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A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential in vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake. On the other hand, mechanistic studies in cancer cells revealed their ability to strongly and selectively inhibit the redox-regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin, a well-known TrxR inhibitor, without affecting other redox enzymes such as Glutathione Reductase (GR). The inhibition of TrxR in H157 human cancer cells caused, in turn, the disruption of cellular thiol-redox homeostasis and of mitochondria pathophysiology, ultimately leading to cancer cell death through apoptosis., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.

A series of neutral mixed-ligand [HB(pz) 3 ]Ag(PR 3 ) silver(I) complexes (PR 3 = tertiary phosphine, [HB(pz) 3 ] - = tris(pyrazolyl)borate anion), and the corresponding homoleptic [Ag(PR 3 ) 4 ]BF 4 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(PPh 3 ) ( 5 ) and [Ag(PPh 3 ) 4 ]BF 4 ( 10 ), both comprising the lipophilic PPh 3 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.

Phosphonium salt (p-OCH 3 -Ph) 2 P(CH 2 OH) 2 Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH 3 -Ph) 2 CH 2 OH (MPOH) and P(p-OCH 3 -Ph) 2 CH 2 SarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV-Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry., Competing Interests: Declaration of competing interest None of the authors of the above manuscript has declared any conflict of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004-2016, and critically analyses biological data (mainly IC 50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

[Cu(thp) 4 ][PF 6 ] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.

The phosphane Cu(I) complex [Cu(thp) 4 ][PF 6 ], 1 (thp=tris(hydroxymethyl)phosphane) shows notable in vitro antitumour activity against a wide range of solid tumours. Uptake experiments performed in 1-treated colon cancer cells by atomic absorption spectrometry, reveal that the antiproliferative activity is consistent with the intracellular copper content. The solution chemistry of this agent, investigated by means of X-ray Absorption Spectroscopy and spectrophotometric titrations in aqueous media, indicates that 1 is labile giving coordinative unsaturated [Cu(thp) n ] + species (n=3 and 2) at micromolar concentrations. [Cu(thp) n ] + are reactive species that yield the mixed-ligand complex [Cu(thp) 2 (BCS)] - (BCS: bathocuproinedisulphonate (2-) ) upon interaction with N,N-diimine. Analogously, [Cu(thp) n ] + interact with the methionine-rich peptide sequence (Ac-MMMMPMTFK-NH 2 ; Pep1), relevant in the recruiting of physiological copper, giving [Cu(thp)(Pep1)] + and [Cu(Pep1)] + species. The formation of these adducts was assessed by electrospray mass spectrometry in the positive ion mode and validated by density functional theory investigations. The possibility to trans-chelate Cu(I) from pure inorganic [Cu(thp) n ] + assemblies into more physiological adducts represents a pathway that complex 1 might follow during the internalization process into cancer cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Homoleptic, tetrahedral Cu(i) complexes of the type [Cu(P)4]BF4 (1-3), where P are the phosphine ligands, 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) and 2-thia-1,3,5-triaza-phosphoaadamantane-2,2-dioxide (PTA-SO2), have been prepared. Novel complexes [Cu(DAPTA)4]BF42 and [Cu(PTA-SO2)4]BF43 have been fully characterized by means of spectroscopic methods, corroborated by XAS-EXAFS analysis of 2. In vitro cell culture experiments revealed a significant antiproliferative activity for Cu(i) compounds against several human cancer cell lines derived from solid tumors with preferential cell growth inhibition towards tumour compared to non-malignant cells. In vitro monitoring of migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) showed an anti-angiogenic effect of copper(i) complexes at sub-cytotoxic concentrations. In vivo studies on the antitumor efficacy and ability to inhibit angiogenesis confirmed the dual cytotoxic and anti-angiogenic properties of Cu(i) derivatives.

Rationale: The cytotoxic activity of the copper(I) complex [Cu(thp)4][PF6] (CP) (thp = tris(hydroxymethyl) phosphine) is correlated with its high accumulation in cancer cells. Human copper transporter 1 (hCtr1) has been described as the main trans-membrane protein involved in cellular trafficking of physiological copper. Methionine-rich peptide sequences incorporated in the extracellular domain of hCtr1 play a key role in the cellular internalization of copper. We wish to investigate the interaction of CP with model peptides that mimic the extracellular domain of hCtr1., Methods: The interaction of CP with methionine-rich and methionine-free model peptides has been investigated by electrospray ionization mass spectrometry and the interaction products have been characterized by multiple collisional experiments, using an ion trap mass instrument., Results: The interaction of CP with selected methionine-rich model peptides, Ac-MMMMPMTFK-NH2 (P1) and Ac-MGMSYMDSK-NH2 (P2), shows that the native copper complex, after sequential loss of phosphines, induces the formation of [Cu(P1)(thp)](+) and [Cu(P1/P2)](+) adducts reasonably by inclusion of the Cu(I) ion in the peptide framework. Collisionally induced fragmentations (MS(n)) of [Cu(P1/P2)](+) give evidence that the metal is coordinated by the thioether-S of two adjacent methionine residues. Interaction of the same peptides with the isostructural complex [Ag(thp)4](+) or AgNO3 yields similar experimental evidence, leading to [Ag(P1/P2)](+)., Conclusions: Methionine sequences incorporated in model peptides are crucial for the recruitment of copper from CP. Such a metal-peptide interaction does not take place when methionine-free Ac-NleGNleSYNleDSK-NH2 (P3) is utilized. A mechanism for tumor cell internalization of CP involving: (i) chemically driven sequential loss of phosphines from the native tetrahedral complex, followed by (ii) transfer of Cu(I) to the methionine-rich sequences typical of the hCtr1 transporter, is proposed., (Copyright © 2014 John Wiley & Sons, Ltd.)

Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.

Ligand-exchange reactions of copper(I) precursors ([Cu(CH(3)CN)(4)]BF(4), CuCl) with a panel of bis(azolyl)borates or poly(pyrazolyl)methanes and a tertiary monodentate phosphine (PTA = 1,3,5-triaza-7-phosphaadamantane, PCN = tris(cyanoethyl)phosphine) produced two series of heteroleptic, either '2 + 1 + 1'- or '3 + 1'-type complexes, which have been characterized by elemental analysis, FT-IR, ESI-MS and multinuclear (31)P and (1)H NMR. '2 + 1 + 1'-type complexes include a N,N-bidentate chelate and two monodentate phosphines (1-8) and '3 + 1'-type complexes comprise a N,N,O- or N,N,N-tridentate chelate and one monodentate phosphine (9-12). All these complexes adopt a four-coordinate, tetrahedral geometry. '3 + 1' complexes show better red-ox stability and a greater tendency to retain the native '3 + 1' mixed-ligand structure. Conversely, '2 + 1 + 1' complexes exhibit increased propensity to dissociation as shown by ESI-MS measurements and X-ray structure determination at low temperature (150 K) of the polymeric complex {[H(2)B(tz(NO2))(2)]Cu[PCN]}(n)6b. In this complex, either the bis(triazolyl)borate and the PCN ligands act as bidentate, with PCN being also the μ(2)-bridiging linker between adjacent monomers. Compound 6b is the first reported example of a polymeric PCN compound with a tetra-coordinate metal centre. Cytotoxic activity of all compounds has been evaluated by MTT test against a panel of several human tumor cell lines including examples of breast (MCF-7), colon (HCT-15 and LoVo), lung (A549), cervix (A431) and ovarian (2008 and its cisplatin resistant variant, C13*) carcinoma, melanoma (A375) and promyelocytic leukemia (HL60). Copper complexes generally show in vitro antitumour activity comparable to that of cisplatin. In particular, neutral '3 + 1'-type complexes 9 and 10, show IC(50) values appreciably lower than those exhibited by the reference metallodrug., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Over the last few years a lot of research has been done to develop novel metal-based anti-cancer drugs, with the aim of improving clinical effectiveness, reducing general toxicity, and broadening the spectrum of activity. The search for novel metal-based antitumour drugs other than Pt agents includes the investigation of the cytotoxic activity of copper(I/II) compounds. Among these copper agents, particular attention has been recently devoted to hydrophilic copper(I) species bearing phosphines because of their noteworthy stability in aqueous media together with their remarkable in vitro cytotoxic activity. In this study we report on the synthesis, characterization and cytotoxic assays of a series of Cu(I) complexes with tris(2-cyanoethyl)phosphine (PCN) and bis(2-cyanoethyl)phenylphosphine (PCNPh). They were prepared by reaction of [Cu(CH(3)CN)(4)](+) or CuX(2) precursors with the pertinent phosphine in acetone or acetonitrile solutions producing compounds of the following formulation: [Cu(PCN)(2)](+) 2, [Cu(CH(3)CN)(PCN)](+) 3, [Cu(X)(PCN)] (X = Cl, 4; Br, 5), and [Cu(PCNPh)(2)](+) 6. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumour cell lines. Cellular copper uptake rate was correlated with cell growth inhibition in 2008 human ovarian cancer cells. Moreover, copper(I)-PCN complexes were evaluated for their ability to alter the most relevant mitochondrial pathophysiological parameters such as respiration, coupling, ATP-synthetase activity and membrane potential in isolated mitochondria. These data were correlated with changes in mitochondrial membrane potential and production of reactive oxygen species (ROS) in drug-treated 2008 cells.

Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.

New copper(I) complexes containing the water soluble N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA) phosphine have been synthesized by ligand-exchange reactions starting from [Cu(CH(3)CN)(4)][BF(4)] or [Cu(CH(3)CN)(4)][PF(6)] precursors and (mPTA)X (X=CF(3)SO(3), I). Depending on the ligand counter ion, the hydrophilic [Cu(mPTA)(4)][(CF(3)SO(3))(4)(BF(4))] 3a and [Cu(mPTA)(4)][(CF(3)SO(3))(4)(PF(6))] 3c complexes or the iodine-coordinated [Cu(mPTA)(3)I]I(3)4 species were obtained respectively and fully characterized by spectroscopic methods. Single crystal structural characterization was undertaken for [Cu(mPTA)(3)I]I(3).H(2)O, 4.H(2)O, and [Cu(mPTA)(4)][(CF(3)SO(3))(2)(BF(4))(3)] .0.25H(2)O, 3b.0.25H(2)O, the latter obtained by crystallization of [Cu(mPTA)(4)][(CF(3)SO(3))(4)(BF(4))] 3a. The cytotoxicity of analogous tetrahedral homoleptic Cu(I) derivatives [Cu(PTA)(4)](BF(4)) 1, [Cu(PTAH)(4)][Cl(4)(BF(4))] 2, [Cu(mPTA)(4)][(CF(3)SO(3))(4)(BF(4))] 3a and [Cu(mPTA)(4)][(CF(3)SO(3))(4)(PF(6))] 3c was evaluated against a panel of several human tumor cell lines. All the complexes showed in vitro antitumor activity comparable to that of the reference metallodrug cisplatin. Tests performed on cisplatin sensitive and resistant cell lines showed that against human ovarian 2008/C13(*) cell line pair, the resistance factor of copper derivatives was roughly 7-fold lower than that of cisplatin, whereas against human cervix cancer A431/A431-Pt cell line pair it was about 2.5-fold lower. These results, confirming the circumvention of cisplatin resistance, support the hypothesis that phosphine copper(I) complexes follow different cytotoxic mechanisms than do platinum drugs.

Monocationic hydrophilic complexes [Cu(thp)4](+) 3 and [Cu(bhpe)2](+) 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tumor cell lines. Complex 3 has been shown to be about 1 order of magnitude more cytotoxic than cisplatin. Chemosensitivity tests performed on cisplatin and multidrug resistance phenotypes suggested that complex 3 acts via a different mechanism of action than the reference drug. Different short-term proliferation assays suggested that lysosomal damage is an early cellular event associated with complex 3 cytotoxicity, probably mediated by an increased production of reactive oxygen species. Cytological stains and flow cytometric analyses indicated that the phosphine copper(I) complex is able to inhibit the growth of tumor cells via G2/M cell cycle arrest and paraptosis accompanied with the loss of mitochondrial transmembrane potential.