Anticancer gold(iii)-bisphosphine complex alters the mitochondrial electron transport chain to induce in vivo tumor inhibition

Expanding the chemical diversity of metal complexes provides a robust platform to generate functional bioactive reagents. To access an excellent repository of metal-based compounds for probe/drug discovery, we capitalized on the rich chemistry of gold to create organometallic gold(iii) compounds by ligand tuning. We obtained novel organogold(iii) compounds bearing a 1,2-bis(diphenylphosphino)benzene ligand, providing structural diversity with optimal physiological stability. Biological evaluation of the lead compound AuPhos-89 demonstrates mitochondrial complex I-mediated alteration of the mitochondrial electron transport chain (ETC) to drive respiration and diminish cellular energy in the form of adenosine triphosphate (ATP). Mechanism-of-action efforts, RNA-Seq, quantitative proteomics, and NCI-60 screening reveal a highly potent anticancer agent that modulates mitochondrial ETC. AuPhos-89 inhibits the tumor growth of metastatic triple negative breast cancer and represents a new strategy to study the modulation of mitochondrial respiration for the treatment of aggressive cancer and other disease states where mitochondria play a pivotal role in the pathobiology.

Expanding the chemical diversity of metal complexes provides a robust platform to generate functional bioactive reagents.     

Tumor chemical suffocation therapy by dual respiratory inhibitions

The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5′-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) via the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes via the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca²⁺. Meanwhile rotenone is to inhibit the mitochondrial OXPHOS. This work provides a novel tumor suffocation strategy by the co-deliveries of glucose metabolism inhibitors, especially by de-functioning glycolytic enzymes via eliminating their co-worker magnesium.

The EDTA- and Rotenone-loaded MPER nanoparticles have been synthesized to suffocate tumor cells to death through inhibiting glycolytic process and mitochondrial oxidative phosphorylation simultaneously in vitro and in vivo.     

On-surface synthesis of organocopper metallacycles through activation of inner diacetylene moieties

The design of organometallic complexes is at the heart of modern organic chemistry and catalysis. Recently, on-surface synthesis has emerged as a disruptive paradigm to design previously precluded compounds and nanomaterials. Despite these advances, the field of organometallic chemistry on surfaces is still at its infancy. Here, we introduce a protocol to activate the inner diacetylene moieties of a molecular precursor by copper surface adatoms affording the formation of unprecedented organocopper metallacycles on Cu(111). The chemical structure of the resulting complexes is characterized by scanning probe microscopy and X-ray photoelectron spectroscopy, being complemented by density functional theory calculations and scanning probe microscopy simulations. Our results pave avenues to the engineering of organometallic compounds and steer the development of polyyne chemistry on surfaces.

The diacetylene skeletons of DNBD precursors are attacked on Cu(111) by copper adatoms resulting in the synthesis of organocopper metallacycles.     

Capturing photochemical and photophysical transformations in iron complexes with ultrafast X-ray spectroscopy and scattering

Light-driven chemical transformations provide a compelling approach to understanding chemical reactivity with the potential to use this understanding to advance solar energy and catalysis applications. Capturing the non-equilibrium trajectories of electronic excited states with precision, particularly for transition metal complexes, would provide a foundation for advancing both of these objectives. Of particular importance for 3d metal compounds is characterizing the population dynamics of charge-transfer (CT) and metal-centered (MC) electronic excited states and understanding how the inner coordination sphere structural dynamics mediate the interaction between these states. Recent advances in ultrafast X-ray laser science has enabled the electronic excited state dynamics in 3d metal complexes to be followed with unprecedented detail. This review will focus on simultaneous X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS) studies of iron coordination and organometallic complexes. These simultaneous XES-XSS studies have provided detailed insight into the mechanism of light-induced spin crossover in iron coordination compounds, the interaction of CT and MC excited states in iron carbene photosensitizers, and the mechanism of Fe–S bond dissociation in cytochrome c.

Ultrafast X-ray scattering and spectroscopy captures photophysical and photochemical transformations of 3d transition metal complexes with atomistic detail.     

Universal endogenous antibody recruiting nanobodies capable of triggering immune effectors for targeted cancer immunotherapy

Developing monoclonal antibodies (mAbs) for cancer immunotherapy is expensive and complicated. Nanobodies are small antibodies possessing favorable pharmacological properties compared with mAbs, but have limited anticancer efficacy due to the lack of an Fc region and poor pharmacokinetics. In this context, engineered universal endogenous antibody-recruiting nanobodies (UEAR Nbs), as a general and cost-effective approach, were developed to generate functional antibody-like nanobodies that could recapitulate the Fc biological functions for cancer immunotherapy. The UEAR Nbs, composed of the IgG binding domain and nanobody, were recombinantly expressed in E. coli and could recruit endogenous IgGs onto the cancer cell surface and trigger potent immune responses to kill cancer cells in vitro. Moreover, it was proved that UEAR Nbs displayed significantly improved half-lives in vivo. The in vivo antitumor efficacy of UEAR Nbs was demonstrated in a murine model using EGFR positive triple-negative breast cancer (TNBC).

Universal endogenous antibody recruiting nanobodies (UEAR Nbs), composed of IgGs binding domain and nanobody, could redirect endogenous IgGs onto target cell surfaces and evoke potent immune responses to eliminate cancer cells in vitro and in vivo.     

A highly X-ray sensitive iridium prodrug for visualized tumor radiochemotherapy

Concomitant treatment of radiotherapy and chemotherapy is widely used in cancer therapy. The search for highly efficient radiochemotherapy drugs for tumor targeting therapy under image-guiding is of considerable interest. Herein we report an Ir-based prodrug Ir-NB with high sensitization efficiency for in vivo tumor microenvironment responsive cancer-targeted bioimaging radiochemotherapy. To the best of our knowledge, the sensitivity enhancement ratio (SER) of the Ir-NB prodrug is the highest among those reported for radiotherapy metal complex drugs. From detailed action mechanism study, we provide evidence that the prodrug is effectively suppresses the tumor growth through inducing mitochondrial dysfunction, and eventually amplifies the apoptotic signal pathway. This study provides an approach for the development of cancer theranostic agents for tumor radiotherapy.

A highly X-ray sensitive molecular prodrug, Ir-NB, was reported for visualized tumor radiochemotherapy. To our knowledge, the sensitivity enhancement ratio of the prodrug is the highest among the reported radiotherapy metal complexes drugs.     

Enantioselective transition metal catalysis directed by chiral cations

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis. Thus far, three strategies have been revealed: ligand scaffolds incorporated on chiral cations, chiral cations paired with transition metal ‘ate’-type complexes, and ligand scaffolds incorporated on achiral anions. Chiral cation ion-pair catalysis has been successfully applied to alkylation, cycloaddition, dihydroxylation, oxohydroxylation, sulfoxidation, epoxidation and C–H borylation. This development represents an effective approach to promote the cooperation between chiral cations and transition metals, increasing the versatility and capability of both these forms of catalysts. In this review, we present current examples of the three strategies and suggest possible inclusions for the future.

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis.     

Surmounting tumor resistance to metallodrugs by co-loading a metal complex and siRNA in nanoparticles

Copper complexes are promising anticancer agents widely studied to overcome tumor resistance to metal-based anticancer drugs. Nevertheless, copper complexes per se encounter drug resistance from time to time. Adenosine-5′-triphosphate (ATP)-responsive nanoparticles containing a copper complex CTND and B-cell lymphoma 2 (Bcl-2) small interfering RNA (siRNA) were constructed to cope with the resistance of cancer cells to the complex. CTND and siRNA can be released from the nanoparticles in cancer cells upon reacting with intracellular ATP. The resistance of B16F10 melanoma cells to CTND was terminated by silencing the cellular Bcl-2 gene via RNA interference, and the therapeutic efficacy was significantly enhanced. The nanoparticles triggered a cellular autophagy that amplified the apoptotic signals, thus revealing a novel mechanism for antagonizing the resistance of copper complexes. In view of the extensive association of Bcl-2 protein with cancer resistance to chemotherapeutics, this strategy may be universally applicable for overcoming the ubiquitous drug resistance to metallodrugs.

Bcl-2-related tumor resistance to anticancer drugs can be overcome by silencing the cellular Bcl-2 gene via RNA interference. The realization of the goal is exemplified by delivering Bcl-2 siRNA and a tumor-resistant Cu complex to cancer cells with an ATP-responsive nanocarrier.     

Phosphorescent metal complexes as theranostic anticancer agents: combining imaging and therapy in a single molecule

Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(iii), ruthenium(ii) and rhenium(i) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.

The recent development in phosphorescent iridium, ruthenium and rhenium complexes as theranostic anticancer agents is summarized.     

Shedding light on the mitochondrial matrix through a functional membrane transporter

The first fluorescent probes that are actively channeled into the mitochondrial matrix by a specific mitochondrial membrane transporter in living cells have been developed. The new functional probes (BCT) have a minimalist structural design based on the highly efficient and photostable BODIPY chromophore and carnitine as a biotargeting element. Both units are orthogonally bonded through the common boron atom, thus avoiding the use of complex polyatomic connectors. In contrast to known mitochondria-specific dyes, BCTs selectively label these organelles regardless of their transmembrane potential and in an enantioselective way. The obtained experimental evidence supports carnitine–acylcarnitine translocase (CACT) as the key transporter protein for BCTs, which behave therefore as acylcarnitine biomimetics. This simple structural design can be readily extended to other structurally diverse starting F-BODIPYs to obtain BCTs with varied emission wavelengths along the visible and NIR spectral regions and with multifunctional capabilities. BCTs are the first fluorescent derivatives of carnitine to be used in cell microscopy and stand as promising research tools to explore the role of the carnitine shuttle system in cancer and metabolic diseases. Extension of this approach to other small-molecule mitochondrial transporters is envisaged.

A BODIPY derivative of carnitine enters mitochondria regardless of their membrane potential and in an enantioselective way through a specific mitochondrial membrane transporter in living cells.     

Computational strategy for intrinsically disordered protein ligand design leads to the discovery of p53 transactivation domain I binding compounds that activate the p53 pathway

Intrinsically disordered proteins or intrinsically disordered regions (IDPs) have gained much attention in recent years due to their vital roles in biology and prevalence in various human diseases. Although IDPs are perceived as attractive therapeutic targets, rational drug design targeting IDPs remains challenging because of their conformational heterogeneity. Here, we propose a hierarchical computational strategy for IDP drug virtual screening (IDPDVS) and applied it in the discovery of p53 transactivation domain I (TAD1) binding compounds. IDPDVS starts from conformation sampling of the IDP target, then it combines stepwise conformational clustering with druggability evaluation to identify potential ligand binding pockets, followed by multiple docking screening runs and selection of compounds that can bind multi-conformations. p53 is an important tumor suppressor and restoration of its function provides an opportunity to inhibit cancer cell growth. TAD1 locates at the N-terminus of p53 and plays key roles in regulating p53 function. No compounds that directly bind to TAD1 have been reported due to its highly disordered structure. We successfully used IDPDVS to identify two compounds that bind p53 TAD1 and restore wild-type p53 function in cancer cells. Our study demonstrates that IDPDVS is an efficient strategy for IDP drug discovery and p53 TAD1 can be directly targeted by small molecules.

A hierarchical computational strategy for IDP drug virtual screening (IDPDVS) was proposed and successfully applied to identify compounds that bind p53 TAD1 and restore wild-type p53 function in cancer cells.     

Triboluminescence of a new family of CuI–NHC complexes in crystalline solid and in amorphous polymer films

Triboluminescent compounds that generate emission of light in response to mechanical stimulus are promising targets in the development of “smart materials” and damage sensors. Among triboluminescent metal complexes, rare-earth europium and terbium complexes are most widely used, while there is no systematic data on more readily available and inexpensive Cu complexes. We report a new family of photoluminescent Cu–NHC complexes that show bright triboluminescence (TL) in the crystal state visible in ambient indoor light under air. Moreover, when these complexes are blended into amorphous polymer films even at small concentrations, TL is easily observed. Observation of TL in polymer films overcomes the limitation of using crystals and opens up possibilities for the development of mechanoresponsive coatings and materials based on inexpensive metals such as Cu. Our results may also have implications for the understanding of the TL effect''s origin in polymer films.

Triboluminescent compounds that generate emission of light in response to mechanical stimulus are promising targets in the development of “smart materials” and damage sensors.     

Visible light driven generation and alkyne insertion reactions of stable bis-cyclometalated Pt(iv) hydrides

Hydride complexes resulting from the oxidative addition of C–H bonds are intermediates in hydrocarbon activation and functionalization reactions. The discovery of metal systems that enable their direct formation through photoexcitation with visible light could lead to advantageous synthetic methodologies. In this study, easily accessible dimers [Pt₂(μ-Cl)₂(C^N)₂] (C^N = cyclometalated 2-arylpyridine) are demonstrated as a very convenient source of Pt(C^N) subunits, which promote photooxidative C–H addition reactions with different 2-arylpyridines (N′^C′H) upon irradiation with blue light. The resulting [PtH(Cl)(C^N)(C′^N′)] complexes are the first isolable Pt(iv) hydrides arising from a cyclometalation reaction. A transcyclometalation process involving three photochemical steps is elucidated, which occurs when the C^N ligand is a monocyclometalated 2,6-diarylpyridine, and a detailed analysis of the photoreactivity associated with the Pt(C^N) moiety is provided. Alkyne insertions into the Pt–H bond of a photogenerated Pt(iv) hydride are also reported as a demonstration of the ability of this class of compounds to undergo subsequent organometallic reactions.

The photochemical generation of isolable bis-cyclometalated Pt(iv) hydrides via photooxidative C–H addition reactions is demonstrated from easily accessible Pt(ii) precursors using visible light.     

Thionated organic compounds as emerging heavy-atom-free photodynamic therapy agents

This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy. Particular attention is given to the use of thionated nucleobase derivatives as “one-two punch” photodynamic agents. These versatile photosensitizers can act as “Trojan horses” upon metabolization into DNA and exposure to activating light. Their incorporation into cellular DNA increases their selectivity and photodynamic efficacy against highly proliferating skin cancer tumor cells, while simultaneously enabling the use of low irradiation doses both in the presence and in the absence of molecular oxygen. Also reviewed are their primary photochemical reactions, modes of action, and photosensitization mechanisms. New developments of emerging thionated organic photosensitizers absorbing visible and near-infrared radiation are highlighted. Future research directions, as well as, other prospective applications of heavy-atom-free, thionated photosensitizers are discussed.

This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy.     

Total synthesis of biseokeaniamides A–C and late-stage electrochemically-enabled peptide analogue synthesis

The first total synthesis of cytotoxic cyanobacterial peptide natural products biseokeaniamides A–C is reported employing a robust solid-phase approach to peptide backbone construction followed by coupling of a key thiazole building block. To rapidly access natural product analogues, we have optimized an operationally simple electrochemical oxidative decarboxylation–nucleophilic addition pathway which exploits the reactivity of native C-terminal peptide carboxylates and abrogates the need for building block syntheses. Electrochemically-generated N,O-acetal intermediates are engaged with electron-rich aromatics and organometallic reagents to forge modified amino acids and peptides. The value of this late-stage modification method is highlighted by the expedient and divergent production of bioactive peptide analogues, including compounds which exhibit enhanced cytotoxicity relative to the biseokeaniamide natural products.

A late-stage electrochemical decarboxylation enables rapid access to structural analogues of biseokeaniamides A–C, cytotoxic lipopeptide natural products.     

Design,scope and mechanism of highly active and selective chiral NHC–iridium catalysts for the intramolecular hydroamination of a variety of unactivated aminoalkenes

Chiral, cationic NHC–iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of a range of 5- and 6-membered N-heterocycles, which are accessed in excellent optical purity, with various functional groups being tolerated with this system. A major deactivation pathway is presented and eliminated by using alternative reaction conditions. A detailed experimental and computational study on the reaction mechanism is performed providing valuable insights into the mode of action of the catalytic system and pointing to future modifications to be made for this catalytic platform.

Chiral, cationic NHC–iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes.     

Fluorogenic Trp(redBODIPY) cyclopeptide targeting keratin 1 for imaging of aggressive carcinomas

Keratin 1 (KRT1) is overexpressed in squamous carcinomas and associated with aggressive pathologies in breast cancer. Herein we report the design and preparation of the first Trp-based red fluorogenic amino acid, which is synthetically accessible in a few steps and displays excellent photophysical properties, and its application in a minimally-disruptive labelling strategy to prepare a new fluorogenic cyclopeptide for imaging of KRT1+ cells in whole intact tumour tissues.

Trp(redBODIPY) is the first red-emitting Trp-based amino acid for the preparation of fluorogenic peptides with retention of target binding affinity.     

Catalysis using transition metal complexes featuring main group metal and metalloid compounds as supporting ligands

Recent development in catalytic application of transition metal complexes having an M–E bond (E = main group metal or metalloid element), which is stabilized by a multidentate ligand, is summarized. Main group metal and metalloid supporting ligands furnish unusual electronic and steric environments and molecular functions to transition metals, which are not easily available with standard organic supporting ligands such as phosphines and amines. These characteristics often realize remarkable catalytic activity, unique product selectivity, and new molecular transformations. This perspective demonstrates the promising utility of main group metal and metalloid compounds as a new class of supporting ligands for transition metal catalysts in synthetic chemistry.

Recent development in catalytic application of transition metal complexes having an M–E bond (E = main group metal or metalloid element), which is stabilized by a multidentate ligand, is summarized.     

Photoactivatable prodrug for simultaneous release of mertansine and CO along with a BODIPY derivative as a luminescent marker in mitochondria: a proof of concept for NIR image-guided cancer therapy

Controlled and efficient activation is the crucial aspect of designing an effective prodrug. Herein we demonstrate a proof of concept for a light activatable prodrug with desired organelle specificity. Mertansine, a benzoansamacrolide, is an efficient microtubule-targeting compound that binds at or near the vinblastine-binding site in the mitochondrial region to induce mitotic arrest and cell death through apoptosis. Despite its efficacy even in the nanomolar level, this has failed in stage 2 of human clinical trials owing to the lack of drug specificity and the deleterious systemic toxicity. To get around this problem, a recent trend is to develop an antibody-conjugatable maytansinoid with improved tumor/organelle-specificity and lesser systematic toxicity. Endogenous CO is recognized as a regulator of cellular function and for its obligatory role in cell apoptosis. CO blocks the proliferation of cancer cells and effector T cells, and the primary target is reported to be the mitochondria. We report herein a new mitochondria-specific prodrug conjugate (Pro-DC) that undergoes a photocleavage reaction on irradiation with a 400 nm source (1.0 mW cm⁻²) to induce a simultaneous release of the therapeutic components mertansine and CO along with a BODIPY derivative (BODIPY(PPH₃)₂) as a luminescent marker in the mitochondrial matrix. The efficacy of the process is demonstrated using MCF-7 cells and could effectively be visualized by probing the intracellular luminescence of BODIPY(PPH₃)₂. This provides a proof-of-concept for designing a prodrug for image-guided combination therapy for mainstream treatment of cancer.

Simultaneous release of two therapeutic reagents, mertansine and CO through photo-induced cleavage of a mitochondria-specific prodrug with improved drug efficacy.     

Olefin metathesis: what have we learned about homogeneous and heterogeneous catalysts from surface organometallic chemistry?

Since its early days, olefin metathesis has been in the focus of scientific discussions and technology development. While heterogeneous olefin metathesis catalysts based on supported group 6 metal oxides have been used for decades in the petrochemical industry, detailed mechanistic studies and the development of molecular organometallic chemistry have led to the development of robust and widely used homogeneous catalysts based on well-defined alkylidenes that have found applications for the synthesis of fine and bulk chemicals and are also used in the polymer industry. The development of the chemistry of high-oxidation group 5–7 alkylidenes and the use of surface organometallic chemistry (SOMC) principles unlocked the preparation of so-called well-defined supported olefin metathesis catalysts. The high activity and stability (often superior to their molecular analogues) and molecular-level characterisation of these systems, that were first reported in 2001, opened the possibility for the first direct structure–activity relationships for supported metathesis catalysts. This review describes first the history of SOMC in the field of olefin metathesis, and then focuses on what has happened since 2007, the date of our last comprehensive reviews in this field.

Surface organometallic chemistry bridges the gap between homogeneous and heterogeneous olefin metathesis catalysts.