Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic

We describe the synthesis of cyclam metal complexes derivatized
with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen
“click” reaction. The linker triazole formed during
the synthesis plays an active coordinating role in the complexes.
The reaction conditions do not racemize the amino acid stereocenters.
However, a methylene group adjacent to the triazole is susceptible
to H/D exchange under ambient conditions, an observation which has
potentially important implications for structures involving stereocenters
adjacent to triazoles in click-derived structures. The successful
incorporation of several amino acids is described, including reactive
tryptophan and cysteine side chains. All complexes are formed rapidly
upon introduction of the relevant metal salt, including synthetically
convenient cases where trifluoroacetate salts of cyclam derivatives
are used directly in the metalation. None of the metal complexes displayed
any cytotoxicity to mammalian cells, suggesting that the attachment
of such complexes to amino acids and peptides does not induce toxicity,
further supporting their potential suitability for labeling/imaging
studies. One Cu­(II)–cyclam–triazole–cysteine
disulfide complex displayed moderate activity against MCF-10A breast
nontumorigenic epithelial cells.