Interaction of Molybdocene Dichloride with Cysteine-Containing Peptides:  Coordination, Regioselective Hydrolysis, and Intramolecular Aminolysis

Reactions of the organometallic compound molybdocene dichloride (Cp₂MoCl₂, Cp = η⁵-cyclopentadienyl) with the cysteine-containing peptides l-cysteinylglycine (Cys-Gly), N-acetyl-l-cysteine (AcCys), glycyl-l-cysteine (Gly-Cys), glycyl-l-cysteinylglycine (Gly-Cys-Gly), and γ-l-glutamyl-l-cysteinylglycine (glutathione, GSH) have been studied in aqueous solution in the pH range 2−9. The dipeptides Cys-Gly and Gly-Cys and the acetylated amino acid AcCys form 1:1 and 2:1 complexes of composition [Cp₂Mo(peptide-S)(OH₍₂₎)]^n+/- and [Cp₂Mo(peptide-S)₂]^n+/- as well as the chelates [Cp₂Mo(AcCys-S,O)], [Cp₂Mo(Gly-Cys-S,O)]⁺, and [Cp₂Mo(Cys-Gly-S,N)] with the Cp₂Mo²⁺ unit binding to the deprotonated thiolate group and the free amino or carboxylate group of the cysteine residue. Upon treatment of Gly-Cys-Gly and the naturally occurring tripeptide GSH with Cp₂MoCl₂ at elevated temperature, release of free glycine was observed. The Cp₂Mo²⁺ entity coordinates to the thiolate group of GSH and mediates regioselective hydrolysis of the Cys-Gly peptide bond by intramolecular metal hydroxide activation. Cp₂Mo²⁺-promoted hydrolysis of GSH was followed at pD 7.4 and 5.2 and 40 and 60 °C. By contrast, the Cys−Gly bond in [Cp₂Mo(Gly-Cys-Gly-S,N)] is cleaved by intramolecular aminolysis at pD ≥ 7.4 and 60 °C leading to glycine and the Cp₂Mo²⁺ complex of the 2,5-diketopiperazine derivative cyclo-(Gly-Cys). Chelating coordination of the Cp₂Mo²⁺ moiety to the thiolate group and to the deprotonated amide nitrogen of the tripeptide changes the configuration of the peptide bond from (preferred) trans to cis, thus enabling nucleophilic attack of the primary amino group at the Cys−Gly bond. The reaction product [Cp₂Mo{cyclo-(Gly-Cys)}]·2H₂O has been characterized by X-ray crystallography.