4-Nitrophenyl-N-substituted carbamates (1) are characterized as pseudosubstrate inhibitors of acetylcholinesterase. The first step is formation of the enzyme-inhibitor tetrahedral intermediate with the inhibition constant (Ki), the second step is formation of the carbamyl enzyme with the carbamylation constant (kc), and the third step is hydrolysis of the carbamyl enzyme with decarbamylation constant (kd). According to pre-steady state kinetics the Ki step is divided further into two steps: (1) formation of the enzyme-inhibitor complex with the dissociation constant (KS) and (2) formation of the enzyme-inhibitor tetrahedral intermediate from the complex with the equilibrium constant (k2/k-2). Since the inhibitors are protonated in pH 7.0 buffer solution, the virtual dissociation constant (KS') of the enzyme-protonated inhibitor complex can be calculated from the equation, -log KS'=-log KS-pKa + 14. The -logKS, -log KS', log k2, and log k-2 values are multiply linearly correlated with the Jave equation (log(k/k0)=rho*sigma* + deltaEs + psi pi). For -log KS'-sigma*-Es)pi-correlation, the rho* value of -0.4 indicates that the enzyme-protonated inhibitor complexes have more positive charges than the protonated inhibitors, the delta value of 0.44 suggests that the bulkily substituted inhibitors lessen the reaction due to the difficulty of the inhibitors to enter the narrow enzyme active site gorge, and the psi value of 0.27 implies that the inhibitors with hydrophobic substituents accelerate the inhibitors entering the active site gorge of the enzyme. For log k2/k-2,-sigma*-Es-pi-correlation, the rho* value of 1.1 indicates that the enzyme-protonated inhibitor tetrahedral intermediates have more negative charges than the enzyme-protonated inhibitor complexes, the delta value of 0.15 suggests that the bulkily substituted inhibitors are difficult to bind into a small acyl binding site of the enzyme, and the psi value of -0.3 implies that the inhibitors with hydrophobic substituents resist binding to the hydrophilic acyl binding site of the enzyme.
Benzene-1,3-di-N-n-octylcarbamate (1), benzene-1-hydroxyl-3-N-n-octylcarbamate (2), benzene-1,3-di-N-n-ocztylthiocarbamate (3), and benzene-1-hydroxyl-3-N-n-octylthiocarbamate (4) are synthesized from 1,3-benzene-diol and are characterized as the pseudo-substrate inhibitors of acetylcholinesterase, butyrylcholinesterase, cholesterol esterase, lipase, trypsin, and chymotrypsin. For these six enzyme inhibitions by 1-4, the pKi values are linearly correlated with their log ki values - Brønsted plots. Therefore, 1-4 inhibit these enzymes through a common mechanism. Moreover, both pKi and log ki values for the inhibitions by 1,3, and 4 are linearly correlated with both pKi and log ki values for the inhibitions by 2, respectively. Thus, the pKi values for the inhibitions by 2 are defined as the nucleophilicity constants of these enzymes (nenzyme). The log k2 values for the inhibitions by 1-4 are also linearly correlated with the nenzyme values. Therefore, the nucleophilicity for serine hydrolases and proteases toward 1-4 also applies the Swain-Scott correlations.
Attempted preparation of phosphono containing trans-1,2-difluoro-1-phenyldimethylsilyl ethylenes R 2 P(O)CF=CFSiMePh 3 by deprotonation of HFC=CFSiMe 2 Ph 2 followed by acylation with R 2 P(O)Cl was unsuccessful. However, acylation of the lithium salt of 2 with R 2 PCl gave R 2 PCF=CFSiMe 2 Ph 4, which on subsequent oxidation with hydrogen peroxide or tert-butylhydroperoxide afforded a series of compounds trans-R 2 P(O)CF=CFSiMe 2 Ph 3 in good yields.
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