Tuning the Biological Activity of RGD Peptides with Halotryptophanst

Kemker, Isabell
Schroeder, David C.
Feiner, Rebecca C.
Mueller, Kristian M.
Marıon, Antoıne
Sewald, Norbert
An array of L- and D-halotryptophans with different substituents at the indole moiety was synthesized employing either enzymatic halogenation by halogenases or incorporation of haloindoles using tryptophan synthase. Introduction of these Trp derivatives into RGD peptides as a benchmark system was performed to investigate their influence on bioactivity. Halotryptophan-containing RGD peptides display increased affinity toward integrin alpha(nu)beta(3) and enhanced selectivity over integrin alpha(5)beta(1). In addition, bromotryptophan was exploited as a platform for latestage diversification by Suzuki-Miyaura cross-coupling (SMC), resulting in new-to-nature biaryl motifs. These peptides show enhanced affinity toward alpha(nu)beta(3), good affinity to alpha(nu)beta(8), and remarkable selectivity over alpha(5)beta(1) and alpha(IIb)beta(3) while featuring fluorogenic properties. Their feasibility as a probe was demonstrated in vitro. Extensive molecular dynamics simulations were undertaken to elucidate NMR and high-performance liquid chromatography (HPLC) data for these late-stage diversified cyclic RGD peptides and to further characterize their conformational preferences.


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The cobalt(II) porphyrin complex (CoTPP) was found to be an efficient catalyst for the Wittig type olefination of acyl phosphonates with ethyl diazoacetate (EDA) in the presence of triphenylphosphine (Ph(3)P). By using this one pot methodology under mild conditions, densely functionalized vinyl phosphonates were obtained in high yields and high E/Z selectivities in relatively short reaction times. A rather broad substrate spectrum and steric influence on the reaction rate were observed.
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Citation Formats
I. Kemker, D. C. Schroeder, R. C. Feiner, K. M. Mueller, A. Marıon, and N. Sewald, “Tuning the Biological Activity of RGD Peptides with Halotryptophanst,” JOURNAL OF MEDICINAL CHEMISTRY, pp. 586–601, 2021, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/89309.