Mimics, enzyme cyclodextrins

Cyclodextrins, products of the degradation of starch by an amylase of Bacillus macerans(1), have been studied in terms of chemical modifications, mainly for the purpose of developing efficient enzyme mimics(2). Not only their unique cyclic structures, but also their ability to form Inclusion complexes with suitable organic molecules, led us to Investigate the total synthesis of this class of molecules(3) We describe here an approach to a total synthesis of alpha(l), gamma(2), and "iso-alpha" cyclodextrin (3). 

Of all the cavity-containing compounds, it is perhaps the cyclodextrins that provide the best basis for the construction of small(ish) molecule enzyme mimics. See Section 6.3 for an introduction to... 

Cyclodextrins, described in Chapter 1, are naturally occurring macrocycles that exist in a number of different sizes. Externally they are decorated with hydroxyl groups but have hydrophobic central cavities that can bind appropriately sized guests. In fact they appear to be ideal molecules to use as a basis for an enzyme mimic. Furthermore the hydroxyl groups can be regioselectively functionalized. 

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. 

The seven chapters in this book describe various approaches to the synthesis and study of artificial enzymes. In Chapter 1,1 describe work in my laboratory over the past almost 50 years creating enzyme models and enzyme mimics. A major theme is the use of hydrophobic binding of substrates into cyclodextrins carrying catalytic groups,... 

The chemistry of interest when cyclodextrin or its derivatives are used as enzyme mimics involves two features. First of all, the substrate binds into the cavity of the cyclodextrin as the result of hydrophobic or lyophobic (4) forces. Then the bound substrate undergoes a reaction, which may involve the cyclodextrin as a reagent or as a catalyst. The speed of this reaction is promoted generally by the proximity induced by binding, and in addition the reactions are often selective because of geometric constraints in the transition state. This selectivity may involve the selective reaction of one potential substrate relative to another, selective production of one regiochemical isomer compared with another, or selective production of one stereoisomer relative to another. This last area, selective stereochemistry and asymmetric synthesis, is still one of the most neglected areas of cyclodextrin chemistry. 

Material Conversion - Natural and Artificial Enzymes Enzymes perform highly selective and highly efficient molecular conversion based on sophisticated three-dimensional arrangements of amino acids. Artificial enzyme mimics can be constructed using cyclodextrins and Hpid bilayer membranes. 

Breslow and Zhang have reported the cleavage of phosphate di- and triesters by a cyclodextrin dimer (Figure 83) in the presence of La and H2O2 [HO]. High rate acceleration, up to 10 , was reported for this enzyme mimic. 

A polymer was made by treating methyl /3-cyclodextrin first then with hexamethylenediisocyanate, then with 2-hy-droxyethyl methacrylate, followed by polymerization with an azo initiator in the presence of cholesterol (i.e., molecu-larly imprinted with cholesterol). After extraction of the cholesterol, it was 30-45 times more effective in picking up cholesterol than /3-cyclodextrin.237 Many others have been prepared as artificial enzymes or enzyme mimics.238 Some of these are chelating agents (5.60) that bind... 

Cyclodextrins have proven to be the most popular enzyme mimics, catalyzing various reactions. Cyclodextrin-based neoglycoenzymes with improved efficiency have also been designed and synthesized. Cyclodextrin-modified enzymes have potential application as biosensors as well as in the formulation of effective and biodegradable drug delivery systems for enzyme replacement therapy [84]. 

Many of the most successful enzyme mimics have involved functionalised cyclodextrins, and the work of Breslow in particular is familiar to anyone who has followed the field. [24] These hosts bind aromatic rings within a hydrophobic cavity. In another seminal contribution Lehn [25,26] has used polyammonium macrocycles to catalyse phosphate transfer reactions of ATP, demonstrating that multiple hydrogen-bonds can also be an effective source of binding between flexible systems in aqueous solution. 

Phosphate esters can be cleaved by template catalysts, especially those with cyclodextrin binding groups and linked catalytic groups. Catalysis of the hydrolysis of a bound cyclic phosphate by ribonuclease mimics has been extensively studied [92-98], as has catalysis by enzyme mimics carrying bound metal ions [99-102]. 

B. Zhang, R. Breslow, Ester hydrolysis by a eatalytic cyclodextrin dimer enzyme mimic with a metaUobipyridyl linking group, J. Am. Chem. Soc., 1997, 119, 1676—1681. 

D.-Q. Yuan, S. D. Dong, R. Breslow, Cyclodextrin-based class I aldolase enzyme mimics to catalyse crossed aldol condensations, Tetrahedron Lett., 1998, 39, 7673-7676. 

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