title: A combined solid- and solution-phase approach provides convenient access to analogues of the calcium-dependent lipopeptide antibiotics.
abstract: The calcium-dependent lipopeptide antibiotics represent a promising new class of antimicrobials for use in combating drug-resistant bacteria. At present, daptomycin is the only such lipopeptide used clinically and displays potent antimicrobial activity against a number of pathogenic Gram-positive bacteria. Given the increasing need for new antibiotics, practical synthetic access to unnatural analogues of daptomycin and related antimicrobial lipopeptides is of value. We here report an efficient synthetic route combining solid- and solution-phase techniques that allows for the rapid preparation of daptomycin analogues. Using this approach, four such analogues, including two enantiomeric variants, were synthesized and their antimicrobial activities and hydrolytic stabilities evaluated.
authors.affiliation: Medicinal Chemistry & Chemical Biology Group, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. n.i.martin@uu.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: 't Hart
authors.forename: Laurens H J
authors.initials: LH
authors.lastname: Kleijn
authors.forename: Gerjan
authors.initials: G
authors.lastname: de Bruin
authors.forename: Sabine F
authors.initials: SF
authors.lastname: Oppedijk
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.forename: Nathaniel I
authors.initials: NI
authors.lastname: Martin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000737:chemistry*; D017576:Daptomycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D012996:Solutions; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D012996:Solutions; D017576:Daptomycin; D002118:Calcium