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.
Highlights
In the last decades, in the search of metal-based antitumor drugs alternative to platinum-based chemotherapeutic agents, many metal complexes have been taken into consideration, and, among them, group 11 metal derivatives have shown encouraging perspectives
In the course of our studies on the cytotoxic activity of hydrophilic monocationic copper(I) compounds of the type [Cu(PR3)4]+ (PR3 = tris(hydroxymethyl)phosphine, thp; 1,3,5-triaza-7-phosphadamantane, PTA; tris(hydroxypropyl)phosphine, thpp), aiming at establishing structure–activity relationships, we have investigated the efficacy of other coinage metal complexes, such as [Ag(PR3 )4 ](PF6 ) and
We previously investigated the ability of the homoleptic phosphino complex [Ag(PTA)4 ]PF6 to inhibit thioredoxin reductase (TrxR) in vitro
Summary
In the search of metal-based antitumor drugs alternative to platinum-based chemotherapeutic agents, many metal complexes have been taken into consideration, and, among them, group 11 metal derivatives have shown encouraging perspectives. Whereas a plethora of different classes of copper(I,II) and gold(I,III) complexes have been investigated in the effort of circumventing platinum drug disadvantages [1,2], so far the antitumor activity of silver complexes has been less widely explored. Molecules 2020, 25, 5484 silver compounds, such as silver salts, complexes and nanoparticles, are well known and extensively exploited in a large number of medical applications [3]. Silver complexes have been shown to possess anticancer activity. Some excellent reviews summarize advances in this field [4,5,6]
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