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 study a number of new potentially selective mechanism-based inactivators for certain P450 enzymes involved in carcinogenesis. In our previous studies, we have established that a number of aromatic acetylenes and certain propargyl ethers are selective suicide inhibitors of cytochrome P450-dependent monooxygenases. In this project, we propose to synthesize a new class of compounds containing a coumarin ring structure, with a propargyl ether or ethynyl moiety. We are planning to synthesize propargyl substituted coumarins, as well as ethynyl substituted coumarins, and assay them in-vitro on a number of P450 enzymes in order to study their relative potential inhibitory effects based on the type, placement, and number of the substituents on the ring system. Due to their structural similarities to coumarin, 7-ethoxycoumarin, and 7-ethoxy-4-trifluoromethylcoumarin (known coumarin P450 substrates), these compounds should interact with human P450 enzymes 2A6, 1A2, 2B1, and 2E1, as well as rat P450s 1A1, 1A2, and 2B1. However the presence or absence of an oxygen on the substituent containing the triple bond should change the polarity, and the shape of the branch, leading to some differences in the interaction with various P450 enzymes' active sites, and hopefully causing selective mechanism-based (suicide) inhibition. The above-mentioned P450 enzymes are extremely important in the metabolism of pharmaceuticals and environmental chemicals including procarcinogens. Due to the special properties of suicide inhibitors, these compounds are useful tools in the studies of cancer development and treatment. Additionally, The mechanism of action of these inhibitors makes it possible to use them as probes into the active sites of P450 enzymes, facilitating the identification of important amino acid residues, leading to better understanding of the structure-activity relationships involved in the P450-dependent reactions.
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