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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Minority Biomedical Research Support - MBRS (S06)
Project #
2S06GM008008-29
Application #
6335819
Study Section
Minority Programs Review Committee (MPRC)
Project Start
1977-06-01
Project End
2004-03-31
Budget Start
Budget End
Support Year
29
Fiscal Year
2000
Total Cost
$38,454
Indirect Cost
Name
Xavier University of Louisiana
Department
Type
DUNS #
020857876
City
New Orleans
State
LA
Country
United States
Zip Code
70125
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
Liu, Jiawang; Pham, Peter T; Skripnikova, Elena V et al. (2015) A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2. J Med Chem 58:6481-93
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; Sridhar, Jayalakshmi; Foroozesh, Maryam (2013) Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules 18:14470-95
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
Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF CARBAZOLE ANALOGS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:92-95
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; 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

Showing the most recent 10 out of 34 publications