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Org Lett. 2014 Dec 5;16(23):6088-91. doi: 10.1021/ol503170b. Epub 2014 Nov 20.

Revisiting N-to-O acyl shift for synthesis of natural product-like cyclic depsipeptides.

Author information

1
†Chemistry and Biochemistry, University of California-Santa Cruz, Santa Cruz, California 95064, United States.
2
‡Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
3
§Pharmacokinetics, Dynamics, and Metabolism, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
4
∥Pharmacokinetics, Dynamics, and Metabolism, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, United States.
5
⊥Worldwide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc., Cambridge, Massachusetts 02139, United States.

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.

PMID:
25412436
DOI:
10.1021/ol503170b
[Indexed for MEDLINE]

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