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A Metalloproteinase Inhibitor from Doliocarpus verruculosus
Author(s) -
Sun Hao H.,
Kaplita Paul V.,
Houck David R.,
Stawicki Mary B.,
McGarry Ruthann,
Wahl Robert C.,
Gillum Amanda M.,
Cooper Raymond
Publication year - 1996
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/(sici)1099-1573(199605)10:3<194::aid-ptr703>3.0.co;2-y
Subject(s) - betulinic acid , moiety , stereochemistry , chemistry , collagenase , hydroxamic acid , active site , matrix metalloproteinase , residue (chemistry) , matrix metalloproteinase inhibitor , biochemistry , enzyme , biology , genetics
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 K i values of 2.2 and 1.3 μ M , 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 K i 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.