Enzymatic cleavage esters

General Preparations of Esters General Cleavage of Esters Transesterification Enzymatically Cleavable Esters Heptyl, 381... 

The enzymatic cleavage of esters is a vast and extensively reviewed area of chemistry. Recently, several new esters have been examined primarily for the preparation of peptides and glycopeptides. 

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

R. Ammon, The Enzymatic Cleavage of Several Pharmaceutical Esters , Arzneim.-Forsch. 1977, 27, 944 - 949. 

For the enzymatic cleavage of esters of racemic naproxen, cloned esterases, which are cheap and easy to produce, have been developed (a 100 tons per annum process is planned). 

Scheme 55 Enzymatic cleavage of esters of racemic naproxen.

Clearly, for oral activity to be achieved, the chelator must also be designed so as to resist the acidity of the stomach and enzymatic cleavage. Thus esters, amides, Schiff-base ligands and simplex hydroxamates should be avoided. 

The human Caco-2 cell line has been shown to be of limited value as an in vitro model for the absorption and enzymatic cleavage of ester prodrugs in the gut wall mucosa because the expression pattern of CES1 and CES2 resembles more closely to the liver rather than the intestine [107]. 

Hirata et al. [4] have noted that activated endothelial cells had increased endothelial lipase mRNA. Jaye et al. found that, upon stimulation with phorbol ester, the intensity of both 68 and 40 kDa bands increased in HCAEC and new bands of approximately 55 kDa, 38 and 36 kDa appeared in both HCAEC and HUVEC upon stimulation [3]. These new bands were not characterized, but may represent alternative splice products or an enzymatic cleavage product. Hirata et al. demonstrated that the expression of endothelial lipase is regulated by cytokines, by fluid shear stress and by cyclic stretch [18]. Using both HUVEC and HCAEC, they examined the effects of IL-1/ and TNF-a on endofhelial hpase mRNA levels. Exposure to IL-1/ for 24 h resulted in a 6.5-fold increase in EL mRNA in both HUVEC and HCAEC. TNF-a produced a ca. 4-fold increase in EL mRNA. The same group examined the response of both HUVEC and HCAEC to shear stress, and found a 2-3-fold increase in EL mRNA after 6 h of exposure. Additionally, cyclic stretch resulted in a 2.7-fold increase in EL mRNA. They concluded fhat EL expression is highly regulated by factors implicated in fhe development of vascular disease. 

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