitutedThiocarbamylpropanols and Conformational Analysis of Rotation on Partial C-NDouble Bonds of These Compounds by Dynamic NMRIn this proposal, we plan to synthesize 3-N-substituted thiocarbamylpropanols (1) aspenicillinase inhibitors. Since penicillinase is a serine hydrolase, compounds 1 like carbamates mayalso act as pseudo substrate inhibitors of penicillinase. The inhibition constant (Ki), carbamylationconstant (kc), and overall inhibition constant (ki = kc /Ki) for these inhibition reactions will be alsocalculated from nonlinear least squares analysis of the absorption-time plot. For these inhibitionreactions, pKi, log kc, and log ki, may exist multiple-parameters linear free energy relationships withsubstituted constants such as Hammett constant (), Taft steric constant (Es), and Hanschhydrophobicity constant () from Järv equation (pKi, log kc, or log ki = + Es + ). Theslopes (parameters from the fitting) from these multiple parameters linear correlations may indicatewhat reaction mechanisms of these inhibitions are. For example, one thiocarbamyl carbon of theinhibitors is attacked by the catalytic serine of the enzyme then formation of the negatively chargedtetrahedral intermediates if the Hammett reaction constant () is greater than zero. The other partof this proposal is conformational analysis of the C-N partial double bonds of compounds 1. Theactivation energies for rotations on the C-N partial double bonds from pseudo-trans to pseudo-cisconformations of compounds 1 can be determined by dynamic NMR from two site slow exchangesof pseudo-trans and pseudo-cis NH protons when temperature changes. The conformationalanalysis of compounds 1 can be also confirmed by Gaussian MP4 calculation by rotation of the C-Npartial double bonds of compounds 1.
其他識別: NSC100-2113-M005-003
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