Cyclodextrins as enzyme mimics

Breslow, R. and Dong, S. D. Biomimetic reactions catalysed by cyclodextrins and their derivatives , Chem. Rev., 1998, 98, 1997-2011. 

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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. 

D. HUvert, R. Breslow, Functionalized cyclodextrins as holoenzyme mimics of thiamine-dependent enzymes, Bioor. Chem., 1984, 12, 206-220. 

While cyclodextrins are used as enzyme mimics in aqueous media, crown ethers can act as a key component of artificial enzymes in organic solutions (Fig. 2). Crown ether was discovered by Pedersen in 1967. which... 

The contribution from Iwao Tabushi (Kyoto) was based on his work with chemically-modified cyclodextrins as enzyme models. The asymmetrically bifunctionalised cyclodextrins (3a,3b) were synthesised in order to mimic the aminotransferase activity of Vitamin B5. The A-B regio-isomer (3a) was used to effect the transformation of keto-acids into L-amino acids with 96% ee. The elegance of the system was demonstrated by the fact that the B-A regioisomer (3b) performs the same reaction on keto-acids to give the corresponding D-amino acids acids with identical enantiomeric excesses. 

We saw in Section 12.3.1 the use of the cyclodextrins as mimics for transacylases, a well-understood class of enzymes that perform the task of transferring an acyl group from one substrate to another (e.g. from an ester to water). Transacylase chemistry has also been addressed by Cram,5 who used chiral corands, such as 12.11, related to 3.106 bearing thiolate nucleophiles situated above and below the plane of the macrocycle. An acyclic analogue 12.12 was also prepared for comparison. The salient features of 12.11 are shown diagrammatically in Figure 12.4. 

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. 

To create artificial enzymes that could bind substrates in water solution with defined geometry, we examined dimers of cyclodextrins. As mentioned above, we used such dimers in mimics of hydrolytic enzymes [119, 120]. Now we wished to use them for mimics of cytochrome P-450. 

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]. 

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]. 

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