Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action

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.

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

“…The Δ Ψ was assayed using the Mito‐ID® Membrane Potential Kit according to the manufacturer's instructions (Enzo Life Sciences, Farmingdale, NY) as previously described. [59] Briefly, PSN‐1 cells (8×10 3 per well) were seeded in 96‐well plates; after 24 h, cells were washed with PBS and loaded with Mito‐ID detection reagent for 30 min at 37 °C in the dark. Afterwards, cells were incubated with increasing concentrations of tested complexes.…”

In vitro and in vivo Anti-leishmanial Potential of [Ag (PTA) 4 ]BF 4 and [Ag(HBPz 3 )(PPh 3 )] Silver Complexes

“…Ag2 was a very strong inhibitor of both the purified enzyme and cell extracts and exerted remarkable cytotoxic activity toward a large panel of cancer cell lines. Interestingly, Ag2, together with TrxR inhibition and reactive oxygen species (ROS) overproduction, led to apoptotic cell death and displayed a marked ability to damage deoxyribonucleic acid (DNA)This dual mechanism is related to the HB(pz) 3 ligand that interacts with DNA 5 .…”

“…Two metal complexes, [Ag (PTA) 4 ]BF 4 , [PTA = 1,3,5-triaza-7-prhophaadamantane] (Ag1) and [Ag(HBPz 3 )(PPh 3 )], [PPH 3 = triphenylphosphine and [HB(pz)3] = tris(pyrazol-1-yl)borate] (Ag2), were used. Chemical synthesis of the compounds 4 , 5 was performed using the Istituto di Chimica della Materia Condensata e di Tecnologie per l’Energia (ICMATE) and sent for biological study at the National Institute for Amazonian Research (INPA). This study was part of the Vaikutus Project Consortium (FP6-PEOPLE-IRES-2011-295262).…”

“…The assay against amastigote forms was performed using murine peritoneal macrophages and human monocytes, obtained as described for the cytotoxicity assay. The cells were incubated for 48 h in a 24 well-plate containing glass coverslips with the RPMI medium, and cell volume adjusted to 10 5 macrophages/monocyte/mL.…”

“…These reports show that metal-phosphine compounds present lower cytotoxicity and indicate that the nature of the ligand is related to the activity of the complex 4 . Some studies have compared the activity of phosphine homoleptic silver complexes to the activity of mixed ligand (phosphine and trispyrazolylborate) complexes against different cancer cell lines endowed with different sensitivities to platinum drugs 5 .…”