A Solid Support‐Based Synthetic Strategy for the Site‐Selective Functionalization of Peptides with Organometallic Half‐Sandwich Moieties

• Published in: Chemistry : a European journal 2022-02, Vol.28 (12), p.e202104049-n/a
• Main Authors: Truong, Dianna, Lam, Nelson Y. S., Kamalov, Meder, Riisom, Mie, Jamieson, Stephen M. F., Harris, Paul W. R., Brimble, Margaret A., Metzler‐Nolte, Nils, Hartinger, Christian G.
• Format: Article
• Language: English
• Subjects: Anticancer properties; Atomic properties; carbene complexes; Catalysts; Chemistry; Conjugates; Coordination Complexes - toxicity; Coordination compounds; Cytotoxicity; Humans; Labeling; Ligands; Lysine; Metals; on-resin synthesis; Organometallic Compounds - toxicity; peptide functionalization; peptide-metal conjugates; Peptides; Peptides - chemistry; Purity; site selectivity; Transition Elements; Transition metals; Tumor cell lines
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202104049

The number of donor atoms available on peptides that can competitively coordinate to metal centers renders the site‐selective generation of advanced metal‐peptide conjugates in high purity a challenging venture. Herein, we present a transmetalation‐based synthetic approach on solid support in which an imidazolium pro‐ligand can be used to selectively anchor a range of transition metal half‐sandwich complexes onto peptides in the presence of multiple coordinative motifs. Amenable to solid support, a range of N‐terminus and/or lysine conjugated metal‐peptide conjugates were obtained in high purity after cleavage from the resin. The metalated peptides were evaluated for their anticancer properties against human cancer cell lines. While no cytotoxic activity was observed, this platform has the potential to i) provide a pathway to site‐selective peptide labelling, ii) be explored as a biorthogonal handle and/or iii) generate a new strategy for ligand design in transition metal catalysts. The site‐selective functionalization of peptides with metal moieties has been achieved with a carbene ligand on solid support which facilitated the isolation and purification of metal‐peptide conjugates. The developed methodology allows the metalation of Lys side chain functional groups and the N‐terminus in presence of competing metal‐binding amino acids.