Coumarin, umbelliferone (7-hydroxycoumarin), scopoletin (7-hydroxy-6-methoxycoumarin), and limettin (5,7-dimethoxycoumarin), four naturally occurring plant constituents, were studied for their effects on 7,12-dimethylbenz(a)anthracene-induced neoplasia of the rat mammary gland. Coumarin was a moderately potent inhibitor, limettin was less effective, and scopoletin showed only marginal inhibitory activity. Umbelliferone did not inhibit. Coumarin and its three derivatives were also investigated for their effects on benzo(a)pyrene-induced neoplasia of the mouse forestomach. Coumarin inhibited, but the three derivatives did not. Coumaranone and phthalide, two related compounds, were inactive as were three substituted pyrones included in the study. Four five-membered ring lactones were also investigated. One of these, α-angelicalactone, inhibited benzo(a)pyrene-induced neoplasia of the mouse forestomach and was more potent in this regard than coumarin. The other three, γ-valerolactone, l-ascorbic acid, and isocitric lactone, were inactive. Three structure-activity relationships are evident from the present study. With the coumarins, increased polarity of substituents results in decreasing activity as inhibitors. For both the coumarins and the five-membered ring lactones studied, protic groups, such as hydroxy and carboxy groups, abolish the capacity to inhibit. While unsaturation in the lactone ring does not always lead to inhibitory activity, the presence of at least one double bond is essential. Thus, the property of inhibition of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene is not a general characteristic of all coumarins and alicyclic lactones but is restricted to those with specific structural features.

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Supported by USPHS Grants CA-14146 and CA-09599 from the National Cancer Institute.

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