Esterase mimics

Recently oxidative coupling reactions of a,a>-diethynyl compounds have been applied in the synthesis of cyclophanes, which are interesting functional host molecules. Whitlock and coworkers, - for example, have reported the synthesis of the water-soluble cyclophane (21), designed as an esterase mimic by the Eglington reaction of (20 Scheme 8). 

Copper-mediated coupling reactions of / -iodocalixarenes with phthalimide followed by hydrazinolysis should be mentioned as an alternative and independent strategy to obtain p-aminocalixarenes . The carbazole-substituted derivatives 50 (Figure 8) were obtained similarly by Ulhnan coupling . CMPO derivatives (51c), urea compounds (51b), available also via the isocyanates (51a), may be mentioned additionally. Mono- (52) and diimides with acidic functions pointing towards the cavity, and the calix[6]arene-based acetylcholine esterase mimic (53) are more sophisticated examples. 

Hydroxyacetophenones C chemical shifts for 338 Acetoxylation 1167 Acetylcholine esterase mimic 1406... 

R. Breslow, N. Nesnas, Burst kinetics and turnover in an esterase mimic. Tetrahedron Lett., 1999, 40, 3335-3338. 

A good esterase mimic, exhibiting burst kinetics and turnover, has been constructed by attaching to 3-amino-/3-cyclodextrin a bound zinc cation and an oxime anion. This construct (186) was observed to catalyse the hydrolysis of p-nitrophenyl acetate (PNPA) extremely effectively (A cat/ unoat = 22 600 for the initial fast deacylation step). As in the hydrolysis of PNPA by chymotrypsin, this fast step was followed by a slower reaction in which the acyl- enzyme intermediate suffered hydrolysis.The attachment to the a-face of yS-cyclodextrin of a series of )-aminoalkyl groups has produced a lengthening arm that has permitted a study of the catalysed aminolysis of jo-nitrophenyl acetate (PNPA). The construct containing the three-carbon linker (187 n = 3) was found to be the most effective accelerant, but only two-fold better than that containing the six-carbon linker (187 n = 6). The proposed mechanism involves the fast reversible formation of a complex between the modified CD and PNPA, which, in a slow step, yields the amide (188) (Scheme 34). 

The reaction between esterase and phosphorus inhibitor (109) is bimolecular, of the weU-known S 2 type, and represents the attack of a nucleophilic serine hydroxyl with a neighboring imida2ole ring of a histidine residue at the active site, on the electrophilic phosphorus atom, and mimics the normal three-step reaction that takes place between enzyme and substrate (reaction ). 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

Mammalian toxicity to pyrethrins is quite low, apparently due to its rapid breakdown by liver microsomal enzymes and esterases. The acute LD50 to rats is about 1500 mg/kg. The most frequent reaction to pyrethrins is contact dermatitis and allergic respiratory reactions, probably as a result of other constituents in the formulation. Synthetic mimics of pyrethrins, known as the pyrethroids, were developed to overcome the lack of persistence. 

Chiral carbon framework of the monoterpenoid secologanin, leading to powerful chiral synthons, from readily available meso-forms. Moderate results were obtained with lipases such as porcine liver esterase (PLE), delivering the (15,2/ )-mono-acetate at a yield of 78% with 96% ee (Fig. 10), though preparation of the enzyme seemed to be crucial for the appropriate result. In contrast, pig pancreatic lipase (PPL) was significantly more efficient in forming the (—)-(l/ ,25) enantiomer at a yield of 96% and 98% ee [86, 87]. 

A similar concept was used in the development of artificial chymotrypsin mimics [54]. The esterase-site was modeled by using the phosphonate template 75 as a stable transition state analogue (Scheme 13.19). The catalytic triad of the active site of chymotrypsin - that is, serine, histidine and aspartic acid (carboxy-late anion) - was mimicked by imidazole, phenolic hydroxy and carboxyl groups, respectively. The catalytically active MIP catalyst 76 was prepared using free radical polymerization, in the presence of the phosphonate template 75, methacrylic acid, ethylene glycol dimethacrylate and AIBN. The template removal conditions had a decisive influence on the efficiency of the polymer-mediated catalysis, and best results were obtained with aqueous Na2CC>3. 

During the last two decades, the mechanisms of many enzymic processes have been established, and model systems have been developed that effectively mimic their action. In particular, the roles of thiamin, NAD, pyridoxal, flavins, Bl2, ferridoxin, and metals in many enzymic processes now are understood. Model systems have been developed to imitate the action of decarboxylases and esterases, to imitate the action of enzymes in binding their substrates, and to approach the stereospecificity of enzymes. Our laboratory recently has found phosphorylating agents that release monomeric methyl metaphosphate, which in turn carries out phosphorylation reactions, including some at carbonyl oxygen atoms, that suggest the actions of ATP. The ideas of biomimetic chemistry are illustrated briefly in terms of the processes mentioned above. 

In accordance with the theory of Yamamoto et ai, nicotine acts in the organism of warm-blooded animals and insects as the mimic of acetylcholine. The nicotinium ion is attached through the positive charge of the pyrrolidine nitrogen atom to the anionic site of the acetylcholine receptor, and then nicotine penetrates in the form of the free base through the synaptic ion barrier. However, nicotine, in contrast to acetylcholine, is not subject to the hydrolytic action of acetylcholine esterase (Yamamoto, 1965 Hamilton, 1963). 

Ethyl-4-[2-(t-butylcarbonyloxy)butoxy] benzoate (ETB, ZR-2646, 71) occupies an intermediate position between the juvenile hormone mimics and the antijuvenile hormones to be discussed later. It acts as an anti-JH at low doses and as a JH mimic at high doses. The nature of this JH agonist/antagonist action is not understood, yet its interference with the induction of juvenile hormone esterase seems to elucidate at least partly its action on insects (Staal, 1977 Sparks et al., 1979). 

Trifluoromethyl ketones (TFKs) have been found to inhibit various hydrolytic enzymes (1-6 ). Series of aliphatic and aromatic trifluoromethyl ketone sulfides (7-10 ) proved to be exceptionally powerful inhibitors of insect juvenile hormone esterase (JHE), an enzyme of key importance in insect metamorphosis. The trifluoroketone moiety is believed to behave as a transition state mimic (11,12) of juvenile hormones (JHs), substrates of the enzyme. The /3 sulfur atom is anticipated to mimic the a-/3 double bond present in all natural JH substrates. In earlier structure-activity relationship (SAR) studies (7,11) clear correlation was found among the molar I50 values of these compounds against JHE and the calculated molar refractivlty of the inhibitors. 

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