Solid-phase synthesis, characterization, and antibacterial activities of metallocene-peptide bioconjugates

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 ₅H ₄)] ⁺, [Fe(Cp)(C ₅H 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 ₅H 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 μM) 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.