CHED 1319 |
| Cytochrome P450 enzymes, a superfamily of hemoproteins, oxidatively metabolize a wide variety of xenobiotics such as drugs, natural products, carcinogens, and other environmental chemicals, as well as endogenous compounds such as prostaglandins, fatty acids, and steroids. The various P450 enzymes exhibit substrate specificity that depends on the identity and orientation of active site amino acids. Human P450 1A2 is involved in the metabolism of many important drugs and environmental chemicals such as caffeine, acetaminophen, cigarette smoke components, and estradiol. The goal of this project is to synthesize and study a number of new potentially selective mechanism-based inactivators of P450 1A2. In our previous studies, we have established that a number of aromatic acetylenes are selective suicide inhibitors of cytochrome P450-dependent monooxygenases. We have also shown that several flavones, a class of phytochemical compounds present in human diet, inhibit the P450 1A2-dependent demethylation of methoxyresorufin in vitro. In this project, we are targeting a new family of flavones as potential mechanism-based inhibitors of this enzyme. These compounds are very similar to the natural flavone substrates of this enzyme but posses the capability of acting as suicide (mechanism-based time dependent) inhibitors. Some of the target compounds are isomeric and the differences in inhibitory activities will be useful in the determination of structural features needed for optimum irreversible inhibition. The mechanism of action of suicide inhibitors makes it possible to use them as probes into the active sites of P450 enzymes leading to better understanding of the structure-activity relationships involved in the P450-dependent reactions. Additionally, suicide inhibitors are useful tools in the studies of cancer development and treatment, as well as the metabolic activation of many environmental chemicals into toxicants. In this presentation, we will discuss the synthesis, purification, structural determination, and in vitro assays of four of our target compounds. |
|
Undergraduate Research Poster Session: Medicinal Chemistry
2:00 PM-4:00 PM, Monday, April 7, 2008 Morial Convention Center -- Hall A, Poster
Division of Chemical Education |