Mechanistic Insight into the Inhibition of Matrix Metalloproteinases by Platinum Substrates

被引：26

作者：

Arnesano, Fabio ^{[2
]}

Boccarelli, Angela ^{[1
]}

Cornacchia, Daniele ^{[2
]}

Nushi, Fiorentin ^{[2
]}

Sasanelli, Rossella ^{[1
]}

Coluccia, Mauro ^{[1
]}

Natile, Giovanni ^{[2
]}

机构：

[1] Univ Bari A Moro, Dipartimento Sci Biomed & Oncol Umana, I-70124 Bari, Italy

[2] Univ Bari A Moro, Dipartimento Farmacochim, I-70125 Bari, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 23期

关键词：

BIOLOGICAL-PROPERTIES; CATALYTIC DOMAIN; DNA INTERACTIONS; NITROGEN DONORS; COMPLEXES; CANCER; CISPLATIN; BINDING; DRUG; DIETHYL;

D O I：

10.1021/jm900845t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7847 / 7855

页数：9

共 53 条

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