Copper (Cu) ions play critical roles in orchestrating several biological processes both in enzyme bound and labile form and yet are toxic when present in excess. Under pathophysiological conditions Cu ions catalyze the production of highly reactive hydroxyl radicals via Fenton reaction rendering irreversible modifications to proteins, lipids, and DNA, leading to severe oxidative damage. Copper overload-induced oxidative stress has been implicated in many neurodegenerative diseases like Alzheimer’s disease, Amyotrophic lateral sclerosis, and Menkes disease. Cu-induced oxidative stress can be mitigated by selective Cu ion chelation provided the chelators do not affect other biologically relevant metal ions. However, most currently used FDA approved Cu2+ chelation based drugs are non-specific leading to unintended side effects. We have developed novel N3O2 based chelators that coordinate to Cu2+ in a pseudo-square planar geometry forming 1:2 metal : chelator complexes. Importantly, the chelators have shown 108 times higher conditional stability constants to Cu2+ over Cu+, Ca2+, Mn2+, Zn2+, Fe2+, Ni2+, and Co2+. The unique Cu2+ selectivity of our chelators prompted us to test the ligands in live cells and in vivo. We observed that the chelators reduce Cu induced oxidative stress in live human embryonic kidney cells. In a critical experiment, the chelators could also relieve oxidative stress in Atp7a-/- Menkes disease model cells which have higher intracellular Cu ion levels compared to wildtype controls. Finally, we have also demonstrated that our chelators significantly reduce Cu induced oxidative stress in live Zebrafish larva. The details of the chelator synthesis, characterization, and in vivo experiments will be presented.

Copper (II) selective chelators attenuate copper-overload induced oxidative stress in vivo

2019 Fall National Meeting

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