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 inhibition assay, led to the isolation of five new active compounds, 5,7,2′,4′-tetrahydroxy-3-geranylflavone (1), isogemichalcone C (8), 3′-[y -hydroxymethyl-(E)-y-methylallyl]-2,4,2′,4′-tetrahydroxychalcone 11′-O-coumarate (9), demethylmoracin I (10), and (2S)-2′,4′-dihydroxy-2"-(1-hydroxy-1-methylethyl) 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 were 9 (IC₅₀ 0.5 μM), 11 (IC₅₀ 0.1 μM), isolicoflavonol (12,IC₅₀ 0.1 μM), and (2S)-abyssinone II (13, IC₅₀ 0.4 νM). Additionally, six new compounds, 5,7,3′,4′-tetrahydroxy-6-geranylflavone (2), 5,7,3′,4′-tetrahydroxy-3-methoxy-6-geranylflavone (3), (2S)-7,4′-dihydroxy-3′-prenylflavan (4), 1 -(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)propane (5), 1 -(2,4-dihydroxy-3-prenylphenyl)-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 known compounds. The structures of the new compounds (1-11) were elucidated by spectroscopic methods. Structure-activity relationships in the aromatase assay were determined for the benzofurans, biphenylpropanoids, coumarins, and various types of flavonoids (chalcones, flavans, flavanones, and flavones) obtained among a total of 42 constituents of B. papyrifera.