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Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

Von Wiley-VCH zur Verfügung gestellt

New octreotide analogs were prepared by replacing the disulfide bond with a functionalized tertiary lactam bridge. The on-resin approach includes an Ugi multicomponent macrocyclization that enables the simultaneous ring closure and incorporation of lipids, fluorophores and functional groups suitable for the subsequent conjugation to cytotoxic moieties.


The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an on-resin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.

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