Acid-base catalysis, cyclodextrins

Ribonuclease A is a member of a group of enzymes that cleave RNA using general acid-base catalysis without a metal ion in the enzyme. In ribonuclease A, such catalysis is performed by two imidazoles of histidine units, one as the free base (Im) and the other, protonated, as the acid (ImH+). To mimic this in an artificial enzyme, we prepared (3-cyclodextrin bis-imidazoles 41 [124]. The first one was a mixture of the... 

Cyclodextrins with two imidazole groups on the primary hydroxyl side can enhance the enolate formation [86] of a simple bound ketone by bifunctional acid-base catalysis and accelerating the intramolecular aldol condensation of bound ketoaldehyde and dialdehyde. The aldolase mimics which catalyzed crossed aldol condensations were obtained by the assembly of (i-CD and various amino moieties as Schiff base [87]. 

The catalytic activity of artificial chymotrypsin in the hydrolysis of m-tert-butylphenyl acetate (k = 2.8xl02 s 1, KM = 13xl05M) was found to be close to the activity of chymotrypsin in the hydrolysis of p-nitrophenyl acetate (k,.at = l.lxlO2 s 1, KM = 4x105M). Another example of mimicking enzyme catalysis by P-cyclodextrin is general acid-base-catalyzed hydrolysis and nitrosation of amines by alkyl nitrites (Iglesias, 1998). 

Classically, the bell-shaped dependence of rate of the enzymic reaction on pH has been attributed to general acid and base catalysis by the two histidine residues in the active site, His-12 and His-119 (66). Support for this explanation based on the kinetic properties of a model system was first provided by an observation by Breslow and co-workers that 8-cyclodextrin functionalized with two imidazole groups will catalyze the 1,2-cyclic phosphate of 4-rert-butylcatechol (67). The dependence of hydrolysis rate on pH mimics that of RNase A, and this behavior demonstrates that the presence of two imidazole functional groups on a nonionizable framework is the simplest kinetic mimic of the enzyme. 

Three kinds of catalysis by the hydroxyl groups of cyclodextrin are known (a) nucleophilic catalysis (b) general base catalysis and (c) general acid catalysis. 

At the end of the review there are some examples involving catalysis by acids and bases, metal ions, micelles, amylose, catalytic antibodies, and enzymes to give the reader a feeling for how Kurz s approach may be usefully applied to other catalysts. Very few of these examples, or those involving cyclodextrins, were discussed in the original literature in the same terms. It is hoped that the present treatment will stimulate further use and exploration of the Kurz approach to analysing transition state stabilization. 

Artificial enzymes with metal ions can also hydrolyze phosphate esters (alkaline phosphatase is such a natural zinc enzyme). We examined the hydrolysis of p-nitro-phenyfdiphenylphosphate (29) by zinc complex 30, and also saw that in a micelle the related complex 31 was an even more effective catalyst [118]. Again the most likely mechanism is the bifunctional Zn-OH acting as both a Lewis acid and a hydroxide nucleophile, as in many zinc enzymes. By attaching the zinc complex 30 to one or two cyclodextrins, we saw even better catalysis with these full enzyme mimics [119]. A catalyst based on 25 - in which a bound La3+ cooperates with H202, not water - accelerates the cleavage of bis-p-nitrophenyl phosphate by over 108-fold relative to uncatalyzed hydrolysis [120]. This is an enormous acceleration. 

Although m-nitrobenzaldehyde (57) is well bound into the cyclodextrin cavity of our above catalysts, there was essentially no catalysis of its reaction with acetone. The aldehyde group is too inaccessible in the complex. However, with 58 there was good catalysis by a cyclodextrin carrying only one ethylenediamine group on its secondary face, and also by cyclodextrins with two groups on the primary A and B methylenes (e.g. 60), with imidazoles as base/acid groups and a primary amine to form the acetone... 

Figure 25 (a) -Cyclodextrin-based catalyst 41 (b) schematic illustration of the catalysis process (c) amino acid sequence and... 

---