Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase π

• Three ruthenium arene anticancer complexes inhibit human GSTπ.
• Inhibitory potencies of Ru complexes towards GSTπ are comparable to their cytotoxicity.
• Ru complexes bind to Cys15, Cys48, Met92 and/or Cys102 of GSTπ.
• Ru binding sites are either within the G-site or at the dimer interface of GSTπ.
• Ru binding induces irreversible oxidation of targeted cysteinyl residues.

The organometallic ruthenium(II) anticancer complexes [(η6-arene)Ru(en)Cl]+ (arene = p-cymene (1), biphenyl (2) or 9,10-dihydrophenanthrene (3); en = ethylenediamine), exhibit in vitro and in vivo anticancer activities. In the present work, we show that they inhibit human glutathione-S-transferase π (GSTπ) with IC50 values of 59.4 ± 1.3, 63.2 ± 0.4 and 37.2 ± 1.1 μM, respectively. Mass spectrometry revealed that complex 1 binds to the S-donors of Cys15, Cys48 within the G-site and Cys102 at the interface of the GSTπ dimer, while complex 2 binds to Cys48 and Met92 at the dimer interface and complex 3 to Cys15, Cys48 and Met92. Moreover, the binding of complex 1 to Cys15 and Cys102, complex 2 to Cys48 and complex 3 to Cys15 induces the irreversible oxidation of the coordinated thiolates to sulfenates. Molecular modeling studies indicate that the coordination of the {(arene)Ru(en)}2 + fragment to Cys48 blocks the hydrophilic G-site sterically, perhaps preventing substrate from proper positioning and accounting for the reduction in enzymatic activity of ruthenated GSTπ. The binding of the ruthenium arene complexes to Cys102 or Met92 disrupts the dimer interface which is an essential structural feature for the proper functioning of GSTπ, perhaps also contributing to the inhibition of GSTπ.

Organoruthenium anticancer complexes [(η6-arene)Ru(en)Cl]+ (arene = p-cymene, biphenyl or dihydrophenanthrene; en = ethylenediamine) bind to thiol and thioetherer sulfurs in the G-site and in the dimer interface of human GSTπ and subsequently induce oxidation of the thiolate ligands, showing different inhibitory potency towards GSTπ.Figure optionsDownload as PowerPoint slide