Some cancers, like acute myeloid leukemia (AML), are addicted to reactive oxygen species and display large increases in their concentrations. The reactive oxygen form of hydrogen peroxide is used to activate cell growth pathways when a growth signal is present. High levels of endogenous hydrogen peroxide allow the cancer cells activate the pathways at will. We designed a new hydrogen peroxide-activated agent with two key modules. The first module is a peroxide-acceptor and the second is a pendant amine. The acceptor module is an amidohydroquinone that oxidizes into a lethal form in the presence of hydrogen peroxide. The pendant amine module induces selectivity between AML and normal cells. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent with two micromolar activity against AML cancer cells and an eleven fold-lower activity in healthy blood stem cells. Interestingly analysis shows that upon oxidation the pendant amine cyclizes with the hydroquinone to give a bicyclic aromatic compound with the amine’s substituents out of the plane. This new bicyclic compound is highly reactive with a variety of nucleophiles. Structural characterization and rates of reaction will be discussed. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-cancer agent.

New ROS-activated agents that specifically targert AML cancer cells

249th National Meeting (2015)

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