Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells

The imidazole alkaloid lepidiline A from the root of Lepidium meyenii has a moderate to low in vitro anticancer
effect. Our aim was to extend cytotoxicity investigations against
a panel of cancer cells, including multidrug-resistant cancer cells,
and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene
precursor, therefore a suitable ligand source for metal complexes.
Thus, we synthesized lepidiline A and its copper(I), gold(I), and
silver(I) complexes and tested them against ovarian, gastrointestinal,
breast, and uterine cancer cells and bone marrow-derived and adipose-derived
mesenchymal stem cells. Lepidiline A and its copper complex demonstrated
moderate cytotoxicity, while silver and gold complexes exhibited significantly
enhanced and consistent cytotoxicity against both cancer and stem
cell lines. ABCB1 in the multidrug-resistant uterine sarcoma line
conferred significant resistance against lepidiline A and the copper-lepidiline
A complex, but not against the silver and gold complexes. Our results
indicate that only the copper complex induced a significant and universal
increase in the production of reactive oxygen species within cells.
In summary, binding of metal ions to lepidiline A results in enhanced
cytotoxicity with the nature of the metal ion playing a critical role
in determining its properties.