Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling


Kemker I., Schnepel C., Schroeder D. C. , MARION A. , Sewald N.

JOURNAL OF MEDICINAL CHEMISTRY, cilt.62, ss.7417-7430, 2019 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 62 Konu: 16
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1021/acs.jmedchem.9b00360
  • Dergi Adı: JOURNAL OF MEDICINAL CHEMISTRY
  • Sayfa Sayıları: ss.7417-7430

Özet

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.