title: Total synthesis and initial structure-activity relationships of longicatenamycin A.
abstract: Natural products have provided the majority of lead structures for marketed antibacterials. In addition, they are biological guide principles to new therapies. Nevertheless, numerous "old" classes of antibiotics such as the longicatenamycins have never been explored by chemical postevolution. Longicatenamycin A is the first defined longicatenamycin congener that has been totally synthesized and tested in pure form. This venture required the de novo syntheses of the non-proteinogenic amino acids (2S,3R)-beta-hydroxyglutamic acid (HyGlu), 5-chloro-D-tryptophan (D-ClTrp), and (S)-2-amino-6-methylheptanoic acid (hhLeu). In the key step, the sensitive HyGlu building block was coupled as a pentafluorophenyl active ester to the unprotected H-D-ClTrp-Glu-hhLeu-D-Val-D-(Cbz)Orn-OH fragment. This first total synthesis of longicatenamycin A provided new congeners of the natural product (deacetyllongicatenamycin, dechlorolongicatenamycin, and longicatenamycin-A-amide).
authors.affiliation: Bayer HealthCare, Global Drug Discovery, 42096 Wuppertal, Germany. franz.nussbaum@bayerhealthcare.com
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.forename: Sonja
authors.initials: S
authors.lastname: Anlauf
authors.forename: Christoph
authors.initials: C
authors.lastname: Freiberg
authors.forename: Jordi
authors.initials: J
authors.lastname: Benet-Buchholz
authors.forename: Jens
authors.initials: J
authors.lastname: Schamberger
authors.forename: Thomas
authors.initials: T
authors.lastname: Henkel
authors.forename: Guido
authors.initials: G
authors.lastname: Schiffer
authors.forename: Dieter
authors.initials: D
authors.lastname: Häbich
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D003500:Cyclization; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; C011014:longicatenamycin