Unveiling the promising anticancer activity of palladium(II)-aryl complexes bearing diphosphine ligands: a structure-activity relationship analysis.

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 IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-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.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands.

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) 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.

The First Example of the Friedel-Crafts Cyclization Leading to (10-Hydroxy-9,10-dihydroanthr-9-yl)phosphonium Salts without the Expected Bradsher Dehydration.

The reaction of (ortho-acetalaryl)arylmethanols with various phosphines PR1R2R3 (R1 = R2 = R3 = Ph; R1 = R2 = Ph, R3 = Me and R1 = R2 = Me, R3 = Ph) under acidic conditions (e.g., HCl, HBF4, TsOH) unexpectedly led to the formation of (10-hydroxy-9,10-dihydroanthr-9-yl)phosphonium salts instead of the corresponding anthryl phosphonium salts. The cyclization occurred according to the Friedel-Crafts mechanism but without the usually observed Bradsher dehydration, giving cyclic products in the form of cis/trans isomers and their conformers. In case of electron-rich and less-hindered dimethylphenylphosphine, all four stereoisomers were recorded in 31P{1H} NMR spectra, while for the other phosphines, only the two most stable cis/trans stereoisomers were detected. This study was supported by DFT and NCI calculations in combination with FT-IR analysis.

Revisiting the anticancer properties of phosphane(9-ribosylpurine-6-thiolato)gold(I) complexes and their 9H-purine precursors.

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 R3PAu 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 IC50 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 R2 of the phosphane ligand and R1 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 77Se NMR monitoring of an exemplary selenopurine complex.

Structure-Reactivity Relationships of Buchwald-Type Phosphines in Nickel-Catalyzed Cross-Couplings.

The dialkyl-ortho-biaryl class of phosphines, commonly known as Buchwald-type ligands, are among the most important phosphines in Pd-catalyzed cross-coupling. These ligands have also been successfully applied to several synthetically valuable Ni-catalyzed cross-coupling methodologies and, as demonstrated in this work, are top performing ligands in Ni-catalyzed Suzuki Miyaura Coupling (SMC) and C-N coupling reactions, even outperforming commonly employed bisphosphines like dppf in many circumstances. However, little is known about their structure-reactivity relationships (SRRs) with Ni, and limited examples of well-defined, catalytically relevant Ni complexes with Buchwald-type ligands exist. In this work, we report the analysis of Buchwald-type phosphine SRRs in four representative Ni-catalyzed cross-coupling reactions. Our study was guided by data-driven classification analysis, which together with mechanistic organometallic studies of structurally characterized Ni(0), Ni(I), and Ni(II) complexes allowed us to rationalize reactivity patterns in catalysis. Overall, we expect that this study will serve as a platform for further exploration of this ligand class in organonickel chemistry as well as in the development of new Ni-catalyzed cross-coupling methodologies.

Cationic palladium(II)-indenyl complexes bearing phosphines as ancillary ligands: synthesis, and study of indenyl amination and anticancer activity.

The reactivity of palladium(II) indenyl derivatives and their applications are topics relatively less studied, though in recent times these compounds have been used as pre-catalysts able to promote challenging cross-coupling processes. Herein, we propose the first systematic study concerning the nucleophilic attack on the palladium(II) coordinated indenyl fragment and, for this purpose, we have prepared a library of new Pd-indenyl complexes bearing mono- or bidentate phosphines as spectator ligands, developing specific synthetic strategies. All novel compounds are thoroughly characterized, highlighting that the indenyl ligand presents always a hapticity intermediate between η3 and η5. Secondary amines have been chosen as nucleophiles for the present study and indenyl amination has been monitored by UV-Vis and NMR spectroscopies, deriving a second order rate law, with dependence on both complex and amine concentrations. The rate-determining step of the process is the initial attack of the amine to the coordinated indenyl fragment, and this conclusion has been supported also by DFT calculations. The determination of second order rate constants has allowed us to assess the impact of the phosphine ligands on the kinetics of the process and identify the steric and electronic descriptors most suitable for predicting the reactivity of these systems. Finally, in vitro tests have proven that these organometallic compounds promote antiproliferative activity towards ovarian cancer cells better than cisplatin and possibly by adopting a different mechanism of action.

Thiol Catalysis of Selenosulfide Bond Cleavage by a Triarylphosphine.

The arylthiol 4-mercaptophenylacetic acid (MPAA) is a powerful catalyst of selenosulfide bond reduction by the triarylphosphine 3,3',3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt (TPPTS). Both reagents are water-soluble at neutral pH and are particularly adapted for working with unprotected peptidic substrates. Contrary to trialkylphosphines such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP), TPPTS has the advantage of not inducing deselenization reactions. We believe that the work reported here will be of value for those manipulating selenosulfide bonds in peptidic or protein molecules.

Treatment of critical aluminum phosphide (rice tablet) poisoning with high-dose insulin: a case report.

BACKGROUND: Aluminum phosphide (rice tablet) is a highly efficient agent for preserving grains against rodents and insects. It accounts for a large number of poisoning cases. Aluminum phosphide poisoning has a high mortality rate of about 90%, and to date, no antidote is available. It releases phosphine gas after exposure to moisture, and this reaction is catalyzed by the acidity of the stomach. Phosphine is then absorbed throughout the respiratory or gastrointestinal tracts and causes toxicity through inhibition of cytochrome c oxidase and formation of highly reactive free radicals. Treatment of patients with aluminum phosphide poisoning is supportive, including mechanical ventilation and vasopressors. The usage of infusion of glucose-insulin-potassium in rice tablet poisoning has been suggested, after its positive beneficial cardiac inotropic effects in patients with beta-blocker and calcium channel blocker poisoning. CASE PRESENTATION: We report the case of a 30-year-old Iranian woman with critical aluminum phosphide poisoning, presented with hypotension and other signs of shock and severe metabolic acidosis, successfully treated with high-dose regular insulin and hypertonic dextrose and discharged from hospital in good condition. In contrast to our previous experiences, in which nearly all patients with critical aluminum phosphide poisoning died, this patient was saved with glucose-insulin-potassium. CONCLUSION: Aluminum phosphide poisoning has a high mortality rate, and to date, no antidote is available. Administration of high-dose intravenous regular insulin and dextrose is suggested as a potential life-saving treatment for patients with critical aluminum phosphide poisoning.

Phosphine addition to dehydroalanine for peptide modification.

Thiols are a functional group commonly used for selective reactions in a biochemical setting because of their high nucleophilicity. Phosphorus nucleophiles can undergo some similar reactions to thiols, but remain underexploited in this setting. In this work we show that phosphine nucleophiles react cleanly and quickly with a dehydroalanine electrophile, itself generated from cysteine, to give a stable adduct in a peptide context. NMR reveals the product to be a phosphonium ion and indicates some backbone conformational constraint, possibly arising from transient carbonyl coordination. The reaction proceeded quickly, with a pseudo-first order rate constant of 0.126 min-1 at 1 mM peptide (80% conversion in 10 min), and with no detectable side products on the peptide. A broad peptide sequence scope and water-soluble phosphines with alkyl as well as aromatic groups were all shown to react efficiently. Phosphine addition proved to be efficient on nisin as a model Dha-containing biologically-derived peptide and on an mRNA-displayed peptide, as well as on TCEP-modified agarose for peptide capture from solution. This reaction thus presents a promising approach for modification of peptides for cargo attachment or altered physical properties in peptide discovery.

Ultra-small bimetallic phosphides for dual-modal MRI imaging guided photothermal ablation of tumors.

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, T1- and T2-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.

Effect of Phosphorus Precursor, Reduction Temperature, and Support on the Catalytic Properties of Nickel Phosphide Catalysts in Continuous-Flow Reductive Amination of Ethyl Levulinate.

Levulinic acid and its esters (e.g., ethyl levulinate, EL) are platform chemicals derived from biomass feedstocks that can be converted to a variety of valuable compounds. Reductive amination of levulinates with primary amines and H2 over heterogeneous catalysts is an attractive method for the synthesis of N-alkyl-5-methyl-2-pyrrolidones, which are an environmentally friendly alternative to the common solvent N-methyl-2-pyrrolidone (NMP). In the present work, the catalytic properties of the different nickel phosphide catalysts supported on SiO2 and Al2O3 were studied in a reductive amination of EL with n-hexylamine to N-hexyl-5-methyl-2-pyrrolidone (HMP) in a flow reactor. The influence of the phosphorus precursor, reduction temperature, reactant ratio, and addition of acidic diluters on the catalyst performance was investigated. The Ni2P/SiO2 catalyst prepared using (NH4)2HPO4 and reduced at 600 °C provides the highest HMP yield, which reaches 98%. Although the presence of acid sites and a sufficient hydrogenating ability are important factors determining the pyrrolidone yield, the selectivity also depends on the specific features of EL adsorption on active catalytic sites.

Biocompatible silver(I) complexes with heterocyclic thioamide ligands for selective killing of cancer cells and high antimicrobial activity - A combined in vitro and in silico study.

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(µ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(µ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6-4.5 µM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32-3.00 µΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.

Evaluation of anticancer activity in vitro of a stable copper(I) complex with phosphine-peptide conjugate.

[CuI(2,9-dimethyl-1,10-phenanthroline)P(p-OCH3-Ph)2CH2SarcosineGlycine] (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.

Chelating Phosphine-N-Heterocyclic Carbene Platinum Complexes via Catalytic Asymmetric Hydrophosphination and Their Cytotoxicity Toward MKN74 and MCF7 Cancer Cell Lines.

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.

Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells.

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.

Ruthenium(II) Diphosphine Complexes with Mercapto Ligands That Inhibit Topoisomerase IB and Suppress Tumor Growth In Vivo.

Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)2]PF6, 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 IC50 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]PF6 (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.

Microwave-assisted Phospha-Michael addition reactions in the 13α-oestrone series and in vitro antiproliferative properties.

Microwave-assisted phospha-Michael addition reactions were carried out in the 13α-oestrone series. The exocyclic 16-methylene-17-ketones as α,ß-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 IC50 values. Moreover, it displayed good tumour selectivity property determined against non-cancerous mouse fibroblast cells.

Homo and heterobimetallic palladium and platinum complexes bearing µ-diphosphane bridges involved in biological studies.

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: [LnM1(µ-R2P(CH2)nPR2)M2Lm] (where M1 is platinum or palladium, M2 is any other transition metal, R = alkyl or aryl substituents, Ln or Lm 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.

Iron-catalysed enantioselective carbometalation of azabicycloalkenes.

The first enantioselective carbometalation reaction of azabicycloalkenes has been achieved by iron catalysis to in situ form optically active organozinc intermediates, which are amenable to further synthetic elaborations. The observed chiral induction, along with the DFT and XAS analyses, reveals the direct coordination of the chiral phosphine ligand to the iron centre during the carbon-carbon and carbon-metal bond forming step. This new class of iron-catalysed asymmetric reaction will contribute to the synthesis and production of bioactive molecules.

Diethynyl Phosphinates for Cysteine-Selective Protein Labeling and Disulfide Rebridging.

Diethynyl phosphinates were developed as bisfunctional electrophiles for the site-selective modification of peptides, proteins and antibodies. One of their electron-deficient triple bonds reacts selectively with a thiol and positions an electrophilic moiety for a subsequent intra- or intermolecular reaction with another thiol. The obtained conjugates were found to be stable in human plasma and in the presence of small thiols. We further demonstrate that this method is suitable for the generation of functional protein conjugates for intracellular delivery. Finally, this reagent class was used to generate functional homogeneously rebridged antibodies that remain specific for their target. Their modular synthesis, thiol selectivity and conjugate stability make diethynyl phosphinates ideal candidates for protein conjugation for biological and pharmaceutical applications.