Background
Alzheimer's disease (AD) is the only top 10 cause of death that cannot be prevented, cured, or even slowed. We are developing attenuated furoxans− thiophilic NO donors that have neuroprotective activity, cross the blood brain barrier (a common obstacle in CNS drug discovery), and improve memory in mice− with the goal of alleviating the symptoms of AD and understanding its pathophysiology. Although Furoxans have been studied extensively, their mechanistic chemistry and protein targets have not been explored; in order to identify the subset of relatively reactive cellular thiols we will need to incorporate binding partners.

Methods
In order to identify the cellular targets responsible for furoxan bioactivation, we will synthesize furoxan analogs incorporating a photoaffinity labeling group and a terminal alkyne to covalently modify target proteins. We used OCF3 due to previously seen activity and incorporated diazirine, a main photoreactive group used in identifying biomolecule targets, to help facilitate a covalent bond between the compound and its target. Mainly diazirines present reactive and alkynyl sites are crucial in understanding cellular interactions with attenuated furoxans. The PAL group will attach the probe to binding partners upon irradiation with UV light. Following the synthesis of the compounds, we performed photolysis analysis via HPLC to determine the affects on photoreactivity.

Results
The tautomeric form of the furoxan being studied (3-aryl versus 4-aryl) does impact photoreactivity. The 4-Aryl OCF3 analog had a half-life of 7.7 minutes at 312 nm and 4.9 minutes and 365 nm. The 3-Aryl OCF3 analog had a half-life of 27.0 minutes at 312 nm and 5.6 minutes and 365 nm.The 4-aryl has a shorter half-life than the 3-aryl at 312 nm, however, 3-aryl has a shorter half-life at 365 nm in comparison to the 4-aryl.

Conclusion
Based on the non-reactive nature of the compounds, utilization of molecular probes will aid in understanding the mechanism of action. Incorporating a photoaffinity labeling cap group to probes that possess the efficacy of our active furoxan library would help to identify the cellular targets responsible for furoxan bioactivation and address the reactivity of our series of compounds. The purpose of the work is to use various molecular probes to broaden our understanding of our furoxan library, how it functions in the biological system, and also to use the obtained information to enhance affinity, efficacy, and metabolic effects.

Synthesis of 3 & 4 Aryl Furoxan Photoaffinity Probes

 Neurology

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