In this renewal application we propose to continue the development of new organic reactions for the facilitated synthesis of natural product inspired bicyclic compounds (resveramorphs) that we have recently shown to protect neuronal cells from oxidative stress. Specifically, several of our resveramorphs protect synaptic transmission from acute oxidative stress in a fruit fly model (at the larval neuromuscular junction) at doses as low as 100 pM. To our knowledge, this level of neuroprotective activity is unprecedented for a small molecule. Moving forward, we seek to continue our focus on the chemistry of unique building blocks (allenoates), using them to prepare these neuroprotective compounds as tools to characterize a potentially new cellular target for neuroprotection against oxidative stress. Our chemical synthesis routes will make possible the compounds needed to narrow down and identify the biological target, as well as to characterize small-molecule interactions with that target. More specifically, we have recently discovered a new addition reaction of carbon nucleophiles to unactivated carbon-carbon triple bonds that takes place in the absence of transition metals. We propose to explore the synthetic potential of this reaction, elucidate its mechanism, and use it to more efficiently prepare resveramorphs. In another aim, we seek an asymmetric route to resveramorph analogs by taking advantage of the axial chirality properties of our allenoate building blocks. Ultimately, this organic reaction development is expected to enhance accessibility to resveramorphs, which, based on our current studies, are beginning to exhibit a structure/activity relationship (SAR). With the additional synthetic tools being proposed as part of this renewal application, we propose to expand this SAR study to define those elements in the molecule important for binding (pharmacophore) and ultimately identify an even more potent “tool compound” for biological study. In this regard, our preliminary data indicate that resveramorphs act by stabilizing the resting membrane potential and prolonging synaptic transmission. From this and other data, we hypothesize that resveramorphs may be modulating potassium channels directly. Through a collaboration with a member of our Biology Department (and coPI), the neuroprotective activity of resveramorphs will be examined. In this phase of the project, genetic manipulations targeting potassium channels in two invertebrate models, Drosophila melanogaster and Caenorhabditis elegans, are proposed to identify the biological target of our active analogs. Ultimately, these studies are expected to provide a firm footing for future medicinal chemistry investigations to identify novel agents against diseases such as Parkinson’s and Alzheimer’s.