- On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases
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Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.
- Darvesh, Sultan,McDonald, Robert S.,Darvesh, Katherine V.,Mataija, Diane,Mothana, Sam,Cook, Holly,Carneiro, Karina M.,Richard, Nicole,Walsh, Ryan,Martin, Earl
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p. 4586 - 4599
(2007/10/03)
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- Ozone-mediated Reaction of Anilides and Phenyl Esters with Nitrogen Dioxide: Enhanced Ortho-reactivity and Mechanistic Implications
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In the presence of ozone, anilides 1 can be nitrated rapidly with nitrogen dioxide in chloroform at 0 deg C to give a high proportion of ortho-nitro derivatives (ortho:para = 1.2-4.4) in good yields.The phenyl esters 15 can be similarly nitrated on the aromatic ring without significant cleavage of the ester bond, giving a mixture of isomeric nitro derivatives in which the ortho-isomer predominantes (ortho:para = 1.1-1.5).The oridin of the enhanced ortho reactivity is discussed in terms of an electron-transfer process involving the nitrogen trioxide as initial electrophile.
- Suzuki, Hitomi,Tatsumi, Atsuo,Ishibashi, Taro,Mori, Tadashi
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p. 339 - 344
(2007/10/02)
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- Ortho-Selective Nitration of Acetanilides with Nitrogen Dioxide in the Presence of Ozone
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In the presence of ozone, nitrogen dioxide rapidly reacts with acetanilides ortho-selectively at low temperatures, giving a high proportion of ortho-nitro derivatives in good yields.
- Suzuki, Hitomi,Ishibashi, Taro,Murashima, Takashi,Tsukamoto, Kenkichi
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p. 6591 - 6594
(2007/10/02)
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- A Comparison of the Reactions of Some Ethyl N-Arylcarbamates with Those of the Corresponding Acetanilides. I. Nitration
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The reactions of some ethyl N-arylcarbamates and of the corresponding acetanilides towards 1 equiv. of sodium nitrate in concentrated sulfuric acid at 0-5 deg have been compared with one another and have been found to exhibit significant differences.Except in the case of the unsubstituted analogues, nitration of the carbamates was found to occur significantly more quickly than that of the acetanilides as shown by (i) a representative competitive nitration, and (ii) the fact the carbamates containing a nitro group are nitrated smoothly whereas the corresponding nitroacetanilides are slow to react.On the basis of competitive reactions, it is suggested that this difference in reactivity is due to steric factors.
- Rosevear, Judi,Wilshire, John F. K.
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p. 723 - 733
(2007/10/02)
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