New Organosulfur Anticarcinogenic Enzyme Inducers

Wake Forest University, Winston Salem NC

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): The project's long term goal is to produce nontoxic cancer chemopreventive agents. A comprehensive cancer treatment strategy will ultimately involve the use of small molecules for both the treatment and prevention of cancer. To date, much more progress has been made in identifying small molecule antitumor agents than small molecule cancer prevention agents. The proposed work helps to close this gap. Chemoprevention of cancer involves the use of chemical agents either to retard or to block the initiation of carcinogenesis. These agents affect the metabolism of xenobiotic procarcinogens by inducing the enzymes that detoxify potential carcinogens. Typically, phase 1 of xenobiotic metabolism involves oxidative processes, and phase 2, redox or conjugation chemistry. This project will search for chemical agents of low toxicity that elevate phase 2, but not phase 1 enzymes as a cancer prevention strategy. Aim 1. To prepare and completely characterize new oxathiolene oxides, dithiolene oxides and aminothiolene oxides, using quinone oxidoreductase (NQO1) inducing ability and three dimensional quantitative structure activity relationships (QSAR) with comparative molecular field analysis (CoMFA) as a guide for the synthesis of new compounds. Aim 2. To test the new compounds' abilities to induce the phase 2 enzyme NQO1 in Hepalclc cells and to measure their cytotoxicity in that cell line. Compounds that prove excellent NQO1 inducers of low toxicity will also be screened for GST, Ferritin H, and cytochrome P450 inducing activity. Aim 3. To observe the reaction between potent inducers and known nucleophilic thiols; to characterize the byproducts of their reaction; and to analyze cell lysates to determine total intracellular levels of inducing compounds and then" metabolites. Most phase 2 detoxification enzyme inducers are thought to work by reacting with nucleophilic thiols. Therefore, study of these reactions will illuminate which structural elements to include in the preparation of more potent enzyme inducers.