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Chiral β-lactam-based integrin ligands through Lipase-catalysed kinetic resolution and their enantioselective receptor response.

Authors
  • Martelli, Giulia1
  • Galletti, Paola1
  • Baiula, Monica2
  • Calcinari, Luca1
  • Boschi, Giacomo1
  • Giacomini, Daria3
  • 1 Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. , (Italy)
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy. , (Italy)
  • 3 Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Bioorganic chemistry
Publication Date
Jul 01, 2019
Volume
88
Pages
102975–102975
Identifiers
DOI: 10.1016/j.bioorg.2019.102975
PMID: 31102807
Source
Medline
Keywords
Language
English
License
Unknown

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 potency, and a specific enantio-recognition by integrin receptors was demonstrated. Copyright © 2019 Elsevier Inc. All rights reserved.

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