Aromatase inhibitors from Broussonetia papyrifera

Bioassay-guided fractionation of an ethyl acetate-soluble extract from the whole plants of Broussonetia papyrifera, using an in vitro aromatase inhibi tion assay, led to the isolation of five new active compounds, 5,7,2',4'-te trahydroxy-3-geranylflavone (1), isogemichalcone C (8), 3'-[gamma -hydroxym ethyl-(E)-gamma -methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'-O-coumarat e (9), demethylmoracin I (10), and (2S)-2',4'-dihydroxy-2 "-(1-hydroxy-1-me thylethyl)dihydrofuro[2,3-h]flavanone (11), and 10 known (12-21) compounds which were also found to be active. Of these compounds, the most potent wer e 9 (IC50 0.5 muM), 11 (IC50 0.1 muM), isolicoflavonol (12, IC50 0.1 muM), and (2S)-abyssinone II (13, IC50 0.4 muM). Additionally, six new compounds, 5,7,3',4'-tetrahydroxy-6-geranylflavonol (2), 5,7,3',4'-tetrahydroxy-3-met hoxy-6-geranylflavone (3), (2S)7,4'-dihydroxy-3'-prenylflavan (4), 1-(2,4-d ihydroxyphenyl)-3-(4-hydroxyphenyl)propane (5), 1-(2,4-dihydroxy-3-prenylph enyl)-3-(4-hydroxyphenyl)propane (6), and 1-(4-hydroxy-2-methoxyphenyl)-3-( 4-hydroxy-3-prenylphenyl)propane (7), were isolated and characterized, but proved to be inactive as aromatase inhibitors, as were an additional 21 kno wn compounds. The structures of the new compounds (1-11) were elucidated by spectroscopic methods. Structure-activity relationships in the aromatase a ssay were determined for the benzofurans, biphenylpropanoids, coumarins, an d various types of flavonoids (chalcones, flavans, flavanones, and flavones ) obtained among a total of 42 constituents of B. papyrifera.