"Click-to-chelate": design and incorporation of triazole-containing metal-chelating systems into biomolecules of diagnostic and therapeutic interest.
The site-specific conjugation of metal chelating systems to biologically relevant molecules is an important contemporary topic in bioinorganic and bioorganometallic chemistry. In this work, we have used the CuI-catalyzed cycloaddition of azides and terminal alkynes to synthesise novel ligand systems, in which the 1,2,3-triazole is an integral part of the metal chelating system. A diverse set of bidentate alkyne building blocks with different aliphatic and aromatic backbones and various donor groups were prepared. The bidentate alkynes were reacted with benzyl azide in the presence of a catalytic amount of CuI to form tridentate model ligands. The chelators were reacted with [ReBr3(CO)3]2- to form well-defined and stable complexes with different overall charges, structures and hydrophilicities. In all cases tridentate coordination of the ligands, including through N3 of the 1,2,3-triazole ring, was observed. The ligand systems could also be quantitatively radiolabelled with the precursor [99 mTc (H2O)3(CO)3]+ at low ligand concentrations. Similarly the alkynes were reacted with an azido thymidine derivative to form a series of compounds, which could be radiolabelled in situ to form single products. Subsequent incubation of the neutral and cationic organometallic 99 mTc thymidine derivatives with human cytosolic thymidine kinase, a key enzyme in tumour proliferation, revealed that only the neutral compounds maintained substrate activity towards the enzyme. Bioconjugation, radiolabelling and enzymatic reactions were successfully performed in a matter of hours. Thus, click chemistry provides an elegant method for rapidly functionalising a biologically relevant molecule with a variety of efficient metal chelators suitable for (radio)labelling with the M(CO)3 core (M=99 mTc, Re), to offer new potential for technetium-99 m in clinical and preclinical tracer development.
Struthers
Harriet
H
Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen, Switzerland.
Spingler
Bernhard
B
Mindt
Thomas L
TL
Schibli
Roger
R
D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D012211:Rhenium / Q000737:chemistry*; D017556:Technetium Compounds / Q000737:chemistry*; D013936:Thymidine / Q000737:chemistry; D013937:Thymidine Kinase / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000737:chemistry*
D002614:Chelating Agents; D008024:Ligands; D017556:Technetium Compounds; D014230:Triazoles; D012211:Rhenium; D013937:Thymidine Kinase; D013936:Thymidine