title: Synthesis and evaluation of novel macrocyclic antifungal peptides.
abstract: Echinocandins are a novel class of macrocyclic antifungal peptides that act by inhibiting the β-(1,3)-D-glucan synthase complex, which is not present in mammalian cells. Due to the large number of hydroxyl groups present in these complex macrocyclic lipopeptides, most structure-activity relationship studies have relied upon semisynthetic derivatives. In order to probe the influence of the cyclic peptide backbone on the antifungal activity we developed a successful strategy for the synthesis of novel echinocandins analogues by on-resin ring closing metathesis or disulfide formation. The specific minimum inhibitory activity of each mimic was determined against Candida albicans. Our results indicate that ring size is an important factor for antifungal activity.
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands.
authors.forename: Monique P C
authors.initials: MP
authors.lastname: Mulder
authors.forename: John A W
authors.initials: JA
authors.lastname: Kruijtzer
authors.forename: Eefjan J
authors.initials: EJ
authors.lastname: Breukink
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Pieters
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D054714:Echinocandins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D004791:Enzyme Inhibitors; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase