The goal of this project is to gain a better understanding of the chemical, biochemical and cell biological mechanisms of hydroxy-9-anthrones (anthrones) with anti-psoriatic and tumor-promoting activities. Knowledge of these mechanisms will be useful for the design of more effective antipsoriatic agents and will provide insights into fundamental mechanisms of cell growth and inflammatory processes, which may also help in the understanding of other diseases such as cancer and arthritis. A series of anthrones have been synthesized and the radicals formed by them were characterized. The ability of anthrones to generate each class of radical was compared to their ability to inhibit keratinoctye proliferation in vitr A good correlation between the formation of a specific secondary radical and inhibition of cell proliferation was found. The mechanism of secondary radical formation and its relationship to chemical structure were studied. Formation of the secondary radical was catalyzed by oxidative enzymes such as horseradish peroxidase. Evidence indicates a meso- naphthodianthrone-like structure or intermediate. Studies utilizing a radioactively-labeled anthrone in order to track its oxidation products are in progress. These studies are intended to reveal the identity of cellular molecules with which the anthrone oxidation products are interacting, the chemical nature of the interactions, and to aid in the determination of the chemical structure of the final oxidation products and any possible covalent adducts formed with cellular molecules. Additionally, studies are underway to determine how interaction of anthrone oxidation products with cellular molecules leads to specific cellular responces. Treatment of keratinocytes with secondary-radical-forming anthrones has been shown to result in increased production of prostaglandin E2. This compound is an important mediator of cell proliferation and inflammation, and is an important component of cellular signaling pathways. Biochemical and molecular biology approaches are being developed in order to determine the origin of the effect.
