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Fluorescence microscopy has emerged as an attractive technique to probe the intracellular processing of Pt‐based anticancer compounds. Herein, we reported the first through‐bond energy transfer (TBET) fluorescent probe NPR1 designed for sensitive detection and quantitation of PtII complexes. The novel TBET probe was successfully applied for ratiometric fluorescence imaging of anticancer PtII complexes such as cisplatin and JM118 in cells. Capitalizing on the ability of the probe to discriminate between PtII complexes and their PtIV derivatives, the probe was further applied to study the activation of PtIV prodrug complexes that are known to release active PtII species after intracellular reduction. [ABSTRACT FROM AUTHOR]

The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer. [ABSTRACT FROM AUTHOR]

Abstract: Both metal complexes and organic molecules are widely used for the treatment of various diseases including cancer – in addition to surgery and radiotherapy. Recent years have witnessed a surge of interest in the application of organometallic compounds to treat cancer and other diseases. Indeed, the unique properties of organometallic compounds, intermediate between those of classical inorganic and organic materials provide new opportunities in medicinal chemistry. In this review, based on the award lecture at ICBOMC’10, we describe a class of ruthenium(II)-arene complexes that are weakly cytotoxic in vitro, but show selective antimetastatic activity in vivo. These compounds, [Ru(η6-p-arene)Cl2(pta)] termed RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. The basic RAPTA structure is quite stable in physiological environments, and studies have shown that aquation of the chloride bonds occurs, it may not be an essential step for anticancer drug activity – direct substitution with biomolecular targets is also possible. Based on the favorable physicochemical properties of RAPTA compounds, combined with their highly promising pharmacological properties, the structure represents an ideal scaffold for rational drug design. Thus far, strategies to overcome drug resistance, by interference with critical enzymes responsible for drug deactivation, and tumor targeting, by tethering to human serum albumin via hydrolyzable linkers, have been demonstrated. However, many more approaches can be envisaged. In any case, the net result are a type of hybrid compounds, that occupy a niche somewhere between classical cisplatin-type anticancer agents that are widely applied to many tumor types and targeted therapies based on organic structures used to inhibit specific enzymes. As such, should these compounds prove themselves in the clinic it is not inconceivable that they could be rapidly refined to form personalized chemotherapies. [Copyright &y& Elsevier]

Abstract: Organometallic half-sandwich complexes based on ruthenium with aminomethyl-substituted 3-hydroxy-2-pyridone ligands exist in aqueous solution as monomeric O,O′-chelate complexes or trimeric metallamacrocycles depending upon the pH. We hypothesized that administration of the compounds as stable trimers, which subsequently convert to active monomers at the reduced pH of the cancer environment, could facilitate their delivery to cancer cells without undergoing deactivation. Thus, the compounds were evaluated against cancer and fibroblast cell lines in vitro. A series of rhodium complexes, which exist mainly as monomers at neutral pH, were also studied for comparative purposes. [Copyright &y& Elsevier]

The reaction of the iminobiphosphines RNPPh2–PPh2, where R = C6H4(p-CN), C6H4(m-CN), C6H4(o-C6H5), C6F5 or C6H4(o-CF3), with one molecular equivalent of M(cod)Cl2 (M = Pd or Pt) results in a rearrangement of the NPP unit to the more commonly encountered P–N–P unit, forming mono-chelating complexes of general formula M{RN(PPh2)2}Cl2. The related reaction of the same range of iminobiphosphines with Pt(cod)Cl2 (but not Pd(cod)Cl2) in 2:1 ratio affords complexes of general formula [Pt{RN(PPh2)2}2]2Cl. All 15 complexes are isolated in moderate to high yield and they have been fully characterised by spectroscopic methods. Six complexes, viz. [M{C6H4(p-CN)N(PPh2)2}Cl2], [M{C6H4(m-CN)N(PPh2)2}Cl2] and [M{C6H4(o-C6H5)N(PPh2)2}Cl2] (M = Pd and Pt), have been characterised in the solid state by single crystal X-ray diffraction analysis. [Copyright &y& Elsevier]

Replacement of a single dA nucleotide positioned at a programmed site in a DNA plasmid with its 7-deaza-analog is described together with its complete resistance to restriction enzymatic cleavage. [ABSTRACT FROM AUTHOR]

Rising antimicrobial resistance (AMR) and lack of innovation in the antibiotic pipeline necessitate novel approaches to discovering new drugs. Metal complexes have proven to be promising antimicrobial compounds, but the number of studied compounds is still low compared to the millions of organic molecules investigated so far. Lately, machine learning (ML) has emerged as a valuable tool for guiding the design of small organic molecules, potentially even in low‐data scenarios. For the first time, we extend the application of ML to the discovery of metal‐based medicines. Utilising 288 modularly synthesized ruthenium arene Schiff‐base complexes and their antibacterial properties, a series of ML models were trained. The models perform well and are used to predict the activity of 54 new compounds. These displayed a 5.7x higher hit‐rate (53.7 %) against methicillin‐resistant Staphylococcus aureus (MRSA) compared to the original library (9.4 %), demonstrating that ML can be applied to improve the success‐rates in the search of new metalloantibiotics. This work paves the way for more ambitious applications of ML in the field of metal‐based drug discovery. [ABSTRACT FROM AUTHOR]

Die steigende antimikrobielle Resistenz (AMR) und der Mangel an Innovation in der Antibiotikaforschung erfordern neue Ansätze zur Entwicklung von Medikamenten. Metallkomplexe haben sich als vielversprechende antimikrobielle Verbindungen erwiesen. Allerdings ist die Anzahl der untersuchten Verbindungen noch klein, besonders im Vergleich zu den Millionen organischer Moleküle die bereits getestet wurden. In den letzten Jahren hat sich maschinelles Lernen (ML) als wertvolle Ressource für die Entwicklung organischer Moleküle herauskristallisiert, selbst wenn nur wenige Daten vorliegen. Erstmals erweitern wir die Anwendung von ML auf die Entdeckung von metallbasierten antimikrobiellen Verbindungen. Mithilfe von 288 modular synthetisierten Ruthenium‐Aren‐Schiff‐Basen‐Komplexen und deren antibakteriellen Eigenschaften haben wir eine Reihe von ML–Modellen trainiert. Die Modelle zeigen gute Leistungen und werden verwendet, um die Aktivität von 54 neuen Verbindungen vorherzusagen. Diese Verbindungen weisen eine 5.7‐fach höhere Trefferquote (53.7 %) gegen Methicillin‐resistente Staphylococcus aureus (MRSA) im Vergleich zur ursprünglichen Bibliothek (9.4 %) auf. Dadurch zeigen wir, dass ML zu höheren Erfolgsraten bei der Suche nach neuen Metalloantibiotika führen kann. Folglich ebnet diese Arbeit den Weg für fortschrittlichere Anwendungen von ML im Bereich der metallbasierten Wirkstoffentwicklung. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo‐immunotherapeutic combination regimens through the establishment of a long‐term cancer immunity. None of the clinically used DNA‐binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII‐carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt‐NHC and compared their efficiency in triggering ICD‐related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD‐associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER‐localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo‐immunotherapeutic combination regimens through the establishment of a long‐term cancer immunity. None of the clinically used DNA‐binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII‐carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt‐NHC and compared their efficiency in triggering ICD‐related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD‐associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER‐localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. [ABSTRACT FROM AUTHOR]

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites. [ABSTRACT FROM AUTHOR]

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites. [ABSTRACT FROM AUTHOR]

Interleukin‐2 (IL‐2) is one of the first FDA‐approved immunotherapeutics, but its use is limited by toxicity and low efficacy. In addition, all immunotherapies are limited by the immunosuppressive and desmoplastic microenvironment of "immunologically cold" tumors, such as pancreatic ductal adenocarcinoma (PDAC) or hepatocellular carcinoma (HCC) with advanced liver fibrosis. Here, a new chemoimmunotherapy nanogel (IL2‐Pt@Nanogel) for dual delivery of IL‐2 and the type II immunogenic cell death inducer Pt‐NHC that reduces the immunosuppressive phenotype of tumor‐associated macrophages and diminishes regulatory T cell infiltration by inducing the production of type I interferon (IFN) by cancer cells is reported. Combining the angiotensin II receptor blocker losartan with IL2‐Pt@Nanogel treatment reduces desmoplasia and reprogrammes the microenvironment of PDAC and HCC toward an immunostimulatory one. These effects result in potent anti‐tumor efficacy in models of primary and metastatic PDAC and HCC with underlying liver fibrosis. This study presents a strategy for IL‐2‐based chemoimmunotherapy with the potential for clinical translation to treat solid tumors. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents. [ABSTRACT FROM AUTHOR]

Platinum(iv) carboxylate scaffolds have garnered considerable research interest because they can be engineered to function as prodrugs of clinical platinum(ii) anticancer drugs. These platinum(iv) prodrug complexes are stable and tunable, and activated by reduction to release their cytotoxic platinum(ii) cargo. Here we propose new platinum(iv) prodrug complexes designed to release cisplatin via photoreduction upon UV irradiation. The central strategy is to utilise aryl carboxylate ligands on the axial positions of that platinum(iv) scaffold that confer significant UV absorption and would stabilise carboxyl radical formation, thus favouring homolytic Pt–O bond cleavage. We isolated and identified aryl carboxyl radicals via spin-trapping and showed that the photoreduced platinum species mirror cisplatin reactivity toward DNA bases, thereby validating the efficacy of this approach. [ABSTRACT FROM AUTHOR]

This article discusses various issues related to rational design of platinum IV compounds to overcome glutathione-S-transferase (GST) mediated drug resistance. One important enzyme responsible for drug resistance in some cancers, is GST. Cytosolic GST enzymes constitute the main cellular defense against xenobiotics, and they are known to catalyze the conjugation of glutathione with cisplatin in vitro. Satraplatin is a promising platinum IV anticancer drug, currently undergoing Phase III clinical trials for combination treatment in patients with hormone-refractory prostate cancer. The article authors decided to tether ethacrynic acid to platinum to give a satraplatin-like compound, capable of targeting GST enzymes in human cancer cells.

There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an 'anticancer vaccine'. In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A PtII N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an 'anticancer vaccine'. In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A PtII N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off-target immune-modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt-based chemotherapeutic agents to exploit their immune-activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal PtIV prodrug containing a FPR1/2-targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach. [ABSTRACT FROM AUTHOR]

There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off-target immune-modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt-based chemotherapeutic agents to exploit their immune-activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal PtIV prodrug containing a FPR1/2-targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach. [ABSTRACT FROM AUTHOR]

The phosphorylation of a series of diaminopyridines (2,3-, 3,4-, 2,5- and 2,6-diaminopyridine), with various molecular equivalents of chlorodiphenylphosphine in the presence of TEA has been studied. Notably, phosphorylation of 2,3- and 3,4-diaminopyridine affords compounds with diphosphinoamine (P-N-P) and iminobiphosphine (N=P-P) entities co-existing in the same molecule. Phosphorylations of 2,5- and 2,6-diaminopyridine afford compounds containing only diphosphinoamine units. The solid-state structure of three compounds has been determined including the first example of a crystallographically characterized compound containing both a diphosphinoamine group and an iminobiphosphine group in the same structure. [ABSTRACT FROM AUTHOR]

Unter Beobachtung: Eine Fluoreszenzsonde zur Detektion von klinisch relevantem Cisplatin innerhalb einer zellulären Umgebung wurde entwickelt. Die Sonde ermöglicht die Visualisierung des Zelleintritts und der Aktivierung von Platin(IV) ‐ Wirkstoffvorstufen in Krebszellen. [ABSTRACT FROM AUTHOR]

Watching closely: A fluorescent probe was engineered to detect the clinically relevant platinum drug cisplatin within a complex cellular environment, thus providing a direct means for visualizing its cell entry and the activation of platinum(IV) prodrugs in cancer cells. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases (PTPs) belong to a large family of important regulatory enzymes involved in vital mammalian signaling pathways. Selective inhibitors of PTPs are highly valuable from a therapeutic standpoint given their association with various pathological conditions. One such target is PTP-1B which has previously been linked to diabetes and cancer. However, developing a selective inhibitor against PTP-1B has proven to be daunting because the enzyme shares a high degree of structural homology with TC-PTP, an essential PTP involved in modulating immune functions. To address this challenge, a series of organoruthenium complexes was developed to bind at the PTP substrate-binding site while simultaneously target the peripheral structural space. By capitalizing on the potential difference in the structural environment proximal to the active site between different PTPs, selectivity toward PTP-1B over TC-PTP was improved, paving the way for organoruthenium complexes as selective PTP-1B metalloinhibitors. [ABSTRACT FROM AUTHOR]

Organometallic ruthenium-arene RAPTA complexes, currently being actively pursued as potential anticancer agents, interact with intracellular biological targets to form covalent adducts. Because their mode of action is still unclear, we investigated their binding with DNA and the ability of ruthenated-DNA adducts to elicit cellular responses such as transcription inhibition and repair. To investigate the influence of the spectator arene ligands on RAPTA activity, a novel RAPTA complex containing the bulky 1,3,5-triisopropylbenzene ligand was synthesized and characterized. Transcription experiments carried out in live mammalian cells using ruthenated plasmid probes revealed that increasing steric bulk of the arene ligand did not improve its ability to arrest transcription. Transcription experiments carried out in live mammalian cells using plasmid probes damaged by RAPTA complexes revealed that increasing steric bulk of arene ligand does not improve their ability to arrest transcription. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy‐disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000‐fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro‐survival responses to induce deadly metabolic catastrophe. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy‐disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000‐fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro‐survival responses to induce deadly metabolic catastrophe. [ABSTRACT FROM AUTHOR]

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria‐targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria‐targeted fluorescent probe for real‐time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry. [ABSTRACT FROM AUTHOR]

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria‐targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria‐targeted fluorescent probe for real‐time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry. [ABSTRACT FROM AUTHOR]

Fluorescence imaging using charge‐coupled device cameras has become the prevailing method for the investigation of cancer drug efficacy in in vivo preclinical trials involving animal models. The lack of imaging depth, however, limits the use of fluorescence techniques to small murine models, and compels large animal models to rely on more‐costly magnetic resonance imaging or positron emission tomography techniques. Here, a wide field‐of‐view fluorescence imaging technique that uses near‐infrared (NIR) laser‐scanning excitation and efficient quantum dot photoluminescence is developed to achieve deep imaging across thick animal tissues. The smaller excitation volume from the scanning laser beam minimizes undesired background fluorescence, and allows signals to be detected and resolved at large tissue depths exceeding 10 mm. By implementing an artificial neural network algorithm, a twofold enhancement in imaging resolution is further demonstrated, which paves a promising way forward for the use of machine intelligence to enhance imaging quality in highly scattering media. The superior contrast of the imaging method is further corroborated by the imaging of a human palm, where bone structures are, for the first time, distinguishable using a NIR technique. In combination, the laser‐scanning approach and the artificial neural network image‐processing can constitute a low‐cost, yet powerful methodology for performing noninvasive deep‐imaging in larger animal models or human tissues. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. [ABSTRACT FROM AUTHOR]

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. [ABSTRACT FROM AUTHOR]

The PtIV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional PtII drug therapy. However, there is a lack of tools to study how this new class of PtIV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate PtIV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its PtIV derivatives, allowing us to probe the intracellular reduction of PtIV prodrug complexes. The correlation between the amount of active PtII species available after intracellular reduction of PtIV complexes and their cytotoxicity and the role glutathione plays in the reduction of PtIV complexes were investigated. [ABSTRACT FROM AUTHOR]

The PtIV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional PtII drug therapy. However, there is a lack of tools to study how this new class of PtIV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate PtIV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its PtIV derivatives, allowing us to probe the intracellular reduction of PtIV prodrug complexes. The correlation between the amount of active PtII species available after intracellular reduction of PtIV complexes and their cytotoxicity and the role glutathione plays in the reduction of PtIV complexes were investigated. Watching closely: A ratiometric fluorescent probe was engineered to detect the clinically relevant platinum drug cisplatin. The ability to distinguish platinum(II) species from their parental platinum(IV) complexes allowed the application of the probe to the study of the activation of platinum(IV) carboxylate prodrug complexes within a complex intracellular environment. [ABSTRACT FROM AUTHOR]

Abstract: The development of new methods to synthesize nanometric metal catalysts has always been an important and prerequisite step in advanced catalysis. Herein, we design a stable nitrogen ligated Pt complex for the straightforward synthesis by carbonization of uniformly sized atomic and sub‐nanometric Pt catalysts supported on mesoporous silica. During the carbonization of the Pt precursor into active Pt species, the nitrogen‐containing ligand directed the decomposition in a controlled fashion to maintain uniform sizes of the Pt species. The nitrogen ligand had a key role to stabilize the single Pt atoms on a weak anchoring support like silica. The Pt catalysts exhibited remarkable activities in the hydrogenation of common organic functional groups with turnover frequencies higher than in previous studies. By a simple post‐synthetic treatment, we could selectively remove the Pt nanoparticles to obtain a mixture of single atoms and nanoclusters, extending the applicability of the present method. [ABSTRACT FROM AUTHOR]

Abstract: A new pre‐assembled ratiometric sensing platform was constructed from a coumarin donor and a rhodamine acceptor designed for through‐bond energy transfer (TBET). A phenylacetylene linker was installed to disrupt the planarity of the extended conjugated system but retaining the efficient energy transfer between the donor and acceptor motifs. To demonstrate its versatility as a sensing platform, we conjugated recognition motifs through amide coupling reactions to yield two TBET chemosensors capable of sensing either endogenously produced NO and ClO−. Both probes possessed high selectivity for their analytes, exhibited good stability under physiological conditions, and performed well as bioimaging probes in living cells. [ABSTRACT FROM AUTHOR]

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, 1H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Nanotechnology has gained much attention over the last decades, as it offers unique opportunities for the advancement of the next generation of sensing tools. Point-of-care (POC) devices for the selective detection of biomolecules using engineered nanoparticles have become a main research thrust in the diagnostic field. This review presents an overview on how the POC-associated nanotechnology, currently applied for the identification of nucleic acids, proteins and antibodies, might be further exploited for the detection of infectious pathogens: although still premature, future integrations of nanoparticles with biological markers that target specific microorganisms will enable timely therapeutic intervention against life-threatening infectious diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Phenotypic plasticity and cancer microbiome were added to "Hallmarks of cancer". • Some metal complexes showed selectivity towards cancer stem cells over cancer bulk. • Endogenous transition metals are important for maintaining intestinal microbiome. • Some metal complexes inhibited oncogenic bacteria and modulated cancer microbiome. • Metal complexes are undervalued therapeutic options for cancer treatment. In this last decade, our understanding of the complex factors and processes that drive cancer development and progression has broadened in scope and grown in depth. Today it is widely held that as a disease, cancer can be characterized in terms of specific hallmarks that normal cells need to acquire to transform into malignant cells. Because it is both logical and intuitive, the hallmarks of cancer concept have been adopted by both the scientific and medical community as an organising principle to understand cancer and to develop new therapeutic approaches. Several new hallmarks have emerged in recent years arising from a better understanding of the crosstalk between cancer cells and their surrounding tumor microenvironment. There is evidence of the so-called "metallic" crosstalk that is linked to neoplastic cell transformation. The current review is based on the collaborative efforts of bioinorganic chemists, molecular biologists and medical doctors. It summarizes the therapeutic strategies developed for targeting phenotypic plasticity and cancer microbiome arising from interactions with transition metals and discusses whether transition metal complexes might offer therapeutic advantages compared to current treatment options. [ABSTRACT FROM AUTHOR]

[Display omitted] • The development of many cancer types is associated with global epigenetic changes. • Metal complexes were shown to interfere with the function of DNMTs, HMDs and HDACs. • Metal prodrugs can be activated upon intracellular triggers. • Selective release of epigenetic modulators might translate into lower toxicity. • Transition metal complexes represent a promising alternative to existing epitherapies. In this last decade, our understanding of the complex factors and processes that drive cancer development and progression has broadened in scope and grown in depth. Today, it is widely held that as a disease, cancer can be characterized in terms of specific hallmarks that normal cells need to acquire to transform into malignant cells. Because it is both logical and intuitive, the hallmarks of cancer concept has been adopted by both the scientific and medical community as an organising principle to understand cancer and to develop new therapeutic approaches. Several new hallmarks have emerged in recent years arising from a better understanding of the crosstalk between cancer cells and their surrounding tumor microenvironment. The current review is based on the collaborative efforts of bioinorganic chemists, molecular biologists and medical doctors. It focuses on the use of transition metals as therapeutic drugs to treat malignancies arising from epigenetic dysregulation and compares the therapeutic approaches of transition metal complexes over existing drugs in clinical use. [ABSTRACT FROM AUTHOR]

Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar- ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy has emerged as an attractive technique for imaging intracellular Pt species arising from exposure to clinical anticancer drugs such as cisplatin. A rhodamine-B based fluorogenic probe termed Rho-DDTC can be activated selectively in the presence of Pt(II) compounds, and possesses the ability to discriminate Pt(II) species from Pt(IV) carboxylate prodrug complexes, thereby providing a unique platform to investigate the reduction of these Pt(IV) complexes after cell entry. In this report, we seek to establish the mechanism of activation of Rho-DDTC through a structure–activity relationship study on its structural analogues. [ABSTRACT FROM AUTHOR]

Thestructural diversity of metal scaffolds makes them a viablealternative to traditional organic scaffolds for drug design. Combinatorialchemistry and multicomponent reactions, coupled with high-throughputscreening, are useful techniques in drug discovery, but they are rarelyused in metal-based drug design. We report the optimization and validationof a new combinatorial, metal-based, three-component assembly reactionfor the synthesis of a library of 442 Ru–arene Schiff-base(RAS) complexes. These RAS complexes were synthesized in a one-pot,on-a-plate format using commercially available starting materialsunder aqueous conditions. The library was screened for their anticanceractivity, and several cytotoxic lead compounds were identified. Inparticular, [(η6-1,3,5-triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayedlow micromolar IC50values in ovarian cancers (A2780, A2780cisR),breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absenceof p53 activation or changes in IC50value between p53+/+and p53–/–cells suggests that 4and possibly the other lead compounds may act independentlyof the p53 tumor suppressor gene frequently mutated in cancer. [ABSTRACT FROM AUTHOR]

Abstract: Among the arsenal of nano-materials, carbon nanotubes (CNTs) are becoming more prominent due to favorable attributes including their unique shape, which promotes cellular-uptake, and large aspect-ratio that facilitates functionalization of bioactive molecules on their surface. In this study, multi-walled carbon nanotubes (MWCNTs) were functionalized with either mitochondrial-targeting fluorescent rhodamine-110 (MWCNT-Rho) or non-targeting fluorescein (MWCNT-Fluo). Despite structural similarities, MWCNT-Rho associated well with mitochondria (ca. 80% co-localization) in contrast to MWCNT-Fluo, which was poorly localized (ca. 21% co-localization). Additionally, MWCNT-Rho entrapping platinum(IV) pro-drug of cisplatin (PtBz) displayed enhanced potency (IC50 = 0.34 ± 0.07 μM) compared to a construct based on MWCNT-Fluo (IC50 ≥ 2.64 μM). Concurrently, preliminary in vitro toxicity evaluation revealed that empty MWCNT-Rho neither decreased cell viability significantly nor interfered with mitochondrial membrane-potential, while seemingly being partially expelled from cells. Due to its targeting capability and apparent lack of cytotoxicity, MWCNT-Rho complex was used to co-encapsulate PtBz and a chemo-potentiator, 3-bromopyruvate (BP), and the resulting MWCNT-Rho(PtBz+BP) construct demonstrated superior efficacy over PtBz free drug in several cancer cell lines tested. Importantly, a 2-fold decrease in mitochondrial potential was observed, implying that mitochondrial targeting of compounds indeed incurred additional intended damage to mitochondria. [Copyright &y& Elsevier]

Abstract: In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNT-based drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs. [Copyright &y& Elsevier]