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Based on bis-hetarylhydrazone H2L, a condensation product of 2,6-diacetylpyridine with 2-hydrazinobenzoxazole, a series of mononuclear copper(II) coordination compounds have been synthesized: [Cu(HL)NO3], [Cu(HL)(H2O)]ClO4, [Cu(HL)X] (X = Br−, X = Cl−). The structure of the compounds has been studied by means of NMR, IR, ESR, X-ray absorption spectroscopy and X-ray single crystal diffraction methods. In the compounds the copper center is in the square pyramidal environment. All compounds have been screened in vitro for their cytotoxic activity against HepG2 and MRC-5 cell lines. The ligand H2L shows no cytotoxicity at tested concentrations (1–100 μM), while all the Cu(II) complexes exhibit significant dose-dependent cytotoxic effects with IC50 values in the range of 1.4–3.0 μM (HepG2 cells). Show less

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment. Show less

Title: Synthesis, characterisation and biological evaluation of monometallic Re(I) and heterobimetallic Re(I)/Fe(II) complexes with a 1,2,3-triazolyl pyridine chelating moiety. Abstract: Bioorganometallic complexes have attracted considerable interest and have shown promise for potential application in the treatment and diagnosis of cancer, as well as bioimaging agents, some acting as theranostic agents. The series of novel ferrocene, benzimidazo[1,2-a]quinoline and fluorescein derivatives with bidentate pyridyl-1,2,3-triazole and 2,2'-dipyridylamine and their tricarbonylrhenium(I) complexes was prepared and fully characterised by NMR, single-crystal X-ray diffraction, UV-Vis and fluorescence spectroscopy in biorelevant conditions. The fluorescein and benzimidazo[1,2-a]quinoline ligands and their complexes with Re(I) showed interactions with ds-DNA/RNA and HSA, characterised by thermal denaturation measurements, fluorimetric and circular dichroism titrations. The binding constants revealed that addition of Re(I) increases the affinity of fluorescein but decreases the affinity of benzimidazo[1,2-a]quinoline. The complexation of Re(I) had the opposite effect on fluorescein and benzimidazo[1,2-a]quinoline ligands' fluorimetric sensitivity upon biomacromolecule binding, Re(I) fluorescein complex emission being strongly quenched by DNA/RNA or HSA, while emission of Re(I) benzimidazo[1,2-a]quinolone complex was enhanced, particularly for HSA, making it a promising fluorescent probe. Some mono- and heterobimetallic complexes showed considerable antiproliferative activity on colon cancer cells (CT26 and HT29), with ferrocene dipyridylamine complexes exhibiting the best inhibitory activity, comparable to cisplatin. The correlation of the cytotoxicity data with the linker type between the ferrocene and the 1,2,3-triazole ring suggests that direct binding of the metallocene to the 1,2,3-triazole is favourable for antitumor activity. The Re(I) benzimidazo[1,2-a]quinolone complex showed moderate antiproliferative activity, in contrast to the Re(I) fluorescein complex, which exhibited weak activity on CT26 cells and no activity on HT29 cells. The accumulation of the Re(I) benzimidazo[1,2-a]quinolone complex in the lysosomes of CT26 cells indicates the site of its bioactivity, thus making this complex a potential theranostic agent. Show less

Abstract The complex [Zn(Phen)(H2O)L2] (I), where HL is 5-benzyltetrazole, Phen is 1,10-phenanthroline, was synthesized. The compound was characterized by standard physicochemical methods (elemental analysis, powder X-ray diffraction, IR spectroscopy). According to X-ray diffraction data (CCDC no. 2220597), zinc coordination environment in the crystal structure of I corresponds to a distorted trigonal bipyramid. The ligand HL is monodentate and is coordinated via tetrazolate ring nitrogen. The stability of complex I was studied by NMR spectroscopy in DMSO. The cytotoxic properties of the compound were assessed against HepG-2 (hepatocellular carcinoma) and MRC-5 (noncancerous human fibroblasts) cells. Complex I exhibits weak cytotoxic properties in the studied concentration range (1–100 µM). Show less

Introduction: Ruthenium(II) complexes have emerged recently as candidates for anti-cancer therapy, where activity is related to lipohilicity, cellular localization, and specific interactions with biomolecules. Methods: In this work, two novel complexes were synthesized and are reported based on the [Ru(phen)₂(dipyrido[3,2-f:2',3'-h]quinoxaline]²⁺ framework. Results: Compared to the parent complex, annealing of cyclopenteno and cyclohexeno rings to the extended ligand substantially increased cytotoxicity towards a number of cancer cell lines, and induced apoptosis. The complexes localize in the nuclei of cancer cells and co-locate with DAPI on DNA. DNA binding studies show that both complexes bind strongly to DNA and one complex intercalates DNA like the parent, whilst the other appears to have multiple modes of interaction. Discussion: It is likely that the increased lipophilicity of the novel complexes is a key factor for increasing their cytotoxicity, rather than their DNA binding mode. Show less

NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation. Show less

Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy. Show less

Cancer is a devastating disease with over 100 types, including lung and breast cancer. Cisplatin and metal-based drugs are limited due to their drug resistance and side effects. Iridium-based compounds have emerged as promising candidates due to their unique chemical properties and resemblance to platinum compounds. The objective of this study is to investigate the synthesis and categorization of iridium complexes, with a particular emphasis on their potential use as anticancer agents. The major focus of this research is to examine the synthesis of these complexes and their relevance to the field of cancer treatment. The negligible side effects and flexibility of cyclometalated iridium(III) complexes have garnered significant interest. Organometallic half-sandwich Ir(III) complexes have notable benefits in cancer research and treatment. The review places significant emphasis on categorizing iridium complexes according to their ligand environment, afterward considering the ligand density and coordination number. This study primarily focuses on several methods for synthesizing cyclometalated and half-sandwich Ir complexes, divided into subgroups based on ligand denticity. The coordination number of iridium complexes determines the number of ligands coordinated to the central iridium atom, which impacts their stability and reactivity. Understanding these complexes is crucial for designing compounds with desired properties and investigating their potential as anticancer agents. Cyclometalated iridium(III) complexes, which contain a meta-cycle with the E-M-C order σ bond, were synthesized in 1999. These complexes have high quantum yields, significant stock shifts, luminescence qualities, cell permeability, and strong photostability. They have been promising in biosensing, bioimaging, and phosphorescence of heavy metal complexes. Show less

Finding suggests that the sugar substitute sucralose could one day be used to treat autoimmune conditions. Finding suggests that the sugar substitute sucralose could one day be used to treat autoimmune conditions. Show less

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease. Show less

Spinal muscular atrophy is an autosomal recessive neuromuscular disease caused by mutations in the multifunctional protein Survival of Motor Neuron, or SMN. Within the nucleus, SMN localizes to Cajal bodies, which are associated with nucleoli, nuclear organelles dedicated to the first steps of ribosome biogenesis. The highly organized structure of the nucleolus can be dynamically altered by genotoxic agents. RNAP1, Fibrillarin, and nucleolar DNA are exported to the periphery of the nucleolus after genotoxic stress and, once DNA repair is fully completed, the organization of the nucleolus is restored. We find that SMN is required for the restoration of the nucleolar structure after genotoxic stress. During DNA repair, SMN shuttles from the Cajal bodies to the nucleolus. This shuttling is important for nucleolar homeostasis and relies on the presence of Coilin and the activity of PRMT1. Show less

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy. Show less

Installing proton-coupled electron transfer (PCET) in Ir-complexes is indeed a newly explored phenomenon, offering high quantum efficiency and tunable photophysics; however, the prospects for its application in various fields, including interrogating biological systems, are quite open and exciting. Herein, we developed various organelle-targeted Ir(iii)-complexes by leveraging the photoinduced PCET process to see the opportunities in phototherapeutic application and investigate the underlying mechanisms of action (MOAs). We diversified the ligands' nature and also incorporated a H-bonded benzimidazole-phenol (BIP) moiety with π-conjugated ancillary ligands in Ir(iii) to study the excited-state intramolecular proton transfer (ESIPT) process for tuning dual emission bands and to tempt excited-state PCET. These visible or two-photon-NIR light activatable Ir-catalysts generate reactive hydroxyl radicals (˙OH) and simultaneously oxidize electron donating biomolecules (1,4-dihydronicotinamide adenine dinucleotide or glutathione) to disrupt redox homeostasis, downregulate the GPX4 enzyme, and amplify oxidative stress and lipid peroxide (LPO) accumulation. Our homogeneous photocatalytic platform efficiently triggers organelle dysfunction mediated by a Fenton-like pathway with spatiotemporal control upon illumination to evoke ferroptosis poised with the synergistic action of apoptosis in a hypoxic environment leading to cell death. Ir2 is the most efficient photochemotherapy agent among others, which provided profound cytophototoxicity to 4T1 and MCF-7 cancerous cells and inhibited solid hypoxic tumor growth in vitro and in vivo. Show less

A new bis-benzoxazolylhydrazone of 2,6-diacetylpyridine and mononuclear Cu(ii) complexes based on it have been synthesized. An in vitro study showed that all Cu(ii) complexes exhibit high cytotoxic activity against the HepG2 cancer cell line. Show less

Six half-sandwich Ru(II) complexes (Ru1-Ru6), integrated with 5-phenyl-2-(pyridin-2-yl)-2,4-dihydro-3H-pyrazol-3-one (PDPO1-PDPO6) ligands, were synthesized and spectroscopically characterized. The structure of Ru3 that crystallized as a monoclinic crystal with P21/c space group was further confirmed by X-ray single crystal diffraction. Prototropic tautomerism within the complexes transformed OH-form ligands to NH-form, forming a hydrogen bond (Cl₁---H-N₃). The complexes and ligands' cytotoxicity was assessed against several cancerous (HepG2, A549, MCF-7) and normal Vero cell lines. Relative to the ligands and Cisplatin, complexes (Ru2, Ru3, Ru5, Ru6) exhibited potent cytotoxicity against cancer cells, with IC₅₀ values from 2.05 to 15.69 μM/L, excluding Ru1 and Ru4. Specifically, Ru2, Ru3, and Ru5 demonstrated superior anti-HepG2 properties. Compared to Cisplatin, Ru2 and Ru5 were less toxic to Vero cells, highlighting their enhanced selectivity in toxicity. Structure-activity relationship (SAR) studies indicated that t-butyl substitution (in Ru2) or -Cl (in Ru5) on the benzene ring significantly improved the selective toxicity. These complexes manifested substantial lipophilicity, cellular uptake, and were quickly hydrolyzed to Ru-H₂O species. Roughly positive correlations were observed between hydrolysis rate, lipophilicity, cellular uptake, and anticancer activities. Ru2, investigated specifically, induced apoptosis in HepG2 cells at concentrations of 10 and 20 μM/L through ROS-mediated mitochondrial dysfunction and G0/G1phase arrest, associated with altered P21, cyclin D, and CDK4 expression levels. Show less

As the potential applications of DNA diagnostics continue to expand, there is a need for improved methods and standards for DNA analysis. This report describes several methods that could be considered for the production of reference materials for the quantitative measurement of DNA damage in mammalian cells. With the focus on DNA strand breaks, potentially useful methods for assessing DNA damage in mammalian cells are reviewed. The advantages and limitations of each method, as well as additional concerns with respect to reference material development, are also discussed. In conclusion, we outline strategies for developing candidate DNA damage reference materials that could be adopted by research laboratories in a wide variety of applications. Show less

Title: Mitochondria-targeted cyclometalated iridium-β-carboline complexes as potent non-small cell lung cancer therapeutic agents. Abstract: Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPβC)](PF6), where PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with β-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model. Show less

AbstractUnderstanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, and prognosis. Emerging approaches for the in situ detection of the major regulators and biological events across cellular, tissue, and in living subjects provide a multiscale perspective for studying ferroptosis. Furthermore, advanced applications that integrate ferroptosis detection and the latest technologies hold tremendous promise in ferroptosis research. In this review, we first briefly summarize the mechanisms and key regulators underlying ferroptosis. Ferroptosis detection approaches are then presented to delineate their design, mechanisms of action, and applications. Special interest is placed on advanced ferroptosis applications that integrate multifunctional platforms. Finally, we discuss the prospects and challenges of ferroptosis detection approaches and applications, with the aim of providing a roadmap for the theranostic development of a broad range of ferroptosis‐related diseases. Show less

The process of patenting inventions may be complex. Academic researchers whose primary goal is getting their work published in scientific journals often face daunting doubts when it comes to understanding the interplay between publishing and patenting their findings. We asked Prof Frank Tietze questions from the perspective of academic researchers who wish to understand how the patenting process works and—most importantly—the relation between patenting and publishing. Show less

Metalation, the acquisition of metals by proteins, must avoid mis-metalation with tighter binding metals. This is illustrated by four selected proteins that require different metals: all show similar ranked orders of affinity for bioavailable metals, as described in a universal affinity series (the Irving-Williams series). Crucially, cellular protein metalation occurs in competition with other metal binding sites. The strength of this competition defines the intracellular availability of each metal: its magnitude has been estimated by calibrating a cells' set of DNA-binding, metal-sensing, transcriptional regulators. This has established that metal availabilities (as free energies for forming metal complexes) are maintained to the inverse of the universal series. The tightest binding metals are least available. With these availabilities, correct metalation is achieved. Show less

The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision Show less