Current chemotherapy approaches for cancer treatment lack selective cytotoxicity, causing unwanted side effects. Recent literature studies have shown that cancer cells show elevated levels of reactive oxygen species (ROS). For example, acute myeloid leukemia (AML) cancer cells have shown a 100-fold increase in superoxide ROS compared to normal blood cells. We are translating this observation into a pro-drug design approach, allowing ROS to oxidize the pro-drug in order to improve selective cytotoxicity. Our current lead agent has shown 10-fold selectivity between AML cells over normal CD34+ blood cells in vitro, but has been found to rapidly metabolize in vivo. We hypothesize, based on calculations, that metabolism predominately occurs via enzymatic reaction with CYP3A19, one of the most common xenobiotic resistance enzymes. I have computationally designed a series of new molecules that impart the same mechanism of action but are resistant to CYP3A19 metabolism. I have synthesized 7 targets and evaluated their metabolism by CYP3A19 using a luminescence assay. Next, I evaluated their anti-AML activity and selectivity compared to CD34+ blood cells.

Targeted synthesis of novel ROS activated cancer pro-drugs resistant to CYP3A19 metabolism

248th National Meeting (2014)

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