Solid‐Phase Synthesis, Characterization, and Antibacterial Activities of Metallocene–Peptide Bioconjugates

Abstract

This work shows how the introduction of an organometallic group enhances and modifies the specificity of biologically active peptides. Ferrocene was chosen as an organometallic group because it has been shown to alter the pharmacodynamic profile of bioactive compounds. A comparison with the isosteric cobaltocenium group allows one to explore the influence of charge and redox potential on the biological activity of the conjugates. Arginine and tryptophan containing peptides H-WRWRWR-NH(2) and H-RWRWRW-NH(2) and the metallocene peptide bioconjugates [M]-C(O)-RWRWR-NH(2) and [M]-C(O)-WRWRW-NH(2), where [M]=[Co(Cp)(C(5)H(4))](+), [Fe(Cp)(C(5)H(4))] were prepared by solid-phase peptide synthesis (SPPS). They were purified by HPLC, characterized by ESIMS and NMR spectroscopy, and tested for antibacterial properties against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the minimum inhibitory concentration (MIC) test. In most cases, no metal-specific activity could be observed. However, the conjugate [Fe(Cp)(C(5)H(4))-C(O)-WRWRW-NH(2)] 6 was found to be particularly effective against the Gram-positive S. aureus. The activity of this metallocene-pentapeptide conjugate (7.1 microM) was even better than the 20 amino acid naturally occurring pilosulin 2, which was used as a positive control. Unlike all other compounds tested, which were most active against the Gram-negative E. coli strain, the ferrocene conjugate 6 was the only compound in this series that was most active against Gram-positive bacteria. Given the health concerns resulting from multidrug resistant S. aureus strains, the incorporation of metallocenes may provide a novel line of attack.

Small cationic antimicrobial peptides delocalize peripheral membrane proteins

“…To achieve this understanding, we studied the synthetic hexapeptide RWRWRW-NH 2 (referred to hereafter as "MP196") (see SI Appendix, Fig. S1 for structure) as a model representing the minimal pharmacophore of positively charged and hydrophobic amino acids (16,17). It is effective against Grampositive bacteria including methicillin-resistant Staphylococcus aureus strains, is moderately effective against Gram-negative bacteria, has low toxicity against human cell lines, and displays low hemolytic activity (18).…”

Ferrocenyl glycopeptides as electrochemical probes to detect autoantibodies in multiple sclerosis patients' sera

“…In fact, decomposition of organometallic peptides and secondary products of SPPS usually affects final yields. 20 Because microwave technology is proposed as a valid support for enhancement of efficiency of coupling reactions in SPPS, we applied this strategy to synthesize the peptide sequences using a microwave assisted automatic solid-phase peptide synthesizer. Microwave technology decreases chain aggregation during the syntheses, improves the coupling rates, and prevents side reactions in difficult peptide sequences.…”

“…However, the final ferrocenyl peptides could be safely obtained when phenol rather than water was used as scavenger in the final cleavage mixture for resin and amino acid side chains deprotection. 20 All the compounds were analyzed by UPLC-ESIMS and HPLC-ESIMS and purified by RP-HPLC (>95%) to be used for autoantibody detection.…”

Synthesis and biological activity of a ferrocenyl ligand derived from thiophenol and its coordination with some transition metals

“…They have found many applications in drug development for the treatment of allergies [21], inflammation [22], schizophrenia [23], HIV infections [24], and more recently for the treatment of pain [25], as fibrinogen receptor antagonists with antithrombotic activity [26], and as new inhibitors of bacterial DNA gyrase B [27][28][29]. A few recent studies have produced ferrocenyl conjugates with a thiazole ligand that demonstrate some distinctive and medicinal properties [12,[30][31][32][33][34][35][36].…”