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A Metalloproteinase Inhibitor from Doliocarpus verruculosus

In our natural products screening programme for the discovery of competitive inhibitors of the matrix metalloproteinases, stromelysin and collagenase, we have isolated an active compound, betulinic acid (1), from the plant Doliocarpus verruculosus. Betulinic acid inhibits stromelysin and collagenase with Ki values of 2.2 and 1.3 μM, respectively. The analogous C‐28 alcohol, betulin, was a less potent inhibitor of these proteases. We therefore postulate that the moiety of 1‐carboxyl‐3‐(2‐propenyl)‐cyclopentane in betulinic acid may mimic the hydroxamate‐containing residue of actinonin (3), a known stromelysin and collagenase inhibitor. Because a hydroxamate can serve as a bidentate ligand for the active site zinc, we synthesized the hydroxamate of 3‐acetoxy‐betulinic acid (2), hoping to observe an increase in potency relative to 1. However, the Ki values against stromelysin and collagenase were essentially equal to those of 1. These data suggest that the rigid cyclopentyl ring is probably restricting the tight binding as seen in the flexible peptidal hydroxamates, or the acid moiety is not interacting directly with the active site zinc of the metalloproteinases.