Roesner, Stefan; Saunders, George J.; Wilkening, Ina; Jayawant, Eleanor; Geden, Joanna V.; Kerby, Paul; Dixon, Ann M.; Notman, Rebecca; Shipman, Michael published an article in 2019, the title of the article was Macrocyclization of small peptides enabled by oxetane incorporation.Product Details of 98946-18-0 And the article contains the following content:
Cyclic peptides are an important source of new drugs but are challenging to produce synthetically. We show that head-to-tail peptide macrocyclizations are greatly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide C:O bonds with an oxetane ring. The cyclization precursors are easily made by standard solution- or solid-phase peptide synthesis techniques. Macrocyclizations across a range of challenging ring sizes (tetra-, penta- and hexapeptides) are enabled by incorporation of this turn-inducing element. Oxetane incorporation is shown to be superior to other established amino acid modifications such as N-methylation. The positional dependence of the modification on cyclization efficiency is mapped using a cyclic peptide of sequence LAGAY. We provide the first direct exptl. evidence that oxetane modification induces a turn in linear peptide backbones, through the observation of dNN (i, i + 2) and dαN (i, i + 2) NOEs, which offers an explanation for these improvements. For cyclic peptide, cLAGAY, a combination of NMR derived distance restraints and mol. dynamics simulations are used to show that this modification alters the backbone conformation in proximity to the oxetane, with the flexibility of the ring reduced and a new intramol. H-bond established. Finally, we incorporated an oxetane into a cyclic pentapeptide inhibitor of Aminopeptidase N, a transmembrane metalloprotease overexpressed on the surface of cancer cells. The inhibitor, cCNGRC, displayed similar IC50 values in the presence or absence of an oxetane at the glycine residue, indicating that bioactivity is fully retained upon amide C:O bond replacement. The experimental process involved the reaction of tert-Butyl trichloroacetimidate(cas: 98946-18-0).Product Details of 98946-18-0
The Article related to cyclic peptide synthesis md simulation hydrogen bond safety, oxetane peptide coupling macrocyclization solid phase synthesis cyclization kinetics, peptide cyclic oxetane aminopeptidase n inhibiting structure activity and other aspects.Product Details of 98946-18-0
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