The xanthine derivative denbufylline (DBF: 1,3-dibutyl-7-(2-oxo-
propyl)- 1H-purine-2,6(3H,7H)-dione) as a cAMP-phosphodiesterase (PDE4) inhibitor has been shown to possess relaxating effects on bronchial smooth muscles as well as anti-inflammatory activity. Therefore it has attracted attention as a remedy for asthmatic patients. DBF has also been shown to ameliorate learning or memory impairment, to increase cerebral blood circulation, and to facilitate cerebral glucose metabolism and improve intracerebral oxygen tension (pO₂). These findings suggest that DBF may be effective in the treatment of cerebral disorders including hypoxic conditions such as cerebral ischemia as well as neuropsychiatric symptoms associated with these diseases. DBF is also effective against osteoporosis in animal models. Pharmacokinetic studies in human have shown that DBF is converted to several metabolites. The most important, pharmacologically active metabolite is (R,S)-1,3-dibutyl-7-(2-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (BRL-31532), which is a chiral compound.

Biological methods for the synthesis of chiral compounds offer some advantages in comparison to chemical methods, e. g. remarkable chemo-, regio-, and enantioselectivity. As biocatalysts alcohol dehydrogenases (ADHs) have gained increasing interest. They can be applied as isolated enzymes or incorporated in whole cells. In comparison to isolated enzymes, whole cell biocatalysts are usually more stable due to the protective cell matrix envelope for the enzyme. For many industrial applications they can be immobilized, via very simple and cost-effective protocols, in order to be re-used over very long periods of time. Whole cells can be immobilized in a matrix by covalent bonds, by physical adsorption or by gel entrapment. This last technique is widely used. Many natural synthetic polymers have been described, such as calcium or barium alginate, κ-carrageenan or polyurethane foams etc.

In this study we report the use of immobilized Lactobacillus kefiri DSM 20587 for the enantioselective reduction of the methyl ketone group of denbufylline for the preparation of the enantiopure (R)-hydroxy metabolite: (R)-1,3-dibutyl-7-(2-hydroxypropyl)- 1H-purine-2,6(3H,7H)-dione. As DBF is insoluble in water (logP 2.64) different co-solvents were used for biotransformation. The influence of co-solvents on the yields and enantioselectivity of the bioreduction process was examined.

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