Mechanistic insight into the inhibition of matrix metalloproteinases by platinum substrates.
Platinum compounds are among the most used DNA-damaging anticancer drugs, however they can also be tailored to target biological substrates different from DNA, for instance enzymes involved in cancer progression. We recently reported that some platinum complexes with three labile ligands inhibit matrix metalloproteinase activity in a selective way. We have now extended the investigation to a series of platinum complexes having three chlorido or one chlorido and a dimethylmalonato leaving ligands. All compounds are strong inhibitors of MMP-3 by a noncompetitive mechanism, while platinum drugs in clinical use are not. Structural investigations reveal that the platinum substrate only loses two labile ligands, which are replaced by an imidazole nitrogen of His224 and a hydroxyl group, while it retains one chlorido ligand. A chlorido and a hydroxyl group are also present in the zinc complex inhibitor of carboxypeptidase A, whose active site has strong analogies with that of MMP-3.
Arnesano
Fabio
F
Dipartimento Farmaco-Chimico, University of Bari A Moro, Via Edoardo Orabona 4, 70125 Bari, Italy.
Boccarelli
Angela
A
Cornacchia
Daniele
D
Nushi
Fiorentin
F
Sasanelli
Rossella
R
Coluccia
Mauro
M
Natile
Giovanni
G
D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013057:Spectrum Analysis; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009944:Organoplatinum Compounds; D019278:Matrix Metalloproteinase 3