title: Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules.
abstract: Hybrid peptide-polyketides are a class of medically and biologically important natural products characterized by stereochemical and functional diversity. In their biosynthesis, hybrids are often macrocyclized to achieve rigid structures that populate bioactive conformations. We herein present a chemoenzymatic strategy to access the stereochemical and functional diversity found in macrocyclic hybrid natural products in a manner amenable to efficient library synthesis. Our method makes use of small building blocks in the form of Fmoc-protected epsilon-amino acids containing embedded polyketide functionality. The building block approach allows for combinatorial synthesis of linear molecules that can be activated as soluble thioesters or tethered to a solid-phase resin. We demonstrate that these linear molecules are substrates for macrocyclization by a tolerant catalyst, TycC TE, derived from a nonribosomal peptide synthetase. The method should allow for access to diverse structures with hybrid peptide-polyketide character that can be screened for improved or novel activities.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rahul M
authors.initials: RM
authors.lastname: Kohli
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
authors.forename: Junhua
authors.initials: J
authors.lastname: Tao
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D000577:Amides / Q000138:chemical synthesis*; D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D018942:Macrolides / Q000138:chemical synthesis*; D010455:Peptides / Q000138:chemical synthesis*; D017434:Protein Structure, Tertiary; D013869:Thiolester Hydrolases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000577:Amides; D000596:Amino Acids; D018942:Macrolides; D010455:Peptides; D013869:Thiolester Hydrolases