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Drug discovery (DD) is a time-consuming and expensive process. Thus, the industry employs strategies such as drug repositioning and drug repurposing, which allows the application of already approved drugs to treat a different disease, as occurred in the first months of 2020, during the COVID-19 pandemic. The prediction of drug–target interactions is an essential part of the DD process because it can accelerate it and reduce the required costs. DTI prediction performed in silico have used approaches based on molecular docking simulations, including similarity-based and network- and graph-based ones. This paper presents MPS2IT-DTI, a DTI prediction model obtained from research conducted in the following steps: the definition of a new method for encoding molecule and protein sequences onto images; the definition of a deep-learning approach based on a convolutional neural network in order to create a new method for DTI prediction. Training results conducted with the Davis and KIBA datasets show that MPS2IT-DTI is viable compared to other state-of-the-art (SOTA) approaches in terms of performance and complexity of the neural network model. With the Davis dataset, we obtained 0.876 for the concordance index and 0.276 for the MSE; with the KIBA dataset, we obtained 0.836 and 0.226 for the concordance index and the MSE, respectively. Moreover, the MPS2IT-DTI model represents molecule and protein sequences as images, instead of treating them as an NLP task, and as such, does not employ an embedding layer, which is present in other models. Academic Editors: Kyriakos Kachrimanis, David Barlow, Jakub Show less

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH₂, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions. Show less

Phosphrescent complexes of monodentate imidazole have been reported before, but their dissociation induced by cellular endogenous stimulus have never been explored. In our work, the dissociation of monodentate imidazole ligands from phosphorescent cyclometalated platinum (II) iridium (III) and polypyridyl ruthenium (II) complexes in GSH abundant reductive solution are firstly investigated. The release rate of ligand follows the order: Pt (II) > Ir (III) > > Ru (II) in vitro, while their corresponding bidentate complexes are barely affected. Moreover, the cellular dissociation of ligand can be monitored in time by Confocal imaging and flow cytometry. In brief, cellular penetration and nucleolus targeting ability of GSH active complexes are mainly interfered by the reductive microenvironment. Our work may help to reveal the dynamic process of coordination and release of monodentate ligands of complexes in cellular microenvironment. Show less

Title: Synthesis, characterization and biological evaluation of two cyclometalated iridium(III) complexes containing a glutathione S-transferase inhibitor. Abstract: The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III) compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photophysical properties of Ir-1 ∼ Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunctionalized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III) agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensitizing the efficacy against cisplatin resistant cancer cells. Show less

Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified. Show less

This review summarises different data, data resources and methods for computational mechanism of action (MoA) analysis, and highlights some case studies where integration of data types and methods enabled MoA elucidation on the systems-level. Show less

The gold(iii) ion increases antifungal effects of selected azoles and induces antivirulence effects offering a lower risk for resistance development. TLDR: In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1-7 of the general formula have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole and voriconazole. Show less

Title: Ru(II)-modified TiO Abstract: The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment. Show less

Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those with the phosphine PPh3—exhibited the highest anticancer activity whilst also displaying significant cancer cell selectivity. [Au(S2CNHSO2C6H5)(PPh3)] (1) and [Au(S2CNHSO2-p-Me-C6H4)(IMePropargyl)] (8) produce cell death, probably by intrinsic apoptosis (mitochondrial membrane potential modification) and caspase 3 activation, causing cell cycle arrest in the G1 phase with p53 activation. Besides this, both complexes might act as multi-target anticancer drugs, as they inhibit the activity of the enzymes thioredoxin reductase (TrxR) and carbonic anhydrase (CA IX) with the alteration of the redox balance, and show a pro-oxidant effect. Show less

Hydrogen peroxide (H2 O2 ) is an important reactive oxygen species that plays a major role in redox signaling. Although H2 O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2 O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2 O2 -responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2 O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2 O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells. Transcription of mRNA and lncRNA. Antioxidants 2022, 11, 495. https:// Show less

SLC7A11/xCT is an antiporter that mediates the uptake of extracellular cystine in exchange for glutamate. Cystine is reduced to cysteine, which is a rate-limiting precursor in glutathione synthesis; a process that protects cells from oxidative stress and is, therefore, critical to cell growth, proliferation, and metabolism. SLC7A11 is expressed in different tissues and plays diverse functional roles in the pathophysiology of various diseases, including cancer, by regulating the processes of redox homeostasis, metabolic flexibility/nutrient dependency, immune system function, and ferroptosis. SLC7A11 expression is associated with poor prognosis and drug resistance in cancer and, therefore, represents an important therapeutic target. In this review, we discuss the molecular functions of SLC7A11 in normal versus diseased tissues, with a special focus on how it regulates gastrointestinal cancers. Further, we summarize current therapeutic strategies targeting SLC7A11 as well as novel avenues for treatment. Show less

The curative effect of sorafenib in hepatocellular carcinoma (HCC) is limited and sorafenib resistance remains a major obstacle for HCC. To overcome this obstacle, a new photoactive sorafenib-Ru(II) complex Ru-Sora has been designed. Upon irradiation (λ = 465 nm), Ru-Sora rapidly releases sorafenib and generates reactive oxygen species, which can oxidize intracellular substances such as GSH. Cellular experiments show that irradiated Ru-Sora is highly cytotoxic toward Hep-G2 cells, including sorafenib-resistant Hep-G2-SR cells. Compared to sorafenib, Ru-Sora has a significant photoactivated chemotherapeutic effect against Hep-G2-SR cancer cells and 3D Hep-G2 multicellular tumor spheroids. Furthermore, Ru-Sora inducing apoptosis and ferroptosis is proved by GSH depletion, GPX4 downregulation, and lipid peroxide accumulation. Metabolomics results suggest that Ru-Sora exerts photocytotoxicity by disrupting the purine metabolism, which is expected to inhibit tumor development. This study provides a promising strategy for enhancing chemotherapy and combating drug-resistant HCC disease. Show less

A small molecule was developed that disrupted the lipid–SH2 domain interaction of the spleen tyrosine kinase (Syk), suppressed oncogenic activities in acute myeloid leukemia cell lines and was refractory to drug resistance. Show less

Targeted therapy showed broad application prospects in the treatment of various types of cancer. Through carriers such as aptamers, antibodies, proteins and peptides, targeted therapy can selectively deliver drugs into tumor cells. Compared with traditional treatment methods such as chemo- and radiotherapy, targeted drug delivery systems can reduce the toxic effects of drugs on normal cells and avoid adverse reactions. Herein, an aptamer-cyclometalated iridium(III) complex conjugate (ApIrC) has been designed and developed as a targeted anticancer agent. Owing to the targeting ability of aptamers, ApIrC specifically bound to nucleolin over-expressed on the surface of cancer cells and showed strong fluorescence signal for tumor imaging and diagnosis. ApIrC had more substantial cellular uptake in cancer cells than the iridium complex alone and exhibited favorable low toxicity to normal cells. After uptake by cells through endocytosis, ApIrC can selectively accumulated in mitochondria and induced caspase-3/7-dependent cell death. Remarkably, ApIrC can also specifically target 3D multicellular spheroids (MCSs) and show excellent tumor permeability. So, it can effectively reach the interior of MCSs and cause cell damage. To our knowledge, this is the first report of the aptamer-cyclometalated iridium(III) complex conjugate which studied for cancer targeted therapy. The developed conjugate has great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment. Show less

Elongating RNA polymerase II (Pol II) can be paused or arrested by a variety of obstacles. These obstacles include DNA lesions, DNA-binding proteins, and small molecules. Hairpin pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA in a sequence-specific manner and induce strong transcriptional arrest. Remarkably, this Py-Im-induced Pol II transcriptional arrest is persistent and cannot be rescued by transcription factor TFIIS. In contrast, TFIIS can effectively rescue the transcriptional arrest induced by a nucleosome barrier. The structural basis of Py-Im-induced transcriptional arrest and why TFIIS cannot rescue this arrest remain elusive. Here we determined the X-ray crystal structures of four distinct Pol II elongation complexes (Pol II ECs) in complex with hairpin Py-Im polyamides as well as of the hairpin Py-Im polyamides-dsDNA complex. We observed that the Py-Im oligomer directly interacts with RNA Pol II residues, introduces compression of the downstream DNA duplex, prevents Pol II forward translocation, and induces Pol II backtracking. These results, together with biochemical studies, provide structural insight into the molecular mechanism by which Py-Im blocks transcription. Our structural study reveals why TFIIS fails to promote Pol II bypass of Py-Im-induced transcriptional arrest. Show less

Cryo-electron microscopy studies of Escherichia coli complex I suggest a conserved mechanism of coupled proton transfers and electrostatic interactions that result in proton ejection from the complex exclusively at the distal NuoL subunit. Show less

AbstractBrain cancer, one of the most lethal diseases, urgently requires the discovery of novel theranostic agents. In this context, molecules based on six‐membered phosphorus heterocycles – phosphaphenalenes – are especially attractive; they possess unique characteristics that allow precise chemical engineering. Herein, we demonstrate that subtle structural modifications of the phosphaphenalene‐based gold(I) complexes lead to modify their electronic distribution, endow them with marked photophysical properties and enhance their efficacy against cancer. In particular, phosphaphenalene‐based gold(I) complexes containing a pyrrole ring show antiproliferative properties in 14 cell lines including glioblastomas, brain metastases, meningiomas, IDH‐mutant gliomas and head and neck cancers, reaching IC50 values as low as 0.73 μM. The bioactivity of this new family of drugs in combination with their photophysical properties thus offer new research possibilities for both the fundamental investigation and treatment of brain cancer. Show less

Three iridium (III) polypyridine complexes [Ir(bzq)₂(maip)](PF₆) (Ir1，bzq = benzo[h]quinoline, maip = 3-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(bzq)₂(apip)](PF₆) (Ir2, apip = 2-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(bzq)₂(paip)](PF₆) (Ir3, paip = 4-aminophenyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The cytotoxic activities of the three complexes against human osteosarcoma HOS, U2OS, MG63 and normal LO2 cells were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The results showed that Ir1-3 exhibited moderate antitumor activity against HOS with IC₅₀ of 21.8 ± 0. 4 μM,10.5 ± 1.8 μM and 7.4 ± 0.4 μM, respectively. We found that Ir1-3 can effectively inhibit HOS cells growth and blocked the cell cycle at the G0/G1 phase. Further studies revealed that complexes can increase intracellular reactive oxygen species (ROS) and Ca²⁺, which accompanied by mitochondria-mediated intrinsic apoptosis pathway. In addition, autophagy was also investigated. Taken together, the complexes induce HOS apoptosis through a ROS-mediated mitochondrial dysfunction pathway and inhibition of the PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) signaling pathway. This study provides useful help for understanding the anticancer mechanism of iridium (III) complexes toward osteosarcoma treatment. Show less

A 2.08 Å structure of an alkaline conformer of the domain-swapped dimer of K72A human cytochrome c (Cytc) crystallized at pH 9.9 is presented. In the structure, Lys79 is ligated to the heme. All other domain-swapped dimer structures of Cytc have water bound to this coordination site. Part of Ω-loop D (residues 70-85) forms a flexible linker between the subunits in other Cytc domain-swapped dimer structures but instead converts to a helix in the alkaline conformer of the dimer combining with the C-terminal helix to form two 26-residue helices that bracket both sides of the dimer. The alkaline transition of the K72A human dimer monitored at both 625 nm (high spin heme) and 695 nm (Met80 ligation) yields midpoint pH values of 6.6 and 7.6, respectively, showing that the Met80 → Lys79 and high spin to low spin transitions are distinct. The dimer peroxidase activity increases rapidly below pH 7, suggesting that population of the high spin form of the heme is what promotes peroxidase activity. Comparison of the structures of the alkaline dimer and the neutral pH dimer shows that the neutral pH conformer has a better electrostatic surface for binding to a cardiolipin-containing membrane and provides better access for small molecules to the heme iron. Given that the pH of mitochondrial cristae ranges from 6.9 to 7.2, the alkaline transition of the Cytc dimer could provide a conformational switch to tune the peroxidase activity of Cytc that oxygenates cardiolipin in the early stages of apoptosis. Show less

The field of oxygen free radicals, antioxidants and reactive oxygen species (ROS) has exploded in the past few decades, and BBRC has published several seminal papers. ROS can cause oxidative damage, but also play fundamental roles in living organisms, in such processes as signal transduction and defence against pathogens. ROS underpin every aspect of human biology. Indeed, an endless stream of published papers refers to the biological roles of "ROS". Sadly, much of this work is mechanistically meaningless. To make progress, the detailed molecular mechanisms of action of ROS must be elucidated and appropriate methodology must be used to measure them and the oxidative damage that they can cause, as emphasized in a recent review by Murphy et al. Attention must also switch from clinical studies involving administration of high-dose supplements of vitamins E, C and β-carotene for the treatment or prevention of human disease into other promising diet-derived cytoprotective agents. One of them may be ergothioneine. Show less

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-R-tetrazolato-N2,N3)]²⁺; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo. Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH₂, CF₂H, or CF₃), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-5-difluoromethyltetrazolato-N2,N3)](NO₃)₂, showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities. Show less

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in H₂O/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 μM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking. Show less

AbstractAuranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well‐known inhibition of thioredoxin reductase. Among these targets, inhibitory‐κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology‐like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation. Show less

For the first time, we herein report on the syntheses of two new Ru(II)/bipyridine/phenanthroline complexes containing lapachol as ligand: complex (1), [Ru (bipy)₂(Lap)]PF₆ and complex (2), [Ru(Lap)(phen)₂]PF₆, where bipy = 2,2'-bipyridine and ph en = 1,10-phenanthroline; Lap = lapachol (2-hydroxy-3-(3-methylbut-2-en-1- yl)naphthalene-1,4-dione). The complexes were synthesized and characterized by elemental analyses, molar conductivity, mass spectrometry, ultraviolet-visible and infrared spectroscopies, nuclear magnetic resonance (¹H, ¹³C), and single crystal X-ray diffraction, for complex (2). In addition, in vitro cytotoxicity was tested against six cancer cells: A549 (lung carcinoma); DU-145 (human prostate carcinoma); HepG2 (human hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma); MDA-MB-231 (human breast adenocarcinoma); Caco-2 (human colorectal adenocarcinoma), and against two non-cancer cells, FGH (human gingival normal fibroblasts) and PNT-2 (prostate epithelial cells). Complex (1) was slightly more toxic and selective than complex (2) for all cell lines, except against the A549 cells, where (2) was more potent than complex (1). The complexes induced an increase in the reactive oxygen species, and the co-treatment with N-acetyl-L-cysteine remarkably suppressed the ROS generation and prevented the reduction of cell viability, suggesting that the cytotoxicity of the complexes is related to the ROS-mediated pathway. Further studies indicated that the complexes may bind to DNA via minor groove interaction. Our studies also revealed that free Lap induces gene mutations in Salmonella Typhimurium, nevertheless, the complexes demonstrated the absence of genotoxicity by the Ames test. The present study provides a relevant contribution to understanding the anti-cancer potential and genetic toxicological events of new ruthenium complexes containing the lapachol molecule as a ligand. Show less

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(II) and osmium(II) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(II)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(II)(cym)(p-curc)/(p-bdcurc)(PTA)][SO₃CF₃] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(II) and Os(II) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes. Show less

Ru(II) polypyridyl complexes are widely used in biological fields, due to their physico-chemical and photophysical properties. In this paper, a series of new chiral Ru(II) polypyridyl complexes (1-5) with the general formula {Δ/Λ-[Ru(bpy)₂(X,Y-sal)]BF₄} (bpy = 2,2'-bipyridyl; X,Y-sal = 5-bromosalicylaldehyde (1), 3,5-dibromosalicylaldehyde (2), 5-chlorosalicylaldehyde (3), 3,5-dichlorosalicylaldehyde (4) and 3-bromo-5-chlorosalicylaldehy (5)) were synthesized and characterized by elemental analysis, FT-IR, and ¹H/¹³C NMR spectroscopy. Also, the structures of complexes 1 and 5 were determined by X-ray crystallography; these results showed that the central Ru atom adopts a distorted octahedral coordination sphere with two bpy and one halogen-substituted salicylaldehyde. DFT and TD-DFT calculations have been performed to explain the excited states of these complexes. The singlet states with higher oscillator strength are correlated with the absorption signals and are mainly described as ¹MLCT from the ruthenium centre to the bpy ligands. The lowest triplet states (T₁) are described as ³MLCT from the ruthenium center to the salicylaldehyde ligand. The theoretical results are in good agreement with the observed unstructured band at around 520 nm for complexes 2, 4 and 5. Biological studies on human cancer cells revealed that dihalogenated ligands endow the Ru(II) complexes with enhanced cytotoxicity compared to monohalogenated ligands. In addition, as far as the type of halogen is concerned, bromine is the halogen that provides the highest cytotoxicity to the synthesized complexes. All complexes induce cell cycle arrest in G0/G1 and apoptosis, but only complexes bearing Br are able to provoke an increase in intracellular ROS levels and mitochondrial dysfunction. Show less

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances. Show less