Synthesis and Characterization of Dicobalthexacarbonyl-Alkyne Derivatives of Amino Acids, Peptides, and Peptide Nucleic Acid (PNA) Monomers

Abstract

The reaction of Co(2)(CO)(8) with alkyne-containing amino acids [1a: phenylalanine (Phe) and 1b: methionine (Met)], two suitably alkyne-functionalized derivatives of the neuropeptide enkephalin (Enk) [3: Ac-Enk-Prop and 5: Ac-Enk(Pgl)-NH(2) (Ac--Acetyl; Pgl--propargylglycine; Prop--propargylamine)], a thymine Peptide Nucleic Acid (T-PNA) monomer (7), and a PNA-like monomer (9) derivative gave the respective dicobalthexacarbonyl bioconjugates in very good yields. Two different sites for labeling of the biomolecules were successfully used: The organometallic moiety was reacted with the C-terminus of alkyne-containing amino acids, peptide or PNA thymine monomers, and alternatively the organometallic compound was complexed to an internal site in the peptide or PNA. To this end, a simple glycine was replaced by propargylglycine in peptides, and a new alkyne-containing PNA-like monomer, in which an alkyne chain replaces the nucleobase, was used for PNA chemistry. For the synthesis of the two alkyne-containing enkephalin derivatives 3 and 5, two different resins, namely sulfamylbutyryl and Rink amid, were used as they allow to selectively insert, on the solid phase, an alkyne moiety at the C-terminus and on a side-chain of a peptide sequence, respectively. The identity and constitution of all cobalt complexes were confirmed by different analytical methods (IR, FAB, ESI-MS, and NMR). Most notably, IR spectroscopy shows intensive bands in the 2100-2000 cm(-1) region because of the Co(2)(CO)(6) moiety. In both (1)H NMR spectra of the dicobalthexacarbonyl PNA monomer derivatives 8 and 10, all signals are doubled because of the cis-trans isomerism about the central amide bond. The X-ray structure of a dicobalthexacarbonyl phenylalanine derivative (2a) confirms the proposed composition of the bioconjugates and shows that, as anticipated, the alkyne group of 2a is no longer linear upon complexation in comparison to the alkyne group of the bioconjugate precursor 1a, as indicated by a C-C[triple bond]C angle of about 143 degrees in 2a. Moreover, the C[triple bond]C bond of 1a was elongated by about 0.15 A upon Co(2) coordination.

Exploring the cellular accumulation of metal complexes

“…No activity was observed for the peptide sequences themselves. Nils Metzler-Nolte and coworkers have synthesized and extensively characterized a wide variety of bioconjugates of amino acids, peptides, and peptide nucleic acids with various transition metals, including iron, copper, zinc, and cobalt with the intention of targeting specific organelles (96, 97). Their work examines metallocene and carbonyl alkyne complexes, and includes fluorescence microscopy and cytotoxicity studies that demonstrate the potential of a class of ferrocene-peptide conjugates to act as anti-microbial agents (98, 99).…”

A Novel Organometallic ReI Complex with Favourable Properties for Bioimaging and Applicability in Solid‐Phase Peptide Synthesis

“…[1] A useful strategy to enhance the bioavailability and target specificity of potentially active compounds is to link them to biological vectors such as peptides, carbohydrates or hormones. [2] In the past we have reported on the successful synthesis of peptide bioconjugates for such purposes, in which we have used a range of different transition metal complexes based on iron, [3][4][5] copper, [6] zinc, [6] cobalt, [4,[7][8][9] ruthenium, [10,11] rhenium, [12] platinum [12] and molybdenum. [13] One major advantage of peptide-based conjugates is their variability.…”

The Outer-Coordination Sphere: Incorporating Amino Acids and Peptides as Ligands for Homogeneous Catalysts to Mimic Enzyme Function

“…Metzler-Nolte and his group have used bis(2-picolyl)amine substituted with alkyl or aromatic carboxylic acids to allow the introduction of amino acids or peptides (99)(100)(101)(102)(103)(104). These ligands were incorporated into Mo, Cu, and Zn complexes (Fig.…”

“…Di-cobalt complexes were obtained and characterized crystallographically by starting with alkyne containing amino acids (Fig. 21C) (101). Pincer metal complexes have also been utilized as ligands for introducing amino acids and larger proteins (Fig.…”