A promising class of ruthenium anticancer drugs are ruthenium(II) arene PTA complexes (RAPTA) which are water-soluble and highly selective for cancer cells. RAPTA-based compounds with ethacrynic acid (EA) ligands have been synthesized, so-called etharapta compounds, and shown to exhibit dual activity of glutathione transferase P1-1 (GST P1-1) inhibition and cancer cell cytotoxicity. The complex was shown to be a more effective GST P1-1 inhibitor than EA alone suggesting that the metal center also is involved in inhibition of the enzyme. Structures of GST P1-1 etharapta complexes derived from crystals of GSTP1-1 incubated with etharapta for varying incubation times reveal that the metal complex binds at the dimer interface first with the metal center bound through Cys-101 residues of opposing monomers and then over time the metal center is released from the protein whilst the EA ligands traverse to the active sites where they bind and inhibit the enzymatic activity. XANES studies demonstrate that that the ruthenium center is reduced from +IV to +II in the process. The intact compound is thought to bind at the dimer interface in a relatively symmetric manner. The compound is then cleaved and the EA moieties transverse to the substrate-binding site while the ruthenium center remains bound to the dimer interface via Cys-101 residues. At some point, the activated metal center is released leading to cell apoptosis. This observation has led to the suggestion that one mode of GST-based resistance might involve sequestering metallodrugs at the subunit interface. Taken together, these results suggest GST inhibitors that block both the dimer interface and active site may prove potent anticancer adjuvants in future drug discovery efforts.

Ang, W.H., Parker, L.J., De Luca, A., Juillerat-Jeanneret, L., Morton, C.J., Lo Bello, M., et al. (2009). Rational design of an organometallic glutathione transferase inhibitor. ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, 48(21), 3854-3857 [10.1002/anie.200900185].

Rational design of an organometallic glutathione transferase inhibitor

De Luca, A;LO BELLO, MARIO;
2009

Abstract

A promising class of ruthenium anticancer drugs are ruthenium(II) arene PTA complexes (RAPTA) which are water-soluble and highly selective for cancer cells. RAPTA-based compounds with ethacrynic acid (EA) ligands have been synthesized, so-called etharapta compounds, and shown to exhibit dual activity of glutathione transferase P1-1 (GST P1-1) inhibition and cancer cell cytotoxicity. The complex was shown to be a more effective GST P1-1 inhibitor than EA alone suggesting that the metal center also is involved in inhibition of the enzyme. Structures of GST P1-1 etharapta complexes derived from crystals of GSTP1-1 incubated with etharapta for varying incubation times reveal that the metal complex binds at the dimer interface first with the metal center bound through Cys-101 residues of opposing monomers and then over time the metal center is released from the protein whilst the EA ligands traverse to the active sites where they bind and inhibit the enzymatic activity. XANES studies demonstrate that that the ruthenium center is reduced from +IV to +II in the process. The intact compound is thought to bind at the dimer interface in a relatively symmetric manner. The compound is then cleaved and the EA moieties transverse to the substrate-binding site while the ruthenium center remains bound to the dimer interface via Cys-101 residues. At some point, the activated metal center is released leading to cell apoptosis. This observation has led to the suggestion that one mode of GST-based resistance might involve sequestering metallodrugs at the subunit interface. Taken together, these results suggest GST inhibitors that block both the dimer interface and active site may prove potent anticancer adjuvants in future drug discovery efforts.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
Con Impact Factor ISI
bioorganometallic chemistry; chemical biology; inhibitors; transferases
http://onlinelibrary.wiley.com/doi/10.1002/anie.200900185/pdf
Ang, W.H., Parker, L.J., De Luca, A., Juillerat-Jeanneret, L., Morton, C.J., Lo Bello, M., et al. (2009). Rational design of an organometallic glutathione transferase inhibitor. ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, 48(21), 3854-3857 [10.1002/anie.200900185].
Ang, W; Parker, L; De Luca, A; Juillerat Jeanneret, L; Morton, C; LO BELLO, M; Parker, M; Dyson, P
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/8067
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