Chiral ß-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response.
Bioorg Chem
; 88: 102975, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-31102807
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 ß-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 ß-lactam enantiomers were obtained in excellent enantiomeric excesses (94% and 98% ee). Synthetic elaborations on the separated enantiomers allowed the synthesis of four chiral ß-lactams which were evaluated in cell adhesion assays on Jurkat cell line expressing α4ß1 integrin, and K562 cell line expressing α5ß1 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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Integrinas
/
Beta-Lactamas
/
Lipasa
Límite:
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article