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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Minority Biomedical Research Support - MBRS (S06)
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Special Emphasis Panel (ZGM1-MBRS-1 (01))
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Xavier University of Louisiana
New Orleans
United States
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Shimada, Tsutomu; Takenaka, Shigeo; Kakimoto, Kensaku et al. (2016) Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. Chem Res Toxicol 29:1029-40
Shimada, Tsutomu; Takenaka, Shigeo; Murayama, Norie et al. (2016) Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13. Xenobiotica 46:211-24
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Goyal, Navneet; Liu, Jiawang; Lovings, La'Nese et al. (2014) Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1. Chem Res Toxicol 27:1431-9
Liu, Jiawang; Taylor, Shannon F; Dupart, Patrick S et al. (2013) Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1. J Med Chem 56:4082-92
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Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF A FAMILY OF PROPARGYL PYRIDINYL ETHERS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:91-94
Shimada, Tsutomu; Kim, Donghak; Murayama, Norie et al. (2013) Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition. Chem Res Toxicol 26:517-28
Liu, Jiawang; Sridhar, Jayalakshmi; Foroozesh, Maryam (2013) Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules 18:14470-95
Liu, Jiawang; Nguyen, Thong T; Dupart, Patrick S et al. (2012) 7-Ethynylcoumarins: selective inhibitors of human cytochrome P450s 1A1 and 1A2. Chem Res Toxicol 25:1047-57

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