The structure-activity relationship of flavonoids as inhibitors of xanthine oxidase and as scavengers of the superoxide radical, produced by the action of the enzyme xanthine oxidase, was investigated. The hydroxyl groups at C-5 and C-7 and the double bond between C-2 and C-3 were essential for a high inhibitory activity on xanthine oxidase. Flavones showed slightly higher inhibitory activity than flavonols. All flavonoid derivatives except isorhamnetin (30) were less active than the original compounds. For a high superoxide scavenging activity on the other hand, a hydroxyl group at C-3' in ring B and at C-3 were essential. According to their effect on xanthine oxidase and as superoxide scavengers, the flavonoids could be classified into six groups: superoxide scavengers without inhibitory activity on xanthine oxidase (category A), xanthine oxidase inhibitors without any additional superoxide scavenging activity (category B), xanthine oxidase inhibitors with an additional superoxide scavenging activity (category C), xanthine oxidase inhibitors with an additional pro-oxidant effect on the production of superoxide (category D), flavonoids with a marginal effect on xanthine oxidase but with a prooxidant effect on the production of superoxide (category E), and finally, flavonoids with no effect on xanthine oxidase or superoxide (category F).

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Many compounds of plant origin have been identified that inhibit different stages in the replication cycle of human immunodeficiency virus (HIV): 1) virus adsorption: chromone alkaloids (schumannificine), isoquinoline alkaloids (michellamines), sulphated polysaccharides and polyphenolics, flavonoids, coumarins (glycocoumarin, licopyranocoumarin) phenolics (caffeic acid derivatives, galloyl acid derivatives, catechinic acid derivatives), tannins and triterpenes (glycyrrhizin and analogues, soyasaponin and analogues); 2) virus-cell fusion: lectins (mannose-and N-acetylglucosamine-specific) and triterpenes (betulinic acid and analogues); 3) reverse transcription: alkaloids (benzophenanthridines, protoberberines, isoquinolines, quinolines), coumarins (calanolides and analogues), flavonoids, phloroglucinols, lactones (protolichesterinic acid), tannins, indoids (fulvoplumierin) and triterpenes; 4) integration: coumarins (3-substituted-4-hydroxycoumarins), depsidones, O-caffeoyl derivatives, lignans (anctigenin and analogues) and phenolics (curcumin); 5) translation: single chain ribosome inactivating proteins (SCRIP's); 6) proteolytic cleavage (protease inhibition):saponins (ursolic and maslinic acids), xanthones (mangostin and analogues) and coumarins; 7) glycosylation: alkaloids including indolizidines (castanospermine and analogues), piperidines (1-deoxynojirimicin and analogues) and pyrrolizidines (australine and analogues); 8) assembly/release: naphthodianthrones (hypericin and pseudohypericin), photosensitisers (terthiophenes and furoisocoumarins) and phospholipids. The target of action of several anti-HIV substances including alkaloids (O-demethyl-buchenavianine, papaverine), polysaccharides (acemannan), lignans (intheriotherins, schisantherin), phenolics (gossypol, lignins, catechol dimers such as peltatols, naphthoquinones such as conocurvone) and saponins (celasdin B, Gleditsia and Gymnocladus saponins), has not been elucidated or does not fit in the proposed scheme. Only a very few of these plant-derived anti-HIV products have been used in a limited number of patients suffering from AIDS viz. glycyrrhizin, papaverine, trichosanthin, castanospermine, N-butyl-1 -deoxynojirirnicin and acemannan.

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A series of 19 related dihydrobenzofuran lignans and benzofurans was obtained by a biomimetic reaction sequence involving oxidative dimerization of p-coumaric, caffeic, or ferulic acid methyl esters, followed by derivatization reactions. All compounds were evaluated for potential anticancer activity in an in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Leukemia and breast cancer cell lines were relatively more sensitive to these agents than were the other cell lines. Compounds 2c and 2d, but especially 2b (methyl (E)-3-¿2-(3, 4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2, 3-dihydro-1-benzofuran-5-ylprop-2-enoate), the dimerization product of caffeic acid methyl ester, containing a 3',4'-dihydroxyphenyl moiety and a hydroxyl group in position 7 of the dihydrobenzofuran ring, showed promising activity. The average GI(50) value (the molar drug concentration required for 50% growth inhibition) of 2b was 0.3 microM. Against three breast cancer cell lines, 2b had a GI(50) value of <10 nM. Methylation, reduction of the double bond of the C(3)-side chain, reduction of the methoxycarbonyl functionalities to primary alcohols, or oxidation of the dihydrobenzofuran ring to a benzofuran system resulted in a decrease or loss of cytotoxic activity. Compound 2b inhibited mitosis at micromolar concentrations in cell culture through a relatively weak interaction at the colchicine binding site of tubulin. In vitro it inhibited tubulin polymerization by 50% at a concentration of 13 +/- 1 microM. The 2R, 3R-enantiomer of 2b was twice as active as the racemic mixture, while the 2S,3S-enantiomer had minimal activity as an inhibitor of tubulin polymerization. These dihydrobenzofuran lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new group of antimitotic and potential antitumor agents that inhibit tubulin polymerization.