diacarnoxideintro - Elucidation of the Mechanism of...

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Elucidation of the Mechanism of Inhibition of Hypoxia-Induced Factor 1 by Diacarnoxide Analogs Under Hypoxic Conditions Brad Hutnick April 20, 2007
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Specific Aims Diacarnoxide B has been shown to inhibit the growth of hypoxic tumor cells. The compound possesses an unusual peroxide moiety that we hypothesize mimics the effect of oxygen in a hypoxic cell on hypoxia-induced factor 1. To test this hypothesis, we plan To synthesize a series of analogs of diacarnoxide B. To test the efficacy of these analogs as inhibitors of the growth of hypoxic tumor cells in order to gain insight into the mechanism of inhibition of HIF-1. Background 1,2 HIF-1 Oftentimes, tumor cells grow too rapidly for the normal cells and blood vessels around them to keep up with, leading to a lack of oxygen, amongst other nutrients, for the tumors, a condition referred to as hypoxia. This can lead to portions of the tumors comprised almost totally of dead cells. This hypoxic environment is dramatically different from healthy cells with an adequate amount of oxygen, referred to as normoxic. Consequently, hypoxic cells can potentially be the subject of therapies that either target delivery of a drug to hypoxic cells specifically over normoxic cells, or therapies that, while reaching both hypoxic and normoxic cells, only become active under the unusual low oxygen conditions in a hypoxic tumor (a pro-drug). How do these cells survive and proliferate under hypoxic conditions? Oxygen is essential for normal cellular processes. Clearly, some pathway becomes operative under hypoxic conditions that allow the cells to survive. The protein hypoxia-induced factor (HIF-1) is expressed and active under hypoxic conditions. This protein is an activating factor for the transcription of genes that control such things as glucose uptake and glycolysis, angiogenesis and vasodilation, acid neutralization, and growth factors that are
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diacarnoxideintro - Elucidation of the Mechanism of...

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