Cyclization of RGD Peptides by Suzuki–Miyaura Cross-Coupling

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, αVβ3. Structure–activity relationship
studies yielded peptides with affinities toward αVβ3 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.