Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response.
Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response.
Bioorg Chem. 2019 May 09;88:102975
Authors: Martelli G, Galletti P, Baiula M, Calcinari L, Boschi G, Giacomini D
Abstract
Obtainment and testing of pure enantiomers are of great importance for bioactive compounds, because of the assessed implications of enantioselectivity in receptor-mediated responses. Herein we evaluated the use of biocatalysis to obtain enantiomerically pure β-lactam intermediates further exploited in the synthesis of novel integrin ligands as single enantiomers. From a preliminary screening on a set of commercially available hydrolases, Burkholderia Cepacia Lipase (BCL) emerged as a suitable and highly performing enzyme for the kinetic resolution of a racemic azetidinone, key intermediate for the synthesis of novel agonists of integrins. Upon optimization of the biocatalytic protocol in terms of enzymes, acylating agents and procedures, the two β-lactam enantiomers were obtained in excellent enantiomeric excesses (94% and 98% ee). Synthetic elaborations on the separated enantiomers allowed the synthesis of four chiral β-lactams which were evaluated in cell adhesion assays on Jurkat cell line expressing α4β1 integrin, and K562 cell line expressing α5β1 integrin. Biological tests revealed that only (S)-enantiomers maintained the agonist activity of racemates with a nanomolar poten...
Source: Bioorganic Chemistry - Category: Chemistry Authors: Martelli G, Galletti P, Baiula M, Calcinari L, Boschi G, Giacomini D Tags: Bioorg Chem Source Type: research