Nitric oxide (NO) plays an essential role in synaptic plasticity and neuronal function. Indeed, molecules capable of enhancing NO signaling have shown promise as potential therapeutics for neurodegenerative disorders. We are engaged in the development of a novel class of NO mimetics known as furoxans. Furoxans are commonly described as thiol-dependent NO mimetics- which must react with biological thiols to exhibit NO effects. We have developed a series of furoxans with attenuated reactivity in order to take advantage of the beneficial effects of NO while avoiding the known deleterious effects associated with large fluxes of NO. Due to this effort, we have created a series of furoxans with attenuated reactivity which do not readily react with generic thiols, such as glutathione or L-cysteine. One may predict that furoxans lacking reactivity would not possess neuroprotective and procognitive effects previously described for NO mimetics, since furoxans must react with thiols to produce NO. However, our furoxans display neuroprotection in cell culture and the ability to reverse scopolamine induced cognition deficits in a model of contextual fear memory. We demonstrated that furoxan neuroprotection is reversed upon blockade of NO/sGC (soluble guanylyl cyclase) signaling with ODQ, a selective sGC inhibitor. In retrospect, our results suggest furoxan activation by a subset of relatively reactive protein thiols to produce NO mimetics effects. The work presented focuses on the synthesis and evaluation of novel furoxans containing 1) a photoaffinity labeling group for transient covalent modification of interacting proteins and 2) a terminal alkyne for conjugation with a fluorophore and subsequent visualization of protein modification by SDS-PAGE. Photoactivation of the probes was analyzed by HPLC-UV analysis and protection against oxygen glucose deprivation was validated relative to the lead compounds. Identification of proteins capable of furoxan bioactivation will provide insight for potential development of CNS targeted furoxans

Examining the interactions of novel furoxans using techniques in chemical biology

255th National Meeting (2018)

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