Synthesis of nisin AB dicarba analogs using ring-closing metathesis: influence of sp(3) versus sp(2) hybridization of the α-carbon atom of residues dehydrobutyrine-2 and dehydroalanine-5 on the lipid II binding affinity.
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| Abstract |
Herein the synthesis of two nisin AB dicarba analogs is described, focusing on amino acid modifications at positions 2 and 5. The nisin mimics were synthesized by a combination of solid phase synthesis of the linear peptides, followed by macrocyclization via ring-closing metathesis and fragment assembly by means of solution phase chemistry. The two N-terminal nisin AB-fragment mimics contain either the native dehydrobutyrine (Dhb)/dehydroalanine (Dha) amino acid residues or alanine at position 2 and 5, respectively. The native dehydrobutyrine at position 2 and dehydroalanine at position 5 were introduced as their precursors, namely threonine and serine, respectively, and subsequent dehydration was carried out by EDCI/CuCl as the condensing agent. Both AB-fragment mimics were analyzed in a lipid II binding assay and it was found that the Ala2/Ala5 AB-mimic (2) showed a reduced activity, while the Dhb2/Dha5 AB-mimic (3) was as active as the native AB-fragment (1).
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| Authors | Jack C Slootweg, Eric F van Herwerden, Mark F M van Doremalen, Eefjan Breukink, Rob M J Liskamp, Dirk T S Rijkers |
| Journal | Organic & biomolecular chemistry (Org Biomol Chem) Vol. 13 Issue 21 Pg. 5997-6009 (Jun 07 2015) ISSN: 1477-0539 [Electronic] England |
| PMID | 25940216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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