title: Copper, nickel, and zinc cyclam-amino acid and cyclam-peptide complexes may be synthesized with "click" chemistry and are noncytotoxic.
abstract: 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.
authors: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors: Mingfeng
authors: M
authors: Yu
authors: Jason R
authors: JR
authors: Price
authors: Paul
authors: P
authors: Jensen
authors: Carrie J
authors: CJ
authors: Lovitt
authors: Todd
authors: T
authors: Shelper
authors: Sandra
authors: S
authors: Duffy
authors: Louisa C
authors: LC
authors: Windus
authors: Vicky M
authors: VM
authors: Avery
authors: Peter J
authors: PJ
authors: Rutledge
authors: Matthew H
authors: MH
authors: Todd
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D041961:Deuterium Exchange Measurement; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D057054:Molecular Imaging / Q000379:methods; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D014230:Triazoles / Q000737:chemistry; D014269:Trifluoroacetic Acid / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D014230:Triazoles; C024560:cyclam; D003300:Copper; D009532:Nickel; D014269:Trifluoroacetic Acid; D015032:Zinc