Synthetic Approaches towards Peptide‐Conjugates of Pt(II) Compounds with an (O,S) Chelating Moiety

Abstract

Metal‐containing peptide (bio−)conjugates have received continuous interest due to their enormous potential for bioinorganic and medicinal research. In many bioconjugates the chemical inertness of the metal‐containing units facilitates synthesis e. g. by copper‐catalyzed alkyne−azide cycloaddition or the formation of peptide bonds. However, when the metal complex contains labile ligands, which are often critical to their biological activity, the synthetic proceeding requires careful planning. Here, we report on the synthesis of a set of peptide bioconjugates with a platinum(II) core, coordinated through widely variable (O,S) chelating β‐hydroxydithiocinnamic ester and two monodentate ligands. We have evaluated the synthetic applicability of metal−peptide bioconjugation techniques between the model peptide Leu5−enkephalin and differently functionalized (O,S)Pt units. Within this, the type and position of anchor used at the β‐hydroxydithiocinnamic unit proved to be crucial for success, but equally important was the synthetic order of conjugation and complexation. In this work, synthetic approaches for the linkage of metal complexes that are coordinated by functionalized ligands towards peptides were explored. Two general methods to link the studied (O,S)Pt pharmacophore to the model peptide, Leu5−enkephalin, have been applied, namely the most prominent “click” reaction, CuAAC, and the linking via amide bonds. Overall, it could be shown that the structural motif of the (O,S)Pt compounds presented here offers multiple possibilities of derivatization, so that bioconjugation towards peptides can be made possible. Depending on the demands made on the resulting metal bioconjugate, both the dithioester and the aromatic unit of β‐hydroxydithiocinnamic esters can be used as anchor for peptides. However, from our results here, it can be concluded that anchoring at the aromatic subsite seems preferable from a synthetic point of view as the spatial distance of the reactive terminal functional group (alkyne or azide) to the metal center may avoid intramolecular reactions. Also, for using azide−alkyne click chemistry as a conjugation strategy, the (O,S) unit should contain the azide function and not the alkyne function, as triple bond hydration may occur. Classical amide‐bond conjugation also proved to be a suitable method in our hands when performed in solution. A coupling of the β‐hydroxydithiocinnamic unit to resin‐bound peptide would not be possible due to the typically harsh cleavage conditions.