Pharmaceutical acyl groups

Polyunsaturated and oxygenated fatty acids, obtained from triacylglycerols (TAG) of several different plant and animal species, are valuable materials feedstock for value-added products in a variety of industries food, pharmaceutical, cosmetics, and paints and coatings. The acyl species, their chemical structure, and their most abundant sources are summarized in Table 1. In contrast to inexpensive Cie and Cig saturated and A9-unsaturated acyl groups, such as palmitic (16 0), stearic (18 0), oleic (18 l-9c), linoleic (18 2-9c, 12c), and a-linolenic acid (ALA 18 3-9c, 12c,15c), recovered from the oil of soybean and other common sources, and C4-C16 saturates from palm oil and milk fat, polyunsaturated and oxygenated acids are derived from less common sources, and particularly for polyunsaturated fatty acid (PUFA), are typically present at only 20 0% purity. 

Amides, like esters, are abundant in all living organisms—proteins, nucleic acids, and many pharmaceuticals have amide functional groups. The reason for this abundance of amides, of course, is that they are stable to the conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. 

Hsu et have cloned two enzymes from Deimcoccus radiodurans for overexpression in E. coli in order to carry out a dynamic kinetic resolution to obtain L-homophenylalanine, frequently required for pharmaceutical synthesis. The starting material is the racemic mixture of A acetylated homophenylalanine, and the two enzymes are an amino acid A -acylase, which specifically removes the acetyl group from the L-enantiomer, and a racemase, which interconverts the D- and L-forms of the A acyl amino acids. The resolution was carried out successfully using whole-cell biocatalysts, with the two enzymes either expressed in separate E. coli strains or coexpressed in the same cells. 

Resolutions of racemic mixtures are by far the most frequent applications of biocatalysts in the pharmaceutical industry. Repic et al., of the process research and development group at Novartis, recently published work to develop a method for the resolution of racemic (3-amino acid esters, an important class of intermediates for the preparation of peptidomimetics [21]. The Novartis group used Chiro-CLEC -EC [22] in 2% aqueous toluene to selectively acylate several different 3-amino esters (Fig. 4). The authors were able to isolate the desired (S) isomer of the amino esters in >95% ee in a simple one-step reaction and described it as a method which could be amenable for large-scale preparation. 

Extensive early studies of in vitro and in vivo structure-activity relationships within the leucomycin family revealed correlations between the number and type of O-acyl substituents and the compounds antibacterial potency, efficacy in treating experimental infections, and serum antibiotic concentrations [26]. Consequently, esterification of all hydroxyl groups within several leucomycin-related macrolides was conducted to find derivatives with better antibiotic activity and pharmaceutical properties (such as greater water solubility and masking their extremely bitter taste). From such investigations with midecamycin, miokamycin was synthesized and characterized as a useful new macrolide antibiotic [24, 27]. It has now been commercially launched in several countries [5]. 

Before it had been discovered that many penicillins could be made from appropi-ate tripeptides using IPNS, a semi-synthetic method was used to convert penicillin G (8.29) into 6-aminopenicillanic acid using a bacterial acylase followed by acylation of the free amino group. Examples of pharmaceutically important penicillins produced by this route include methicillin (8.41), ampicillin (8.42) and amoxycillin (8.43). There is a more important method of enzymically degrading penicillins than... 

A different strategy for preparing enzymes for immobilization is to introduce vinyl groups by alkylating or acylating enzymes with activated vinyl monomers [40]. The modified enzymes are then polymerized with mono- and bifunctional acrylamide derivatives to yield elastic particles of irregular shape after crushing of the formed polymer blocks. Such copolymerization processes have yielded stable industrial biocatalysts for pharmaceutical application which are especially suited for stirred tank applications [41]. 

The work from Sheldon s group [10] was the first to present the use of ionic liquids in the enzymatic synthesis of esters. Since then, there have been many reports on biosynthesis of esters in ionic liquids. De los Rios et al. [64,65] synthesised a wide range of aliphatic organic esters, commonly used in the perfumery, flavour and pharmaceutical industries, by transesteriflcation from vinyl esters and alcohols catalysed by free CaLB in different 1,3-dialkylimidazolium-based ILs (Fig. 7.2). They analysed the effects of the alkyl chain lengths of the acyl donor and the alcohol. The optimum (C6 for acyl donor and C4 for alcohol) chain lengths were found because the activity decreased with further increase in alkyl chain length. The authors attributed the enzyme behaviour to a substrate modulation mainly due to the different affinity of the lipase towards the different substrates and steric hindrance and denaturalisation by small alcohol molecules. 

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