We are developing a cancer pro-drug strategy that is sensitive to levels of reactive oxygen species (ROS) in a cell. It has been shown that certain cancers, such as acute myeloid leukemia, possess elevated levels of ROS. One roadblock is poor stability under physiological conditions. We have designed analogs with hydrolysable groups to improve drug stability in vivo. After synthesis, analog stability in aqueous media was examined by HPLC. The half-life at pH7 was 25.4 +/- 0.77 hr. As expected we found a strong pH dependence with pH 8 causing increase of hydrolysis of 88-fold. Next, Michaelis-Menten kinetics values for porcine esterase catalyzed hydrolysis was quantified by UV spectroscopy. This esterase mimics in vivo enzyme action. Upon enzymatic hydrolysis the product increases absorbance at 292 nm, allowing accurate assessment of Km and Vmax values. The simplest hydrolysable group was an acetyl analog with a Vmax value of 3.4�10-6 +/- 8.9�10-7 �mol/min and a Km value of 14 +/- 3.4 �M at pH 7. This work is now being expanded to numerous other hydrolysable groups. Future work includes using a mouse model of AML to determine if hydrolysable groups enhance in vivo stability.

<i>In vitro</i> stability of novel metabolically resistant anticancer agents

247th National Meeting (2014)

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In vitro stability of novel metabolically resistant anticancer agents