Platinum complexes can inhibit matrix metalloproteinase activity: platinum-diethyl[(methylsulfinyl)methyl]phosphonate complexes as inhibitors of matrix metalloproteinases 2, 3, 9, and 12.
Platinum complexes able to inhibit matrix metalloproteinases (MMPs) through a noncompetitive mechanism are reported for the first time in this study. [PtCl2(SMP)] and [Pt(dimethylmalonato)(SMP)], characterized by the bisphosphonate-analogue ligand diethyl[(methylsulfinyl)methyl]phosphonate (SMP), are slight inhibitors of MMP-2 (IC50 = 258 +/- 38 and 123 +/- 14 microM, respectively) but markedly inhibit MMP-9 (IC50 = 35.5 +/- 6 and 17 +/- 4 microM), MMP-3 (IC50 = 5.3 +/- 2.9 and 4.4 +/- 2.2 microM), and MMP-12 (IC50 = 10.8 +/- 3 and 6.2 +/- 1.8 microM). In contrast, cisplatin, carboplatin, and the SMP ligand are inactive, and the bisphosphonate clodronate shows a broad-spectrum inhibitory activity in the high micromolar range (mean IC50 > 200 microM). These results, along with mechanistic investigations (DNA interaction and tumor cell growth inhibition), demonstrate that ligand modifications of platinum compounds can be exploited to target also biological substrates distinct from DNA.
Sasanelli
Rossella
R
Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Bari, 70124 Bari, Italy.
Boccarelli
Angelina
A
Giordano
Domenico
D
Laforgia
Mariarita
M
Arnesano
Fabio
F
Natile
Giovanni
G
Cardellicchio
Cosimo
C
Capozzi
Maria A M
MA
Coluccia
Mauro
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C523405:(diethyl((methylsulfinyl)methyl)phosphonate)(dimethylmalonato)platinum(II); D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009944:Organoplatinum Compounds; C523404:dichloro(diethyl((methylsulfinyl)methyl)phosphonate)platinum(II); D004247:DNA; D002945:Cisplatin