Multicomponent Functionalization of the Octreotide Peptide Macrocyclic Scaffold

Abstract

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.

Instant Macrocyclizations via Multicomponent Reactions

“…29,35,36 Moreover, peptide multicomponent macrocyclization has been designated as a strategy able to compete with the classic peptide cyclization. 37,38 Very recently, we classified the diverse macrocyclization tactics via MCR chemistry. 26,39 Based on the pioneer work of Zhu, 40 Yudin, 41 Wessjohann and Rivera, 42 we identified all the strategies, underlining the importance of introducing more synthetic approaches by which the installation of orthogonal functional groups on a primary MCR-based adduct could lead to effective macrocyclization at a secondary level.…”

“…Knapp et al in their comprehensive review concluded that multicomponent reaction (MCR) chemistry could constitute a technology of the future that had the potential to improve macrocyclization reactions. Indeed, over the last five years, MCR chemistry has emerged as an alternative and very effective synthetic strategy for the synthesis of different sizes of artificial macrocycles. ,, Moreover, peptide multicomponent macrocyclization has been designated as a strategy able to compete with the classic peptide cyclization. , Very recently, we classified the diverse macrocyclization tactics via MCR chemistry. , Based on the pioneer work of Zhu, Yudin, Wessjohann and Rivera, we identified all the strategies, underlining the importance of introducing more synthetic approaches by which the installation of orthogonal functional groups on a primary MCR-based adduct could lead to effective macrocyclization at a secondary level . Of particular interest is how to gain access to difficult medium-sized rings and macrocycles. , …”