title: Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A.
abstract: The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 μg/mL. The approach is readily adaptable to large-scale synthesis and industrial production.
authors.affiliation: Kalexsyn, Inc., 4502 Campus Drive Kalamazoo, Michigan 49008, United States.
authors.forename: Peter G M
authors.initials: PG
authors.lastname: Wuts
authors.affiliation: Kalexsyn, Inc., 4502 Campus Drive Kalamazoo, Michigan 49008, United States.
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Simons
authors.affiliation: AureoGen Biosciences, Inc., Southwest Michigan Innovation Center, 4717 Campus Drive, Suite 2300, Kalamazoo, Michigan 49009, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Metzger
authors.affiliation: AureoGen Biosciences, Inc., Southwest Michigan Innovation Center, 4717 Campus Drive, Suite 2300, Kalamazoo, Michigan 49009, United States.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Sterling
authors.affiliation: AureoGen Biosciences, Inc., Southwest Michigan Innovation Center, 4717 Campus Drive, Suite 2300, Kalamazoo, Michigan 49009, United States.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Slightom
authors.affiliation: AureoGen Biosciences, Inc., Southwest Michigan Innovation Center, 4717 Campus Drive, Suite 2300, Kalamazoo, Michigan 49009, United States.
authors.forename: Ake P
authors.initials: AP
authors.lastname: Elhammer
keywords: C−H borylation; SAR; antifungal; aureobasidin A