Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling

Date

2019-08-22

Author

Kemker, Isabell
Schnepel, Christian
Schroeder, David C.
Marıon, Antoıne
Sewald, Norbert

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Halogenated L- or D-tryptophan obtained by biocatalytic halogenation was incorporated into RGD peptides together with a variety of alkyl or aryl boronic acids. Suzuki-Miyaura cross-coupling either in solution or on-resin results in side chain-to-tail-cyclized RGD peptides, for example, with biaryl moieties, providing a new dimension of structure-activity relationships. An array of RGD peptides differing in macrocycle size, the presence of D-amino acid, N-methylation, or connectivity between the indole moiety and the boronic acid showed that, in particular, connectivity exhibits a major impact on affinities toward integrins, for example, a(v)beta(3). Structure-activity relationship studies yielded peptides with affinities toward a(v)beta(3) in the low nanomolar range, good selectivity, and high plasma stability. Structural characteristics of representative molecules have been investigated by molecular dynamics simulations, which allowed understanding the observed activity differences.

Subject Keywords

Molecular Medicine, Drug Discovery

URI

https://hdl.handle.net/11511/47347

Journal

JOURNAL OF MEDICINAL CHEMISTRY

DOI

https://doi.org/10.1021/acs.jmedchem.9b00360

Collections

Department of Chemistry, Article

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Citation Formats

I. Kemker, C. Schnepel, D. C. Schroeder, A. Marıon, and N. Sewald, “Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling,” JOURNAL OF MEDICINAL CHEMISTRY, pp. 7417–7430, 2019, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/47347.