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Herein, we present a comprehensive review focusing on synthetic strategies, detailed structural analysis, and anticancer activity investigations of complexes following the general formula [L n M(μ-diphosphine)M'L m ] where M = group 8 metal; M' = any transition metal; μ-diphosphine = bridging ligand; L n and L m  = ligand spheres). Both homo- and heteromultimetallic complexes will be discussed in detail. We review in vitro, in vivo and in silico anticancer activity investigations, in an attempt to draw comparisons between the various complexes and derive structure-activity relationships (SAR). This review solely focuses on complexes falling under the general formula stated above that have been studied for their anticancer activities, other complexes falling into that scheme but which have not undergone anticancer testing are not included in this review. We compare the anticancer activities of these complexes to their mononuclear counterparts, and a positive control (cisplatin) when possible and present a summary of all existing data to date and attempt to draw some conclusions on the future development of these complexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series ( FEACYP ) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg -1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.

The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)-phosphine-mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF 6 [(1), HL1 = 2-mercapto-pyridine and (2), HL2 = 2-mercapto-pyrimidine, bipy = 2,2'-bipyridine, dppen = cis -1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [ 1 H, 31 P( 1 H), and 13 C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between n -octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log  P values. Also, their stability was confirmed over 48 h in different media ( i.e. , DMSO, PBS and cell culture medium) via HPLC, UV-Vis and 31 P{ 1 H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer.

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu 3 P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu 3 P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential., (© 2024 Wiley-VCH GmbH.)

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC 50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI( p -CH 3 -Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh 3 ) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES - OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

New mono- and di-nuclear thio-purine and thio-purine nucleoside gold(I) complexes were synthesized, characterized, and evaluated in vitro for biological activities in comparison to related known purine complexes. By combining known anti-tumoral thio-purines with R 3 PAu moieties as present in auranofin, complexes with enhanced effects and selectivities were obtained, which not only act as cytostatics, but also disrupt tumor-specific processes. Their IC 50 values in cytotoxicity test with tumor cell lines ranged from three-digit nanomolar to single-digit micromolar, revealing a tentative structure-activity relationship (SAR). Both the residues R 2 of the phosphane ligand and R 1 at C2 of the pyrimidine ring had a significant impact on the cytotoxicity. In most cases, the introduction of a ribo-furanosyl group at N9 of the purine led to a distinctly more cytotoxic complex. Most complexes were more active against multi-drug-resistant tumor cells or such lacking functional p53 when compared to the respective untreated wild type cell lines. Some nucleoside complexes displayed an interesting dose-dependent dual mode of action regarding cell cycle arrest and DNA repair mechanism. Some phosphane(purine-6-thiolato)gold (I) complexes had a stronger inhibitory effect on the thioredoxin reductase (TrxR) and on the reactive oxygen species (ROS) generation in cancer cells than is typical of other gold complexes. They also led to DNA fragmentation and showed anti-angiogenic effects. Their stability under test conditions was demonstrated by 77 Se NMR monitoring of an exemplary selenopurine complex., (© 2022. The Author(s).)

Metal phosphides have been proved to be potential theranostic agents of tumors. However, the limitations of single-modal imaging or the treatment effect of such materials need to be further improved. Here, we successfully prepared polyvinylpyrrolidone-modified bimetallic nickel cobalt phosphide (NiCoP/PVP) nanoparticles as a theranostic agent of tumors. Owing to the different types of magnetic properties of Ni and Co components, T 1 - and T 2 -weighted magnetic resonance imaging (MRI) could be simultaneously achieved to compensate the low accuracy brought about by single-modal MRI. In addition, NiCoP/PVP possesses excellent photothermal properties owing to its obvious absorption in the near-infrared (NIR) region, which endows NiCoP/PVP with high photothermal conversion efficiency (PCE) to serve as a photothermal agent for tumor ablation. Therefore, NiCoP/PVP is a promising theranostic agent for accurate diagnosis and effective treatment of tumors.

[CuI(2,9-dimethyl-1,10-phenanthroline)P(p-OCH 3 -Ph) 2 CH 2 SarcosineGlycine] (1-MPSG), highly stable in physiological media phosphino copper(I) complex-is proposed herein as a viable alternative to anticancer platinum-based drugs. It is noteworthy that, 1-MPSG significantly and selectively reduced cell viability in a 3D spheroidal model of human lung adenocarcinoma (A549), in comparison with non-cancerous HaCaT cells. Confocal microscopy and an ICP-MS analysis showed that 1-MPSG effectively accumulates inside A549 cells with colocalization in mitochondria and nuclei. A precise cytometric analysis revealed a predominance of apoptosis over the other types of cell death. In the case of HaCaT cells, the overall cytotoxicity was significantly lower, indicating the selective activity of 1-MPSG towards cancer cells. Apoptosis also manifested itself in a decrease in mitochondrial membrane potential along with the activation of caspases-3/9. Moreover, the caspase inhibitor (Z-VAD-FMK) pretreatment led to decreased level of apoptosis (more pronouncedly in A549 cells than in non-cancerous HaCaT cells) and further validated the caspases dependence in 1-MPSG-induced apoptosis. Furthermore, the 1-MPSG complex presumably induces the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. It was also observed that the 1-MPSG mediated intracellular ROS alterations in A549 and HaCaT cells. These results, proved by fluorescence spectroscopy, and flow cytometry, suggest that investigated Cu(I) compound may trigger apoptosis also through ROS generation., (© 2021. The Author(s).)

Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging., (© 2021 Wiley-VCH GmbH.)

Microwave-assisted phospha-Michael addition reactions were carried out in the 13α-oestrone series. The exocyclic 16-methylene-17-ketones as α,β-unsaturated ketones were reacted with secondary phosphine oxides as nucleophilic partners. The addition reactions furnished the two tertiary phosphine oxide diastereomers in high yields. The main product was the 16α-isomer. The antiproliferative activities of the newly synthesised organophosphorus compounds against a panel of nine human cancer cell lines were investigated by means of MTT assays. The most potent compound, the diphenylphosphine oxide derivative in the 3- O -methyl-13α-oestrone series ( 9 ), exerted selective cell growth-inhibitory activity against UPCI-SCC-131 and T47D cell lines with low micromolar IC 50 values. Moreover, it displayed good tumour selectivity property determined against non-cancerous mouse fibroblast cells.

A series of activated vinyl azoles was hydrophosphinated in the presence of a chiral palladacycle catalyst under mild conditions to give enantioenriched phosphine azoles with moderate enantioselectivities and yields. The racemic phosphine azoles were transformed into eleven novel chelating phosphine-N-heterocyclic carbene (NHC) platinum complexes. The drug efficacies of nine selected phosphine-NHC platinum(II) chlorides in two cancer cell lines (MKN74 and MCF7) were evaluated, and two were found to exhibit activities comparable to that of cisplatin.

Given the increasing reports of well-defined bimetallic molecular complexes as potential anticancer agents in the last decades, along with the prevalence of platinum in anticancer therapy, we report here a detailed survey of bimetallic platinum and palladium complexes investigated as potential anticancer agents. Specifically, we will concentrate on the synthesis, characterisation and biological (anticancer) studies of a sub-class of these agents, namely homo and heterobimetallic complexes bearing a bridging phosphane ligand of the type: [L n M 1 (μ-R 2 P(CH 2 ) n PR 2 )M 2 L m ] (where M 1 is platinum or palladium, M 2 is any other transition metal, R = alkyl or aryl substituents, L n or L m are co-ligands, n = 1-6). We will review the in vitro and in vivo activities and any mechanistic anticancer studies of these complexes with a view of trying to delineate patterns in biological activity and structure-activity relationships (SAR). We do not include the review of bimetallic complexes in this class that have not undergone any anticancer testing, nor those that have been involved in other biological investigations unrelated to cancer studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ruthenium(II) complexes ( Ru1 - Ru5 ), with the general formula [Ru(N-S)(dppe) 2 ]PF 6 , bearing two 1,2- bis (diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC 50 values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe) 2 ]PF 6 ( Ru3 ), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1 - Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests.

A new approach for the preparation of (2-amino-3-cyano-4H-chromen-4-yl)phosphonate derivatives is described. The multicomponent reaction of salicylaldehydes, malononitrile and dialkyl phosphites catalyzed by pentamethyldiethylenetriamine (PMDTA) provided the bicyclic derivatives in high yields. The method developed did not require chromatographic separation, since the products could be recovered from the reaction mixture by simple filtration. Our approach made also possible condensation with secondary phosphine oxides, and this reaction has not been previously reported in the literature. The crystal structures of five derivatives were studied by single-crystal XRD analysis. The in vitro cytotoxicity on different cell lines and the antibacterial activity of the (2-amino-4H-chromen-4-yl)phosphonates synthesized were also explored. According to the IC 50 values determined, several derivatives showed moderate or promising activity against mouse fibroblast (NIH/3T3) and human promyelocytic leukemia (HL-60) cells. Furthermore, three (2-amino-3-cyano-4H-chromen-4-yl)phosphine oxides were active against selected Gram-positive bacteria.

We report the anti-breast cancer stem cell (CSC) properties of a series of Group 10-bis(azadiphosphine) complexes 1-3 under exclusively three-dimensional cell culture conditions. The breast CSC mammosphere potency of 1-3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-active compound, or any reported anti-CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase-dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti-CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three-dimensional CSC culture conditions., (© 2020 Wiley-VCH GmbH.)

Based on the recent studies depicting the potential of heterometallic gold complexes as potent antiproliferative agents, herein we first reported the preliminary mechanistic data on the in-vitro antiproliferative activity of tricyclohexylphosphanegold(I) n-mercaptobenzoate, Cy 3 PAu(n-MBA) where n = 2 (1), 3 (2) and 4 (3), and MBA = mercaptobenzoic acid, treated using MCF-7 breast cancer and A2780 ovarian cancer cells, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cytotoxicity of both cancer cells treated with 1-3, respectively. The IC 50 of 1-3 were applied to the subsequent assays including cell invasion and thioredoxin reductase (TrxR) as well as ubiquitin activities specifically on Lys48 and Lys63-linked polyubiquitin chains via flowcytometric analysis. The mechanistic effect of 1-3 towards both cells were evaluated on human p53 signaling gene expressions via RT 2 profiler Polymerase Chain Reductase (PCR) array. 1-3 were found to be highly cytotoxic towards both MCF-7 and A2780 cancer cell lines with the compounds were more sensitive towards the latter cells. 1-3 also suppressed TrxR and cell invasion activities by modulating p53 related genes related with proliferation, invasion and TrxR activities i.e. CCNB1, TP53, CDK4 etc. 1-3 also regulated Lys48 and Lys63-linked polyubiquitination by reactivation of p53, suggesting the ability of this gene in regulating inhibition of cytoskeletal reorganization via epithelial-mesenchymal transition (EMT), required for tumor progression. Taken together, the overall findings denoted that 1-3 exerted potent antiproliferative activity in MCF-7 and A2780 cells via activation of the p53 signaling pathway.

The preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) [Ru(Lap)(dppm) 2 ]PF 6 and (2) [Ru(Law)(dppm) 2 ]PF 6 , where dppm = bis(diphenylphosphino)methane, is reported here. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, 31 P{ 1 H}, 1 H and 13 C NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC 50 values in the micromolar range (0.03 to 2.70 μM). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibits cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (ΔΨm). Furthermore, complex (1) induces ROS (Reactive Oxygen Species) generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA (Bovine Serum Albumin), with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment. SYNOPSIS: The naphthoquinones Lapachol and Lawsone can form new ruthenium compounds with promising anticancer properties., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

We report cytotoxic ruthenium(ii) complexes of the general formula [RuCl(cis-tach)(diphosphine)]+ (cis-tach = cis-cis-1,3,5-triaminocyclohexane) that have been characterised by 1H, 13C and 31P{1H} NMR spectroscopy, mass spectrometry, X-ray crystallography and elemental analysis. The kinetics of aquation and stability of the active species have been studied, showing that the chlorido ligand is substituted by water at 298 K with first order rate constants of 10-2-10-3 s-1, ideal for potential clinical use as anti-tumour agents. Strong interactions with biologically relevant duplex and quadruplex DNA models correlate with the activity observed with A549, A2780 and 293T cell lines, and the degree of activity was found to be sensitive to the chelating diphosphine ligand. A label-free ptychographic cell imaging technique recorded cell death processes over 4 days. The Ru(ii) cis-tach diphosphine complexes exhibit anti-proliferative effects, in some cases outperforming cisplatin and other cytotoxic ruthenium complexes.

The development of both chemotherapeutic drug resistance as well as adverse side effects suggest that the current chemotherapeutic drugs remain ineffective in treating the various types of cancers. The development of new metallodrugs presenting anti-cancer activity is therefore needed. Ruthenium complexes have gained a great deal of interest due to their promising anti-tumour properties and reduced toxicity in vivo. This study highlighted the effective induction of cell death in a malignant melanoma cell by two novel bis-amino-phosphine ruthenium(II) complexes referred to as GA105 and GA113. The IC 50 concentrations were determined for both the complexes, the ligand and cisplatin, for comparison. Both complexes GA105 and GA113 displayed a high anti-cancer selectivity profile as they exhibited low IC 50 values of 6.72 µM and 8.76 µM respectively, with low toxicity towards a non-malignant human cell line. The IC 50 values obtained for both complexes were lower than that of cisplatin. The new complexes were more effective compared to the free ligand, GA103 (IC 50  = >20 µM). Morphological studies on treated cells induced apoptotic features, which with further studies could indicate an intrinsic cell death pathway. Additionally, flow cytometric analysis revealed that the mode of cell death of complex GA113 was apoptosis. The outcomes herein give further insight into the potential use of selected Ru(II) complexes as alternative chemotherapeutic drugs in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Herein, we review developments in synthesis, structure, and biological (anti-cancer) activities of 1,1-bis(diphenylphosphino)methane (dppm) bridged homo- and heterobimetallic systems of the type L m M(μ 2 -dppm)M'L n (M and M' are transition metals which may be different or the same and L n,m are co-ligands) since the first such reported bimetallic system in 1987 until the present time (2020). As the simplest diphosphine, dppm enables facile formation of bimetallic complexes, where, given the short spacer between the PPh 2 groups, close spatial proximity of the metal centres is ensured. We concentrate on complexes bearing no M-M interaction and contrast biological activities of these complexes with mononuclear counterparts and positive control agents such as cisplatin, in an attempt to elucidate patterns in the biological activities of these complexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Aiming at obtaining new copper complexes with good cytotoxicity against cancer cells, triphenylphosphine (TPP) was introduced to obtain insight into the influence of the co-ligands. In this paper, two copper complexes, Cu(2-pbmq)(CH 3 OH)Br 2 (1) and [Cu(2-pbmq)(TPP)Br] 2 (2) were designed, synthesized, and characterized by X-ray crystallography, 2-((2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)methyl))quinolone (2-pbmq), to investigate the influence of the TPP group on the anticancer activity of the metal complex. Although the presence of the TPP group diminished the intensity of the interaction properties of the complex with DNA, the in vitro anticancer activity and cellular uptake of the TPP-containing complex were markedly superior to those of its TPP-lacking counterpart. Detailed studies on the more potently cytotoxic complex 2 revealed that it accumulated in nucleus, arrested the cell cycle at the G0-G1 phase, causing mitochondrial dysfunction, involving the potential simultaneous mitochondrial membrane collapse, cellular ATP level depletion, and Ca 2+ leakage, eventually inducing cell apoptosis. In summary, the introduction of a TPP group enhances the biological activity and cytotoxicity of the complex., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Several propargyl functionalised substrates with different heteroatoms (N, O or S) have been used for the preparation of propargyl gold(i) phosphine complexes. The complexes were prepared in high yields either by reaction of the substrate with [Au(acac)PPh3] or by reaction of [AuCl(PPh3)] with potassium hydroxide and the substrate in methanol. Several of the complexes have been characterised by X-ray diffraction showing the presence of secondary bonds such as π-stacking and aurophilic interactions. The reaction of the propargyl gold(i) phosphine complexes with [Cu(NO3)(PPh3)2] or [Ag(OTf)(PPh3)2] afforded heterobimetallic complexes with π-coordination of {Cu(PPh3)2} or {Ag(PPh3)2} to the alkyne bond. When the substituent of the propargyl unit contained more strongly coordinating pyridine moieties, [(PyCH2)2NCH2C[triple bond, length as m-dash]CAuPPh3], coordination of the heterometal to the pyridine units occurred, displacing the phosphine groups and giving rise to a dimeric structure. The antiproliferative activity of the complexes against cisplatin resistant lung cancer cell line A549 was determined by MTT assay. The mononuclear gold complexes showed excellent activities with IC50 values < 14 μM. Coordination of copper of silver to the alkynyl fragment resulted in a significant increase in activity suggesting a synergistic effect between the two metal centres.

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C-N double bond of 2 H -azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N-C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2 H -azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O - or S -nucleophiles to the starting 2 H -azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested.

This work describes the synthesis of the gold(i) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(i) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(i)-complexed compounds against the cancer line A549 with IC 50 values in the nanomolar range and IC 50 values below 5 μM against the SKOV3 cell line. It should be noted that the cytotoxicities observed for the new gold(i) complexes are higher than those observed for phosphine sulphide ligands before binding to gold. Furthermore, the results also indicate that the presence of a nitrogenated heterocycle, such as tetrahydroquinoline or quinoline, is also necessary for the TopI inhibition to be maintained. In addition, no toxicity was observed when the non-cancerous lung fibroblast cell line (MRC5) was treated with the new phosphine sulphide gold(i) complexes prepared.

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses. We hypothesized that Au complexes that induce severe ER stress might counteract pro-survival cellular attempts leading to the ER stress-mediated apoptosis and reduced platinum resistance. In this work, we prepared a series of highly cytotoxic AuI-dialkyldithiocarbamate complexes and investigated their anticancer potential in ovarian cancer cells. Complexes demonstrated surprisingly low stability in chloroform, resulting in the formation of an Au chain polymer, which also displayed excellent cytotoxicity. Lead complex 2 induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly, 2 caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response.

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.)

A series of the structurally related platinum(II) saccharinate (sac) complexes with alkylphenylphosphines, namely cis-[Pt(sac) 2 (PPh 2 Me) 2 ]·DMSO (1), cis-[Pt(sac) 2 (PPhMe 2 ) 2 ] (2), cis-[Pt(sac) 2 (PPh 2 Et) 2 ] (3), and cis-[Pt(sac) 2 (PPhEt 2 ) 2 ]·2DMSO (4), were synthesized and fully characterized; their structures were determined by X-ray crystallography. All the complexes were investigated for their anticancer potentials on three human cancer cells including A549 (lung), MCF-7 (breast), and HCT116 (colon) in addition to a noncancerous human bronchial epithelial cells (BEAS-2B). Specifically, 1 and 3 showed significant cytotoxic effects against MCF-7 and HCT116 cell lines in comparison to cisplatin, and were considered as the most potent ones in the series. The cytotoxic complexes were found to cleave DNA efficiently. In addition, the binding interactions of the complexes with DNA were confirmed by enzyme inhibition and molecular docking studies. Complexes 1 and 3 were capable of inducing apoptosis and arrested the cell cycle at the DNA synthesis (S) phase in MCF-7 cells. Furthermore, 1 and 3 caused the excessive generation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and double-strand DNA breaks.

A series of phosphino-thiosemicarbazone gold(I) dinuclear complexes obtained by two different synthetic procedures have been prepared. All the compounds have been spectroscopically characterized including single crystal X ray diffraction analysis in some of cases. [Au 2 (HL 1 )Cl 2 ] (1), [Au 2 (HL 2 ) 2 ]Cl 2 (2) and [Au 2 (HL 3 ) 2 ]Cl 2 (3) have been prepared by chemical synthesis using a gold(III) salt as precursor; while [Au 2 (L 1 ) 2 ] (4), [Au 2 (L 2 ) 2 ]∙2CH 3 CN (5) and [Au 2 (L 3 ) 2 ] (6) have been isolated from an electrochemical synthesis (HL n  = 2-[2-(diphenylphosphanyl)-benzylidene]-N-R-thiosemicarbazone; HL 1 : R = methyl, HL 2 : R = methoxyphenyl, HL 3 : R = nitrophenyl). The in vitro cytotoxic activity of these gold(I) complexes was tested against some human tumor cell lines: HeLa 229 (cervical epithelial carcinoma), MCF-7 (ovarian adenocarcinoma), NCI-H460 (non-small-cell lung cancer) and MRC5 (normal human lung fibroblast), and the IC 50 values compared with those of cisplatin. The neutral methyl-substituted complexes 1 and 4 and methoxyphenyl 5 displayed significant cytotoxic activities in all investigated cancer cell lines, being 1 and 4 the most effective. The ability of complexes 1 and 4 to induce cell death by apoptosis in Hela 229 was also investigated by fluorescence microscopy using the apoptotic DNA fragmentation as marker. These results indicated that the inhibition of cell proliferation is mainly due to an apoptotic process. In order to obtain more information about the mechanism of action of these metallocompounds, the interactions of complexes 1 and 4 with the thioredoxin reductase (TrxR) enzyme were analyzed. Both complexes exhibited a strong inhibition of the thioredoxin reductase activity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The design of multi-targeted drugs has gained considerable interest in the last decade thanks to their advantages in the treatment of different diseases, including cancer. The simultaneous inhibition of selected targets from cancerous cells to induce their death represents an attractive objective for the medicinal chemist in order to enhance the efficiency of chemotherapy. In the present work, several alkynyl gold(I) phosphane complexes derived from 3-hydroxyflavones active against three human cancer cell lines, colorectal adenocarcinoma Caco-2/TC7, breast adenocarcinoma MCF-7 and hepatocellular carcinoma HepG2, have been synthesized and characterized. Moreover, these compounds display high selective index values towards differentiated Caco-2 cells, which are considered as a model of non-cancerous cells. The antiproliferative effect of the most active complexes [Au(L2b)PPh 3 ] (3b) and [Au(L2c)PTA] (4c) on Caco-2 cells, seems to be mediated by the inhibition of the enzyme cyclooxygenase-1/2 and alteration of the activities of the redox enzymes thioredoxin reductase and glutathione reductase. Both complexes triggered cell death by apoptosis, alterations in cell cycle progression and increased of ROS production. These results provide support for the suggestion that multi-targeting approach involving the interaction with cyclooxygenase-1/2 and the redox enzymes that increases ROS production, enhances cell death in vitro. All these results indicate that complexes [Au(L2b)PPh 3 ] and [Au(L2c)PTA] are promising antiproliferative agents for further anticancer drug development., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The anticancer activity of novel platinum derivative, a complex of platinum with tris(2-carboxyethyl)phosphine (Pt-TCEP), has been evaluated in canine (D-17) and human osteosarcoma (U2-OS) cell lines. Viability of cells after incubation for 24 or 72 hours with increasing concentrations (0.625, 1.25, 2.50, 5, 10 and 20 μM) of Pt-TCEP was tested in an MTT assay and compared to effect of cisplatin. Longer-term effect of Pt-TCEP was evaluated in the colony-forming unit assay after 24 hours exposure to the Pt-TCEP (2 and 3 μM) and subsequent incubation for 2 weeks. The influence of the compound on the cell cycle was measured after 24 hours treatment with Pt-TCEP (3 μM). Its pro-apoptotic activity was examined after 24 hours treatment with Pt-TCEP (1.25, 2.50, 5, 10 and 20 μM) using flow cytometry. Expression of main proteins involved in apoptosis was measured after exposure for 24 hours to 3 or 5 μM Pt-TCEP in Western Blot. The compound much more effectively decreased cell viability than cisplatin in case of both cell lines. IC 50 of Pt-TCEP was 5.93 ± 0.12 in D-17 and 3.45 ± 0.14 in U2-OS cell lines after 24 hours, and 1.77 ± 0.14 in D-17 and 1.53 ± 0.11 in U2-OS after 72 hours (P < .05). The compound arrested cells in the G2/M phase and inhibited the ability of cells to form colonies. Pt-TCEP induced caspase-dependent apoptosis. The expression of the anti-apoptotic Bcl-X L protein was decreased after Pt-TCEP treatment in both cell lines. The results confirmed anti-cancer activity of Pt-TCEP against canine and human osteosarcoma cell lines., (© 2019 John Wiley & Sons Ltd.)

Background: In recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br 2 ] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells., Methods: Multiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo., Results: CTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo., Conclusion: In human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).

New alkynylgold(I) with P(NMe 2 ) 3 (HMPT) phosphane complexes, [Au(C≡C-R)(HMPT)] (R= 4-Ph, 4-MePh, 4-OMe, 4-Br, 4-Cl, 2-py, and 3-py) have been synthesized and characterized, including X-ray studies of complexes with R= 4-OMe and 4-Br; additionally, their physicochemical properties and anticancer activity have been tested. Due to the great water solubility of the HMPT phosphane, all the complexes exhibit an optimal balance of hydrophilicity/lipophilicity. Also, all of these complexes are quite stable in physiological conditions and interact well enough with the transport protein BSA. All complexes exhibit a higher anticancer activity against Caco-2 cells than cisplatin, and some of them do not present cytotoxic activity against enterocyte-like differentiated cells. The selective complexes are proapoptotic drugs by the exposure of phosphatidylserine, results that are also confirmed in primary cultures from mouse colon tumors. Complexes with a halogen unit also arrest the cell cycle in G2/M phase. It is thought that maybe these apoptosis processes are promoted by the observed oxidative damage in the membrane lipids, as a consequence of the inhibition of the thioredoxin reductase enzyme. Based on our results, we conclude that five of our complexes are good candidates to be used in chemotherapy.

Four cycloaurated phosphine sulfide complexes, [Au{κ 2 -2-C 6 H 4 P(S)Ph 2 } 2 ][AuX 2 ] [X=Cl (2), Br (3), I (4)] and [Au{κ 2 -2-C 6 H 4 P(S)Ph 2 } 2 ]PF 6 (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showed excellent cytotoxicity against a broad range of cancer cell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer (HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductase and induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showed that treatment with compounds 4 and 5 resulted in significant inhibition of tumor growth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexes were also evaluated for their in vitro and in vivo anti-inflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edema in rats, respectively., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We herein describe the synthesis and characterization of the new amido-phosphinic ligand 3,7‑bis(dichloroacetyl)‑1,3,7‑triaza‑5‑phosphabicyclo[3.3.1]nonane (DCP), a derivative of dichloroacetic acid (DCA), whose ability to reverse the suppressed mitochondrial apoptosis in cancer cells is known. DCP was obtained by a double N-acylation of PTA (1,3,5‑triaza‑7‑phosphaadamantane) occurring with loss of CH 2 , in appropriate conditions . Due to the hindered rotation around the amidic CN bonds, three rotameric forms of DCP were observed, whose ratio in solution was dependent on the solvent, while the X-ray crystal structure of DCP showed an opposite orientation of the two amidic carbonyl groups (anti rotamer). The lipophilic, air and thermally stable DCP was found able to act regiospecifically as a P-donor ligand toward soft metal ions. By ligand substitution on appropriate precursors, we obtained the complexes 1-9, where proapoptotic DCA is associated with metal ions of known cytotoxic activity on cancer cells (Pt 2+ , Pd 2+ , Ru 2+ , Re + , Au + ). The antiproliferative activity of DCP and its complexes was tested in vitro, in comparison with cisplatin, on three human tumor cell lines: A2780 (ovarian cisplatin-sensitive), A2780cis (ovarian cisplatin-resistant) and K562 (erythroleukemic). The results showed that the simultaneous presence of DCP (containing two residues of proapoptotic DCA) and Pt(II) produces the best performances with respect to non-platinum complexes. Experiments of pro-apoptotic activity indicated that the antiproliferative activity of the most active DCP-Pt(II) complexes is associated with induction of apoptosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of alkynylgold(I) phosphine complexes containing methoxy-substituted cinnamide moieties (3a-3c and 4a-4c) have been synthesized and characterized. All of the synthesized complexes were evaluated for their cytotoxicity against three human cancer cell lines A549 (lung), D24 (melanoma), and HT1080 (fibrosarcoma) and the human embryonic kidney 293 cell line (Hek293T) as a proxy model for noncancer cells. Most of the synthesized compounds showed antiproliferative activity against cancer cell lines at low micromolar concentrations. Among these, complex 3c showed a broad spectrum of anticancer activity with IC 50 values in the range of 1.53-6.05 μM against all tested cancer lines. Complex 3c possessed 20 times higher cytotoxicity than the reference drug cisplatin against D24 melanoma cells and showed significant anticancer activity in 3D spheroidal models of melanoma cells. Mechanistic investigations of 3c activity indicate thioredoxin reductase inhibition through steric and hydrogen-bonding interactions, followed by the induction of oxidative stress and a mitochondrial pathway of cell death. Compound 3c also showed significant antiangiogenic properties in a transgenic zebrafish Tg(fli1a:EGFP) in vivo model.

Cleavage of the bromide bridges in [Pd2(μ-Br)2{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (1) by diphosphine ligands gave the mono- and dinuclear palladacycles [Pd(L)Br{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}] [L = dppe (2) dppm (3), ortho-dppBz (4)] and [Pd2Br2(para-dppBz){κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (5). The interactions of these complexes with DNA (CT-DNA) and proteins (human serum albumin) were studied by UV-Vis and fluorescence spectroscopy, respectively. The results confirmed the interaction of these palladium complexes with CT-DNA through groove binding, and their strong binding affinity to HSA. The anti-proliferative activities of complexes 1-5 were tested against four human cancer cell lines (HeLa, A549, PC-3, and HT1080) and normal keratinocytes (HaCaT). Among the series, the palladium(ii) complex containing the 1,2-bis(diphenylphosphino)benzene ligand (4) showed the highest cytotoxicity against HeLa, PC-3 and HT1080 cells, with IC50 values of 0.25 ± 0.08, 0.85 ± 0.11, and 0.66 ± 0.15 μM, respectively. Interestingly, compound 4 exhibited lower cytotoxic activity toward normal HaCaT cells (IC50 = 4.65 ± 0.16 μM). Additionally, this complex exhibited lower toxicity and better anti-cancer activity than cisplatin. Further mechanistic studies, including Hoechst staining and flow cytometry, confirmed that complex 4 induced G2/M phase cell cycle arrest and apoptotic cell death in HeLa cells.

Considering the promising previous results of ct-[RuCl(CO)(dppb)(bipy)]PF 6 (where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine) as an antitumor agent, novel biological assays evaluating its toxicogenic potential were performed. The genotoxicity of the compound was evaluated by the in vitro micronucleus test (V79, Chinese hamster lung fibroblasts; HepG2, hepatocellular carcinoma cells), in vivo bone marrow micronucleus test and comet assay in hepatocytes (Swiss mice). The animals were treated with 0.63, 1.25, 2.5 and 5.0 mg/kg body weight (bw) of the compound. Negative (water) and positive (cisplatin, 1.5 mg/kg bw; methyl methanesulfonate, 40 mg/kg bw) controls were included. The parameters considered in the comet assay were the percentage of tail DNA, tail moment and tail length. The results of the in vitro micronucleus tests showed the absence of genotoxicity in V79 cells, while the compound was genotoxic in HepG2 cells at a concentration of 1.25 μm. In the in vivo micronucleus test, the compound was not genotoxic at the different doses evaluated. In the comet assay, only the dose of 5.0 mg/kg bw resulted in a significant increase in the frequency of DNA damage in hepatocytes when compared to the negative control. The genotoxic effect observed in HepG2 cells and in the liver comet assay indicates that the compound was metabolized by hepatic cells., (© 2018 John Wiley & Sons, Ltd.)

The stringent reaction conditions for an effective Fenton reaction (pH range of 3-4) hinders its application in cancer therapy. Therefore, how to improve the efficiency of the Fenton reaction in a tumor site has been the main obstacle in chemodynamic therapy (CDT). Herein, we report biocompatible one-dimensional (1D) ferrous phosphide nanorods (FP NRs) with ultrasound (US)- and photothermal (PT)-enhanced Fenton properties and excellent photothermal conversion efficiency (56.6 %) in the NIR II window, showing synergistic therapeutic properties. Additionally, the high photothermal conversion efficiency and excellent traverse relaxivity (277.79 mm -1  s -1 ) of the FP NRs means they are excellent photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) agents. This is the first report on exploiting the response of metallic phosphides to NIR II laser (1064 nm) and ultrasound to improve the CDT effect with a high therapeutic effect and PA/MR imaging., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two series of neutral luminescent pentafluorophenyl cycloplatinated(II) complexes [Pt(C^N)(C 6 F 5 )L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref (14) )] or biocompatible phosphine [L = PPh 2 C 6 H 4 COOH (dpbH; 2), PPh 2 C 6 H 4 CONHCH 2 COOMe (dpbGlyOMe; 3), P(C 6 H 4 SO 3 Na) 3 (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC 50 3.89-20.29 μM) than compounds 1 (9.03-20.50 μM), whereas the activities of complexes 3 and 4 are negligible. All cytotoxic complexes show low selective toxicities toward cancer cells. Interestingly, except 1a, these complexes do not show evidence of DNA intercalation. Along the same lines, fluorescence costaining with Hoechst (2,5'-bi-1 H-benzimidazole, 2'-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl), a nuclear DNA stain) reveals that all complexes easily internalize, being mainly localized in the cytoplasm. In order to deepen the mechanism of biological action, the effect of the most cytotoxic complex 2b toward the dynamics of tubulin was explored. This complex displays tubulin depolymerization activity, exhibiting more potent inhibition of microtubule formation in A549 than in HeLa cells, in accordance with its higher antiproliferative activity (IC 50 6.98 vs 12.45 μM), placing this complex as a potential antitubulin agent.

Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene-gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(η-C 5 H 5 ) 2 TiMe(μ-mba)Au(PEt 3 )] (4) Titanofin. The compound is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(η-C 5 H 5 ) 2 TiMe(μ-mba)Au(PPh 3 )] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(η-C 5 H 5 ) 2 TiMe(μ-mba)Au(PR 3 )] (PR 3  = PPh 3 2 Titanocref and PEt 3 4 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR 3 )] (PR 3  = PPh 3 1 cref; PEt 3 3 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers associated with these processes such as prometastatic IL(s), MMP(s), TNF-α, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overexpressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1α whose overexpression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Since the serendipitous discovery of the antitumor activity of cisplatin there has been a continuous surge in studies aimed at the development of new cytotoxic metal complexes. While the majority of these complexes have been designed to interact with nuclear DNA, other targets for anticancer metallodrugs attract increasing interest. In cancer cells the mitochondrial metabolism is deregulated. Impaired apoptosis, insensitivity to antigrowth signals and unlimited proliferation have been linked to mitochondrial dysfunction. It is therefore not surprising that mitochondria have emerged as a major target for cancer therapy. Mitochondria-targeting agents are able to bypass resistance mechanisms and to (re-) activate cell-death programs., Methods: Web-based literature searching tools such as SciFinder were used to search for reports on cytotoxic metal complexes that are taken up by the mitochondria and interact with mitochondrial DNA or mitochondrial proteins, disrupt the mitochondrial membrane potential, facilitate mitochondrial membrane permeabilization or activate mitochondria-dependent celldeath signaling by unbalancing the cellular redox state. Included in the search were publications investigating strategies to selectively accumulate metallodrugs in the mitochondria., Results: This review includes 241 references on antimitochondrial metal complexes, the use of mitochondria-targeting carrier ligands and the formation of lipophilic cationic complexes., Conclusion: Recent developments in the design, cytotoxic potency, and mechanistic understanding of antimitochondrial metal complexes, in particular of cyclometalated Au, Ru, Ir and Pt complexes, Ru polypyridine complexes and Au-N-heterocyclic carbene and phosphine complexes are summarized and discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of gold(i), gold(iii) and cationic gold(i) complexes of tris(4-methoxyphenyl)phosphine and tris(2,6-dimethoxyphenyl)phosphine were synthesised and fully characterised by spectroscopic methods. The molecular structures of selected complexes were also determined by X-ray diffraction analysis. The prepared complexes [AuX{P(C 6 H 4 -4-OMe) 3 }] [X = Cl (1), Br (2), I (3)], [AuCl 3 {P(C 6 H 4 -4-OMe) 3 }] (4), [Au{P(C 6 H 4 -4-OMe) 3 } 2 ]PF 6 (5), [AuX{P(C 6 H 3 -2,6-{OMe} 2 ) 3 }] [X = Cl (6), Br (7), I (8)], [AuCl 3 {P(C 6 H 3 -2,6-{OMe} 2 ) 3 }] (9) and [Au{P(C 6 H 3 -2,6-{OMe} 2 ) 3 } 2 ]PF 6 (10) were investigated for their anticancer activity against five human tumor cell lines [ovarian (SKOV-3), fibrosarcoma (HT1080), glioblastoma (U87MG), prostate (PC-3), and cervical (HeLa)] as well as against 3D spheroidal models of HeLa cells. The cationic complex 10 was found to exhibit a remarkably broad spectrum of anticancer activity with approximately 30-fold higher toxicity than cisplatin against PC-3 and U87MG cancer cells; this complex also showed the strongest inhibition of spheroid growth in 3D models of HeLa cells. The mechanism of anticancer activity of these gold complexes was found to be strong inhibition of thioredoxin reductase, increased ROS production and subsequent apoptosis induction as evidenced by the sub G1 cell accumulation, DNA fragmentation, and caspase-3 activation.

Cyrhetrenyl aldehyde derivatives [(η5-C5H4CHO)Re(CO)2PR3] with R = methyl (Me, 2a), phenyl (Ph, 2b), and cyclohexyl (Cy, 2c) were synthesized by a photochemical reaction from the starting material [(η5-C5H4CHO)Re(CO)3] (1) and the corresponding phosphines. The complexes were fully characterized by FT-IR, 1H, 13C and 31P NMR spectroscopy, elemental analysis and mass spectrometry. The molecular structures of 2a-c have also been determined. Electronic structure calculations by TD-DFT and electrochemical studies are in sound agreement with the effect of the substitution of one carbonyl group by a phosphine ligand. Additionally, the antiproliferative activity of complexes 1 and 2a-c was studied on the human cancer cell lines HT-29 and PT-45 using an MTT assay. Out of all new compounds, only the triphenylphosphine derivative 2b exhibited pronounced cytotoxic effects on both cell lines, being ca. 1.5 times more potent than cisplatin.

[M(sac) 2 (dppp)] (1 and 2), [M(dppp) 2 ](sac) 2 (3 and 4) and [M(sac) 2 (dppb)] (5 and 6) complexes, where M = Pd II (1, 3 and 5) and Pt II (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A series of 4-ethynylaniline gold(I) complexes containing monophosphane (1,3,5-triaza-7-phosphaadamantane (pta; 2), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (3), and PR 3 , with R=naphthyl (4), phenyl (5), and ethyl (6)) and diphosphane (bis(diphenylphosphino)acetylene (dppa; 7), trans-1,2-bis(diphenylphosphino)ethene (dppet; 8), 1,2-bis(diphenylphosphino)ethane (dppe; 9), and 1,3-bis(diphenylphosphino)propane (dppp; 10)) ligands have been synthesized and their efficiency against tumor cells evaluated. The cytotoxicity of complexes 2-10 was evaluated in human colorectal (HCT116) and ovarian (A2780) carcinoma as well as in normal human fibroblasts. All the complexes showed a higher antiproliferative effect in A2780 cells, with the cytotoxicity decreasing in the following order 5>6=9=10>8>2>4>7>3. Complex 4 stands out for its very high selectivity towards ovarian carcinoma cells (IC 50 =2.3 μm) compared with colorectal carcinoma and normal human fibroblasts (IC 50 >100 μm), which makes this complex very attractive for ovarian cancer therapy. Its cytotoxicity in these cells correlates with the induction of the apoptotic process and an increase of intracellular reactive oxygen species (ROS). The effects of the nuclearity, rigidity, and solubility of these complexes on their biological activity were also analyzed. X-ray crystal structure determination allowed the identification of short N-H⋅⋅⋅π contacts as the main driving forces for the three-dimensional packing in these molecules., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The main disadvantage of conventional anticancer chemotherapy is the inability to deliver the correct amount of drug directly to cancer. Those molecular delivering systems are very important to destroy cancer cells selectively. Herein we report synthesis of phosphine-peptide conjugate (Ph 2 PCH 2 -Sar-Gly-OH, PSG) derived from SarGly (sarcosine-glycine), which can be easily exchanged to other peptide carriers, its oxide (OPh 2 PCH 2 -Sar-Gly-OH, OPSG) and the first copper(I) complex ([CuI(dmp)(P(Ph) 2 CH 2 -Sar-Gly-OH)], 1-PSG, where dmp stands for 2,9-dimethyl-1,10-phenanthroline). The compounds were characterized by elemental analysis, NMR (1D, 2D), UV-Vis spectroscopy and DFT (Density Functional Theory) methods. PSG and 1-PSG proved to be stable in biological medium in the presence of atmospheric oxygen for several days. The cytotoxicity of the compounds and cisplatin was tested against cancer cell lines: mouse colon carcinoma (CT26; 1-PSG IC 50  = 3.12 ± 0.1), human lung adenocarcinoma (A549; 1-PSG IC 50  = 2.01 ± 0.2) and human breast adenocarcinoma (MCF7; 1-PSG IC 50  = 0.98 ± 0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSG IC 50  = 78.56 ± 1.1). Therapeutic index for 1-PSG (MCF7) equals 80. Intracellular accumulation of 1-PSG complex increased with time and was much higher (96%) inside MCF7 cancer cells than in normal MRC5 cells (20%). Attachment of SarGly to cytotoxic copper(I) complex via phosphine motif improved selectivity of copper(I) complex 1-PSG into the cancer cells. Precise mechanistic study revealed that the 1-PSG complex causes apoptotic cells MCF7 death with simultaneous decrease of mitochondrial membrane potential and increase of caspase-9 and -3 activities. Additionally, 1-PSG generated high level of reactive oxygen species that was the reason for oxidative damages to the sugar-phosphate backbone of plasmid DNA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble gold I complex with tris-(2-carboxyethylphosphine) (AuTCEP). The two phosphines coordinate linearly to the metal as solved by single crystal X-ray diffraction. Complete spectroscopic characterization is also reported. In vitro growth inhibition (GI 50 ) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-03) with GI 50 of 3.04 nmol mL -1 . Moreover, non-differential uptake of AuTCEP was observed between OVCAR-03 (tumor) and HaCaT (non-tumor) two cell lines. Biophysical evaluation with the sulfur-rich biomolecules showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. However, AuTCEP demonstrated to cleave plasmidial DNA, suggesting DNA as a possible target. No antibacterial activity was observed in the strains evaluated. Besides, it inhibits 15% of the activity of a mixture of serine-β-lactamase and metallo-β-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to metallo-β-lactamase but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with Au I complexes and its lack of specificity, generating very selective compounds with unexpected targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A series of new Pt(II) saccharinate complexes containing PR 3 ligands (PPh 3 , PPh 2 Cy, PPhCy 2 and PCy 3 ) with progressive phenyl (Ph) replacement by cyclohexyl (Cy) were synthesized and structurally characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes was tested against human breast (MCF-7), lung (A549), colon (HCT116), and prostate (DU145) cancer cell lines as well as against normal bronchial epithelial (BEAS-2B) cells. Trans-configured complexes 1, 3 and 5 emerged as potential anticancer drug candidates. The mechanism of action of the potent complexes was then investigated in detail. The three complexes interacted with DNA by groove binding and with HSA via hydrophobic IIA subdomain. Furthermore, the complexes cleaved plasmid DNA efficiently. Cellular uptake studies in MCF-7 cells showed that the biologically active complexes were mainly localized in cytoplasm. The cytotoxic activity was a function of the lipophilicity and cellular accumulation of the complexes. As determined by M30, Annexin V and Caspase 3/7 activity assays, the complexes induced apoptosis in MCF-7 and HCT116 cells. Mechanistic studies showed that the potent complexes cause excessive generation of reactive oxygen species (ROS) and display a dual action, concurrently targeting both mitochondria and genomic DNA., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)