Neighboring group inhibition

As far as neighboring group inhibition is concerned, sequence distribution can play an important role, e.g. Morowetz [5] showed that partially hydrolyzed polyacrylamide hydrolyzes more slowly than an acrylic acid copolymer of the same charge. The former has a more even distribution of groups leading to a greater proportion of the least reactive BAB triad (where A are the acrylamide and B are the acrylic acid moieties). 

In principle, the reactivity of a functional group should not be altered when it is attached to a polymer ( 1). However, special effects may be encountered when a reagent is attracted to a polymer or repelled from it, when the polymer-bound reactive group is activated or inhibited by a neighboring group or when the local polarity of the polymer domain differs from that of the bulk solvent. A review of studies of such effects... 

Figure 1 compares the conversion predicted for any reduced time I = k t with the use of Keller s theory and the above values of k /k and k2/k with experimental results obtained when polyacrylamide was exposed to 0.2N NaOH at 53 C. It may be seen that the reaction slows down at large x much more than predicted by Keller s model. In fact, this decrease of the reaction rate is even more pronounced than predicted by Keller s equations for the case where a single reacted nearest neighbor completely inhibits amide hydrolysis. We believe that this discrepancy is due to the repulsion of the catalyzing hydroxyl ions from amide residues by non-neighboring carboxylate groups. 

Reaction at a carbon atom may be inhibited by the proximity of neighboring groups. Steric effects of hydrogen atoms on carbon atoms, five atoms removed from the site of attack, are important. This principle, called by Newman (150) the rule of six, has been used (63) to explain yield distribution in hydrocarbon oxidation. Steric effects are probably important in the high resistance of some tertiary C—H bonds to attack (63,... 

The presence of the methylene group inhibits the cleavage of the neighboring bondings. Thus, in the mass spectrum of 1,2,4-butanetriol triacetate, the intensity of the peak at m/e 145 is strongly diminished due to inhibition of splitting of the C-2-C-3 bond. 

We interpret these observations as follows. dNAD first enters the NAD binding site (8), and competes with the binding of NAD, It is unable to progress to the growing polymer chain, but at a slow rate can engage in a side reaction with a neighboring group. The latter is probably not a component of the active center but is sufficiently close to the active center to inhibit enzyme activity. 

How do these NRRIs interact with their final target, the HCV RNA replicase They are phosphorylated to their 5 -triphosphate form, and then inhibit the HCV replicase. As they possess a 3 -hydroxyl function, they may not be considered as obligate chain terminators, but they may act as virtual chain terminators, viz. by steric hindrance exerted by the neighboring 2 -C-methyl and/or 4 -C-azido groups. Similar to their NRTI and NNRTI counterparts in the case of HIV reverse transcriptase, the NRRIs (2 -C-methylnucleosides) interact, upon their phosphorylation to the corresponding 5 -triphosphates, with a region of the HCV RNA replicase (or NS5B RNA-dependent RNA polymerase) that is clearly distinct from the site(s) of interaction of the NNRRIs (Tomei et al. 2005). 

The hydrolysis of polyacrylamide and acrylamide/sodium acrylate copolymers has been extensively studied [1,2,3,5,6,7,8,-9,10], in relatively strongly alkaline conditions, above pH 12. These studies demonstrated that the hydrolysis of the amide groups is hydroxide-catalyzed and that neighboring ionized carboxyl groups in the polymer inhibit the hydrolysis by electrostatic repulsion of the hydroxide ions. Senju et al. [6] showed that at temperatures up to 100°C, there is an apparent limit to the extent of hydrolysis of polacrylamide when approximately 60% of the amide groups are hydrolyzed. 

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