The Design and Synthesis of Neuroprotectants Based on an Endogenous Platform

There is a pressing need for the development of a neuroprotective therapy that limits neuronal injury in ischemic stroke patients. A diversity of neurotoxic factors, including divalent metal cations, are released during ischemia that result in brain damage. The goal of this research is to develop a method to mitigate the neurotoxic influxes of such cations (focusing on Zn(II)) using histidine as a model chelating molecule, thereby limiting neuronal death during an ischemic stroke. Through the use of computational methods, several small molecules have been identified that bind favourably with Zn(II); nuclear magnetic resonance experiments involving Zn(II) in combination with these small molecules supports these in silico predictions. A subset of active molecules shows measurable binding constants through calorimetric methods. Several molecules provide protection from Zn(II) toxicity in vitro; Zn(II) imaging experiments confirm the mechanism of protection is metal chelation.M.Sc