Enantioselective reduction of pentoxifylline to lisofylline using whole-cell Lactobacillus kefiri biotransformation

摘要

Lisofylline (LSF) is a drug candidate that has been under investigation for acute respiratory distress syndrome, acute lung injury, septic shock and mucositis. As LSF is not commercially available in our country, we produced it for pharmacokinetic studies. In the present work whole-cell reduction of pentoxifylline [1-(5-oxohexyl)-3,5-dimethylxanthine] to LSF [1-(5R-hydroxyhexyl)-3,5-dimethylxanthine] using Lactobacillus kefiri DSM 20587 was investigated. Glucose or 2-propanol was used as a co-substrate to regenerate the NADPH cofactor. The reaction conditions were optimized. The influence of different concentrations of co-substrates on the yield and enantioselectivity of the biotransformation of pentoxifylline into LSF were tested. Maximum yield (100%) of biotransformation was reached in the presence of glucose as a co-substrate. At glucose concentrations of 675 and 900 mM the bioreduction of pentoxifylline proceeded highly enantioselectively (enantiomeric excess for the R enantiomer of 98%).