Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism of endogenous and xenobiotic compounds. The goal of this project is to synthesize and assay a number of new potential selective mechanism based activations for certain P450 isozymes involved in carcinogenesis. In our previous studies, we have established that a number of aromatic acetylenes are selective suicide inhibitors Of cytochrome P450-dependent monooxygenases. In this project, we propose to synthesize a new class of compounds containing a propargyl moiety. We are planning to synthesize a new class of compounds containing a propargyl moiety. We are planning to synthesize families of related propargyl substituted compounds and assay them in-vitro on a number of P450 isozymes in order to study their relative potential inhibitory effects based on the size and shape of the aromatic ring systems and the placement and length of the substituent chain of the molecule. These compounds should behave very similarly to the selective ethynyl and propynyl substituted aromatic inhibitors previously studied. However the presence of an oxygen on the substituent should increase the polarity, and change the shape of the branch leading to some differences in the selectivity towards various P450 isozymes. Due to the special properties of suicide inhibitors, these compounds are useful tools in the studies of cancer development and treatment. Additionally, the mechanisms of action of these inhibitors makes it possible to use them as probes into the active sites of P450 isozymes leading to better understanding of the structure-activity relationships involved in the P450-dependent reactions.
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