Prev. Article Next Article Table of Contents

Article

Platinum Complexes Can Inhibit Matrix Metalloproteinase Activity: Platinum−Diethyl[(methylsulfinyl)methyl]phosphonate Complexes as Inhibitors of Matrix Metalloproteinases 2, 3, 9, and 12

Supporting Info

Rossella Sasanelli,^† Angelina Boccarelli,^† Domenico Giordano,^† Mariarita Laforgia,^‡^§ Fabio Arnesano,^‡ Giovanni Natile,^‡ Cosimo Cardellicchio, Maria A. M. Capozzi, and Mauro Coluccia*^†

Dipartimento di Scienze Biomediche e Oncologia Umana, Universit di Bari, 70124 Bari, Italy, Dipartimento Farmaco-Chimico, Universit di Bari, 70125 Bari, Italy, Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (C.I.R.C.M.S.B.), 70126 Bari, Italy, Consiglio Nazionale delle Ricerche, Istituto di Chimica dei Composti Organometallici (ICCOM), Sezione di Bari, 70125 Bari, Italy, and Dipartimento di scienze Agro-Ambientali, Chimica e Difesa Vegetale, Facolt di Agraria, Universit di Foggia, 71100 Foggia, Italy

J. Med. Chem., 2007, 50 (15), pp 3434–3441

DOI: 10.1021/jm061435l

Publication Date (Web): June 21, 2007

†

Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Bari.

‡

Dipartimento Farmaco-Chimico, Università di Bari.

C.I.R.C.M.S.B.

ICCOM.

Università di Foggia.

Corresponding author. Phone: +390805478412. Fax: +390805478524. E-mail: mauro.coluccia@dimo.uniba.it.

Abstract

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 μM, respectively) but markedly inhibit MMP-9 (IC₅₀ = 35.5 ± 6 and 17 ± 4 μM), MMP-3 (IC₅₀ = 5.3 ± 2.9 and 4.4 ± 2.2 μM), and MMP-12 (IC₅₀ = 10.8 ± 3 and 6.2 ± 1.8 μM). 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 μM). 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.

View: Full Text HTML | Hi-Res PDF