Abstract
Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by 1H, 13C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients.
Highlights
IntroductionSugar alcohols are polyols obtained by the reduction of sugars [1]
Catalyzed esterification reactions between hydroxyl-carrying molecules and poorly water-soluble drugs were exploited for prodrug synthesis
This study reports the optimized enzymatic esterification of ibuprofen with xylitol
Summary
Sugar alcohols are polyols obtained by the reduction of sugars [1] Polyols, such as glycerol, erythritol, xylitol, and sorbitol, are hydrogenated carbohydrates often used as sugar substitutes [2,3]. Xylitol (pentane-1,2,3,4,5-pentanol) naturally occurs in fruits and vegetables, such as plums, strawberries, cauliflower, and pumpkin [4]. Polyalcohols, such as xylitol, with their great water solubility, can be used as hydrophilization moieties to produce enhanced water-soluble prodrugs. Low water solubility represents a great obstacle in drug and formulation development [5]. For this reason, much attention is being paid to the development of protocols to produce highly watersoluble prodrugs. Catalyzed esterification reactions between hydroxyl-carrying molecules and poorly water-soluble drugs were exploited for prodrug synthesis. Similar hydrophilization strategies can be employed with anti-inflammatory, poorly bioavailable drugs, such as ibuprofen
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