Luis E. Iglesias

Biocatalytic approaches applied to the synthesis of nucleoside prodrugs

Nucleosides are valuable bioactive molecules, which display antiviral and antitumour activities. Diverse types of prodrugs are designed to enhance their therapeutic efficacy, however this strategy faces the troublesome selectivity issues of nucleoside chemistry. In this context, the aim of this review is to give an overview of the opportunities provided by biocatalytic procedures in the preparation of nucleoside prodrugs. The potential of biocatalysis in this research area will be presented through examples covering the different types of nucleoside prodrugs: nucleoside analogues as prodrugs, nucleoside lipophilic prodrugs and nucleoside hydrophilic prodrugs.

Complete and regioselective deacetylation of peracetylated uridines using a lipase

Lipase-catalysed alcoholysis and hydrolysis of 2′,3′,5′-tri-O-acetyluridine (1a) and 2′,3′,5′-tri-O-acetyl-2′-C-methyluridine (1b) were studied. Conditions for full and regioselective deacetylation of 1aand 1b are shown in the present work. New compound 2′,3′-di-O-acetyl-2′-C-methyluridine (3b) was prepared by regioselective lipase-catalysed deacetylation.

Regioselective preparation of 2′, 3′-di-O-acylribonucleosides carrying lipophilic acyl groups through a lipase-catalysed alcoholysis

Candida antarctica B lipase-catalysed alcoholysis of 2′, 3′, 5′-tri-O-hexanoyluridine (1a), 2′, 3′, 5′-tri-O-dodecanoyluridine (1b), 2′, 3′, 5′-tri-O-hexanoylinosine (1c) and 2′, 3′, 5′-tri-O-dodecanoylinosine (1d) proceeded regioselectively to produce the corresponding 2′, 3′-di-O-acylribonucleosides 2a–d, providing a simple and efficient access to these new lipophilic compounds. Contrasting to the alcoholysis, enzymatic hydrolysis of 1a–d using different enzymes and experimental conditions did not proceed regioselectively.

A simple and efficient enzymatic procedure for the deprotection of two base labile chlorinated purine ribosides

Base-labile 6-chloro-2′,3′,5′-tri-O-acetylpurine riboside (1c) and 2-amino-6-chloro-2′,3′,5′-tri-O-acetylpurine riboside (1d) were fully deacetylated through Candida antarctica B lipase hydrolysis, affording respectively 6-chloropurine riboside (2c) and 2-amino-6-chloro-purine riboside (2d). Quantitative results were found at pH 7 and 60 °C in 24 h for 1c and 72 h for 1d. This mild and simple enzymatic technique represents a convenient procedure for the removal of acetyl groups from such base labile halogenated nucleosides.

Microbial Hydrolysis of Acetylated Nucleosides

Enzymatic hydrolysis of acetylated nucleosides using microbial whole cells has been carried out for the first time. Unlike Candida antarctica B lipase-catalysed alcoholysis, none of the tested microorganisms displayed a common deacetylation profile. Depending on the substrate and the biocatalyst used, 5′-selective deprotection or mixtures of mono O-acetylated products were obtained.

Lipase-catalyzed chemospecific O-acylation of 3-mercapto-1-propanol and 4-mercapto-1-butanol

Abstract The lipase-catalyzed chemospecific O -acylation of 3-mercapto-1-propanol and 4-mercapto-1-butanol by several aliphatic carboxylic acid ethyl esters are described. Similar treatment on 1-mercapto-2-propanol and 3-mercapto-2-butanol did not yield the expected O -acyl derivatives.

Lipases in Green Chemistry: Acylation and Alcoholysis on Steroids and Nucleosides

In this article, we describe the application of lipases in acylation and alcoholysis reactions on steroids and nucleosides. In the field of steroids, a variety of acetyl and fatty acid derivatives of androstanes, pregnanes, and cholestanes have been prepared through lipase-catalyzed acylation and alcoholysis reactions taking advantage of the high regio- and stereoselectivity of these enzymes. The substrates as well as the products show a high degree of biological activity as neurosteroids, hormones, and glucocorticoids. The regioselective preparation of diacylated nucleosides by means of an enzymatic alcoholysis allowed the synthesis of nucleosides prodrugs or modified nucleosides. The quantitative full deacylation and dealkoxycarbonylation of nucleosides and steroids is a mild synthetic method for the deprotection of these labile compounds. Some of the reported steroid and nucleoside products are novel, and it is not possible to obtain them satisfactorily by following traditional synthetic procedures. The advantages presented by this methodology, such as selectivity, mild reaction conditions, and low environmental impact, make the lipases an important tool in the application of the principles of Green Chemistry, offering a convenient way to prepare derivatives of natural compounds with a great potential in the pharmaceutical industry.

An improved procedure for chemospecific acylation of 2-mercaptoethanol by lipase-catalyzed transesterification

SummaryVarious O-acyl derivatives of 2-mercaptoethanol have been obtained enzymatically by lipase-catalyzed chemospecific esterification reactions of the substrate and several aliphatic carboxylic acid ethyl esters.

An update of biocatalytic selective acylation and deacylation of monosaccharides

Partially acylated monosaccharides (PAMs) exhibit diverse and interesting applications but due to their polyhydroxylated nature, their synthesis requires regio- and stereoselective reactions. These features are provided by biocatalytic processes and in particular by hydrolases, which offer mild conditions and selective routes for the preparation of PAMs. Since this strategy has been extensively explored, the aim of the present review is to update research on enzymatic selective acylation and deacylation of monosaccharides, focusing on enzymatic preparation of synthetic useful PAMs and drug–monosaccharide conjugates involving PAMs.

A Simple Enzymatic Preparation of 2’,3’-Di-OAcetylnucleosides Through a Lipase Catalyzed Alcoholysis

Several 2’,3’-di-O-acetylnucleosides (2a-d) were obtained regioselectively through a Candida antarctica B lipase catalyzed alcoholysis.