Junior biochemistry concentrator Ben Wesley received a Sigma Xi Grants-in-Aid of Research (GIAR) award for a proposal titled “Development of a Continuous Flow Reactor for Synthesis of Izidine Alkaloids.” Each year, several hundred to 1000 proposals are submitted to Sigma Xi to fund research-related expenses in many different areas of science.  The award program is highly competitive, and only about 15 percent of applications are funded.  Since 1922, Sigma Xi has awarded such grants to more than 30,000 young researchers who show promise in their field.

Wesley’s proposal was based on a project that evolved from summer research with Assistant Professor of Chemistry Max Majireck to build a special type of reaction apparatus for the synthesis izidine alkaloids, a class of molecules which can possess interesting neuroactivity.

The research team hopes to use these molecules as “chemical probes” to study the cellular/molecular mechanisms within neurological diseases by, for example, targeting a gene or genes involved in neurological processes and observing the effect.  Using molecules as tools to study biology (a field known broadly as chemical biology) has historically uncovered new information about living systems, human diseases and development of therapeutics.

Wesley and Majireck hope to build what is known as a continuous flow reactor, an apparatus that continually pumps a reaction mixture in a closed loop.  Within the loop, different chemical reagents, purification systems, or other features can be implemented so that a compound in solution can experience a variety of different conditions in a controlled sequence.

Their idea is to adapt an existing protocol that was recently invented by another research group at the University of Delaware (led by Prof. Joseph Fox) to develop a streamlined process for making izidine alkaloids, which they hope to study in different biological contexts.  In this setup, which they refer to as the Fox protocol, the team has assembled a device that contains a reaction vessel irradiated by light from a mercury lamp.  The molecule they are studying contains a carbon-carbon double bond within an 8-membered ring.  Some of the light energy from the mercury lamp is absorbed by the double bond in the molecule, allowing it to convert from the more stable “cis-configuration” to the less stable and more reactive “trans-configuration” in a process called photoisomerization.

“This overall process is not trivial,” remarked Majireck “and older methods to generate the type of strained trans-double bond in similar systems have relied upon multi-step syntheses that are often very tedious and not practical for our purposes.”  In fact, only a small percentage of the double bond is actually converted to the desired trans-configuration in the photoisomerization process, Majireck explained, and this is where the continuous flow system comes to play.

Fox solved this problem by developing a system that included a silver nitrate “trap” that selectively coordinates to the trans-alkene, allowing the cis-alkene to pass through and continue on for another photoisomerization cycle.  After multiple cycles, the amount of trans-alkene builds up in the silver nitrate trap and can later be washed off with a solvent to be used in subsequent chemical reactions that will directly convert this material into izidine alkaloids. 

Over the next year, Wesley and Majireck hope to build a similar system that can be used to synthesize substrates that they hypothesize will have useful neuroactivity and eventually work with collaborators to use these compounds as probes to study neurological diseases.  For example, the Majireck group will be donating any interesting compounds to large biomedical research institutes such as the Broad Institute of Harvard & MIT and MIT’s Koch Institute for Integrative Cancer Research.  These compounds are also being evaluated in collaboration with Hamilton Biology Professor Herm Lehman. 

Ultimately, they hope one or more of their compounds will be used to identify new information about neurological processes that may one day contribute toward a better understanding of neurological diseases and how to treat them.

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