Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 23, Pages 7847-7855Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900845t
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Funding
- University of Bari, the Consorzio Interuniversitario, di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB)
- Italian Ministero dell'Universita della Ricerca [PRIN 2005 032730]
- European Commission
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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 all 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.
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