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 α 4 β 1 integrin, and K562 cell line expressing α 5 β 1 integrin. Biological tests revealed that only (S)-enantiomers maintained the agonist activity of racemates with a nanomolar potency, and a specific enantio-recognition by integrin receptors was demonstrated.
Martelli G., Galletti P., Baiula M., Calcinari L., Boschi G., Giacomini D. (2019). Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response. BIOORGANIC CHEMISTRY, 88, 1-9 [10.1016/j.bioorg.2019.102975].
Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response
Martelli G.Membro del Collaboration Group
;Galletti P.Membro del Collaboration Group
;Baiula M.Membro del Collaboration Group
;Giacomini D.Membro del Collaboration Group
2019
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 α 4 β 1 integrin, and K562 cell line expressing α 5 β 1 integrin. Biological tests revealed that only (S)-enantiomers maintained the agonist activity of racemates with a nanomolar potency, and a specific enantio-recognition by integrin receptors was demonstrated.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
