Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action |
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Authors: | Khouloud Dammak Marina Porchia Michele De Franco Mirella Zancato Houcine Naïli Valentina Gandin Cristina Marzano |
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Institution: | 1.Laboratoire Physico-Chimie de l’Etat Solide, Département de Chimie, Faculté des Sciences de Sfax, Université de Sfax, B.P. 1171, Sfax 3000, Tunisia; (K.D.); (H.N.);2.CNR-ICMATE, Corso Stati Uniti 4, 35127 Padova, Italy;3.Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy; (M.D.F.); (M.Z.); (C.M.) |
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Abstract: | A series of neutral mixed-ligand HB(pz)3]Ag(PR3) silver(I) complexes (PR3 = tertiary phosphine, HB(pz)3]− = tris(pyrazolyl)borate anion), and the corresponding homoleptic Ag(PR3)4]BF4 compounds have been synthesized and fully characterized. Silver compounds were screened for their antiproliferative activities against a wide panel of human cancer cells derived from solid tumors and endowed with different platinum drug sensitivity. Mixed-ligand complexes were generally more effective than the corresponding homoleptic derivatives, but the most active compounds were HB(pz)3]Ag(PPh3) (5) and Ag(PPh3)4]BF4 (10), both comprising the lipophilic PPh3 phosphine ligand. Detailed mechanistic studies revealed that both homoleptic and heteroleptic silver complexes strongly and selectively inhibit the selenoenzyme thioredoxin reductase both as isolated enzyme and in human ovarian cancer cells (half inhibition concentration values in the nanomolar range) causing the disruption of cellular thiol-redox homeostasis, and leading to apoptotic cell death. Moreover, for heteroleptic Ag(I) derivatives, an additional ability to damage nuclear DNA has been detected. These results confirm the importance of the type of silver ion coordinating ligands in affecting the biological behavior of the overall corresponding silver complexes, besides in terms of hydrophilic–lipophilic balance, also in terms of biological mechanism of action, such as interaction with DNA and/or thioredoxin reductase. |
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Keywords: | silver(I) complexes phosphine ligands cytotoxicity |
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