NOVEL ANTIMUTAGENIC COMPOUNDS

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We have undertaken a study of novel naturally occuring antimutagenic agents. Antimutagens are individual chemical compounds that decrease the numbers of spontaneous or injury- induced mutations in intact cell populations. This proposal is to use short-term tests to screen for; isolate by use of bioassay directed methodology; determine chemical structure by spectroscopic and wet chemical methodology of; determine structure-activity relations by systematic syntheses and chemical transformations of; explore the biological properties of; and explore the molecular mechanisms of action of novel antimutagens of natural origin. The long-term objectives are to make potential chemopreventive agents against genetic damage and, perhaps, cancer. Using a bioassay specially developed for the purpose, Glycyrrhiza glabra, a well known plant used by humans since ancient times for its flavoring and medicinal properties, was shown to be reproducably active. The activity was present in the phenolic fractions and, after chromatographic resolution, the flavanoids glabrene and, to a lesser extent, glabridin and glabrol, were found to be the active constituents. The bioassay which produced these successful results in this trial study is based upon the well known Ames short-term Salmonella mutagenicity assay but modified through the use of an alkylating agent (ethyl methanesulfonate) to induce mutations. Based upon this success, it is proposed to use the screen, with the inclusion of other mutagenic treatments as well, to screen for additional examples of natural antimutagenic substances in related plants and to identify the active constituents. A program of chemical modification accompanied by biotesting is proposed so as to explore in a systematic way the relationship between structure and activity in these novel series. In addition to the insights into the mutagenic phenomenon and the other biological areas where mutagenicity is believed to play an important role (ageing, heredity, carcinogenicity, environmental concerns) these compounds may have some potential in preventive human medicine.