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Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.

In the presence of the Vilsmeier-Haack reagent, suitably activated styrene analogs afford previously unreported 2-substituted 3-dimethylamino-5,6-methylenedioxyindenes. The indenes were hydrolyzed to the corresponding indanones. This constitutes a new synthesis of indanones. Cinnamaldehydes are also obtained under Vilsmeier-Haack conditions. Reaction conditions and electronic and other structural requirements which govern the formation of cinnamaldehydes and aminoindenes are discussed. Selected cinnamaldehydes were shown to have the E configuration by X-ray crystallography. Aminoindenes result from cyclization of Vilsmeier-Haack intermediates (4) having the Z configuration while aldehydes result from Vilsmeier-Haack intermediates (4) having the E configuration.