Flavonoids and other benzopyrone substances, having an appropriate hydroxylation profile, may inhibit the metalloenzymes leucine aminopeptidase (LAP), aminopeptidase M (AP-M), and carboxypeptidase A (CP-A). A structural feature that evidently favours the interaction between flavonoids and the three metalloenzymes is the 2,3-double bond conjugating the A and B rings and conferring a planar structure. This can be considered virtually indispensable for inhibition of the three metallopeptidases, though the hydroxylation profile required differed for each of the enzymes, and the interaction mechanism and behaviour also differed. The inhibitory effect of flavonoids on LAP was reversible, and to be effective the flavonoid had to have conjugated A and B rings and ortho-dihydroxylation on at least one of the aromatic rings. This same requirement was essential for inhibition by coumarins and was attributed to a catechol-like mechanism of interaction. The inhibitory effects on AP-M were due to inactivation of the enzyme, irreversibly altered by flavonoids with a 2,3-double bond and a minimum of one hydroxyl substituent on each of the aromatic rings. With CP-A, conjugation of the A and B rings enhanced the inhibitory effect of flavonoids, though it was not strictly required. The interaction between the polyphenolic substances tested and the two zinc aminopeptidases was not reversed by adding zinc to the reaction medium, indicating that the inhibition is not due to the coordination of the phenolic hydroxyl groups with the catalytical zinc of active site, though the presence of zinc affected the interaction behaviour differently according to each substance's hydroxylation profile.

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Extracts of the root of B. fruticosum L. showed in a biological screening hemolytical activity, hepatoprotective and phagocytosis stimulating effects, and a specific inhibitory activity of leucine aminopeptidase. Further monitoring of the fraction with antihepatotoxic activity led to the isolation of an hepatoprotective saikosaponin identified as buddlejasaponin IV and the new malonylbuddlejasaponin IV, determined as saikogenin F-3-O-[6-O-malonyl-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl (1-->3)]-beta-D-fucopyranoside. The structures were elucidated on the basis of the chemical and spectroscopic data.

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The inhibitory behavior of flavonoids against trypsin and leucine aminopeptidase followed sigmoidal curves similar to those of any dose-biological response relationship. Statistical analysis using several mathematical equations showed that the relationship may be expressed by a logistic equation, which yielded a high correlation between the experimental data and the predicted results, together with an objective criterion for estimating the IC50 value. Flavones and flavonols exhibited a strong inhibitory effect on trypsin; the presence of hydroxyl groups at positions C-5 and C-7 in ring A is necessary for inhibition of the enzyme, while the simultaneous presence of free hydroxyl groups at positions C-3' and C-4' enhances the inhibitory activity. Inhibition of leucine aminopeptidase by flavonoids does not require 5,7-hydroxylation, but dihydroxylation at C-3' and C-4' and a double bond at positions C-2, C-3 are essential for this activity.

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