Synthesis and Characterization of Folic Acid-Conjugated Terbium Complexes as Luminescent Probes for Targeting Folate Receptor-Expressing Cells

J Med Chem. 2024 Aug 22;67(16):14062-14076. doi: 10.1021/acs.jmedchem.4c00919. Epub 2024 Aug 13.

Abstract

Several conjugates between folic acid and a series of kinetically stable lanthanide complexes have been synthesized, using amide coupling and azide-alkyne cycloaddition methodologies to link the metal-binding domain to folate through a variety of spacer groups. While all these complexes exhibit affinity for the folate receptor, it is clear that the point of attachment to folate is essential, with linkage through the γ-carboxylic acid giving rise to significantly enhanced receptor affinity. All the conjugates studied show affinities consistent with displacing biological circulating folate derivatives, 5-methyltetrahydrofolate, from folate receptors. All the complexes exhibit luminescence with a short-lived component arising from ligand fluorescence overlaid on a much longer lived terbium-centered component. These can be separated using time-gating methods. From the results obtained, the most promising approach to achieve sensitized luminescence in these systems requires incorporating a sensitizing chromophore close to the lanthanide.

MeSH terms

  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / metabolism
  • Folate Receptors, GPI-Anchored / metabolism
  • Folic Acid* / chemistry
  • Folic Acid* / metabolism
  • Humans
  • Luminescent Agents / chemical synthesis
  • Luminescent Agents / chemistry
  • Terbium* / chemistry

Substances

  • Coordination Complexes
  • Folate Receptors, GPI-Anchored
  • Folic Acid
  • Luminescent Agents
  • Terbium
  • Carboxylic Acids