title: Revisiting N-to-O acyl shift for synthesis of natural product-like cyclic depsipeptides.
abstract: Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.
authors.affiliation: †Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Schwochert
authors.affiliation: †Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
authors.forename: Cameron
authors.initials: C
authors.lastname: Pye
authors.affiliation: †Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ahlbach
authors.affiliation: †Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
authors.forename: Yashar
authors.initials: Y
authors.lastname: Abdollahian
authors.affiliation: ‡Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Farley
authors.affiliation: ‡Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Bhagyashree
authors.initials: B
authors.lastname: Khunte
authors.affiliation: ‡Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.affiliation: §Pharmacokinetics, Dynamics, and Metabolism, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: ∥Pharmacokinetics, Dynamics, and Metabolism, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.affiliation: ‡Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
authors.affiliation: ⊥Worldwide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: ⊥Worldwide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: ⊥Worldwide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.affiliation: †Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000215:Acylation; D000595:Amino Acid Sequence; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic
chemical_list: D001688:Biological Products; D047630:Depsipeptides; D010455:Peptides; D010456:Peptides, Cyclic