Human thioredoxin reductase 1 (TrxR1) is an enzyme of therapeutic interest in cancer treatment, due to its involvement in regulating the redox-signaling enzyme thioredoxin 1. Interestingly, cancerous cells can attribute many of their negative clinical features as a result of thioredoxin 1's interaction with the cellular redox cycle. Reduced (activated) thioredoxin is involved in a host of intra and extra cellular signaling pathways that can lead to increased cellular proliferation and decreased apoptosis. Predictably, thioredoxin has also been shown to be overly expressed in cancerous cells, particularly the most malignant (e.g., pacreatic, liver and breast). We are currently working towards a small molecule inhibitor developed to target TrxR1, the only known enzyme that reduces and activates thioredoxin. Current research suggests that inhibition of TrxR1 leads to decreased cancer cell fitness through interaction with the previously discussed mechanisms, (i.e., cellular growth control). Encouragingly, computational modeling has demonstrated the possible effectiveness of highly functionalized benzofulvene moieties. We have determined quite high in-silico binding affinities (i.e. >10 kcal/mole) to the TrxR1 active site.                  From readily available indanone a pharmaceutically relevant synthetic route for the benzofulvene scaffold has been developed.  We can access highly functionalized benzofulvenes through a four step/two pot route that utilizes reduced toxicity solvents, avoids the use of heavy metals, and eliminates cryogenic conditions. Currently, we have synthesized twelve novel benzofulvenes with various functional properties. We will apply this route to synthesizing in-silico directed target molecules that could possibly inhibit TrxR1.

Functionalized benzofulvenes: Coupling synthesis and computational chemistry to develop small molecule inhibitors at a primarily undergraduate institution

247th National Meeting (2014)

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