Ligand Taxonomy for Bioinorganic Modeling of Dioxygen-Activating Non-Heme Iron Enzymes

Novel functions emerge from novel structures. To develop efficient catalytic systems for challenging chemical transformations, chemists often seek inspirations from enzymatic catalysis. A large number of iron complexes supported by nitrogen-rich multidentate ligands have thus been developed to mimic oxo-transfer reactivity of dioxygen-activating metalloenzymes. Such efforts have significantly advanced our understanding of the reaction mechanisms by trapping key intermediates and elucidating their geometric and electronic properties. Critical to the success of this biomimetic approach is the design and synthesis of elaborate ligand systems to balance the thermodynamic stability, structural adaptability, and chemical reactivity. In this Concept article, representative design strategies for biomimetic atom-transfer chemistry are discussed from the perspectives of “ligand builders”. Emphasis is placed on how the primary coordination sphere is constructed, and how it can be elaborated further by rational design for desired functions.     

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)Pt^IV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.     

DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation

Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.     

Bismuth(III) Flavonolates: The Impact of Structural Diversity on Antibacterial Activity,Mammalian Cell Viability and Cellular Uptake

A series of homoleptic and heteroleptic bismuth(III) flavonolate complexes derived from six flavonols of varying substitution have been synthesised and structurally characterised. The complexes were evaluated for antibacterial activity towards several problematic Gram-positive (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE)) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. The cell viability of COS-7 (monkey kidney) cells treated with the bismuth flavonolates was also studied to determine the effect of the complexes on mammalian cells. The heteroleptic complexes [BiPh(L)₂] (in which L=flavonolate) showed good antibacterial activity towards all of the bacteria but reduced COS-7 cell viability in a concentration-dependent manner. The homoleptic complexes [Bi(L)₃] exhibited activity towards the Gram-positive bacteria and showed low toxicity towards the mammalian cell line. Bismuth uptake studies in VRE and COS-7 cells treated with the bismuth flavonolate complexes indicated that Bi accumulation is influenced by both the substitution of the flavonolate ligands and the degree of substitution at the bismuth centre.     

Nanostructures for Electrocatalytic CO2 Reduction

One of the most effective ways to cope with the problems of global warming and the energy shortage crisis is to develop renewable and clean energy sources. To achieve a carbon-neutral energy cycle, advanced carbon sequestration technologies are urgently needed, but because CO₂ is a thermodynamically stable molecule with the highest carbon valence state of +4, this process faces many challenges. In recent years, electrochemical CO₂ reduction has become a promising approach to fix and convert CO₂ into high-value-added fuels and chemical feedstock. However, the large-scale commercial use of electrochemical CO₂ reduction systems is hindered by poor electrocatalyst activity, large overpotential, low energy conversion efficiency, and product selectivity in reducing CO₂. Therefore, there is an urgent need to rationally design highly efficient, stable, and scalable electrocatalysts to alleviate these problems. This minireview also aims to classify heterogeneous nanostructured electrocatalysts for the CO₂ reduction reaction (CDRR).     

MUC1 Aptamer-Capped Mesoporous Silica Nanoparticles for Navitoclax Resistance Overcoming in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. In the last years, navitoclax has emerged as a possible treatment for TNBC. Nevertheless, rapid navitoclax resistance onset has been observed thorough Mcl-1 overexpression. As a strategy to overcome Mcl-1-mediated resistance, herein we present a controlled drug co-delivery system based on mesoporous silica nanoparticles (MSNs) targeted to TNBC cells. The nanocarrier is loaded with navitoclax and the Mcl-1 inhibitor S63845 and capped with a MUC1-targeting aptamer ( apMUC1-MSNs(Nav/S63845) ). The apMUC1-capped nanoparticles effectively target TNBC cell lines and successfully induce apoptosis, overcoming navitoclax resistance. Moreover, navitoclax encapsulation protects platelets against apoptosis. These results point apMUC1-gated MSNs as suitable BH3 mimetics nanocarriers in the targeted treatment of MUC1-expressing TNBC.     

A Bis-Chelating / Ligand for the Synthesis of Heterobimetallic Platinum(II)/Rhenium(I) Complexes: Tools for the Optimization of a New Class of Platinum(II) Anticancer Agents

The two independent and coordination sites of a newly synthesized bis[2-(hydroxyphenyl)-1,2,4-triazole] platform have been exploited to prepare four monometallic neutral ()Pt^II complexes carrying DMSO, pyridine, triphenylphosphine, or N-heterocyclic carbene as the fourth ligand. Then, the second coordination site was used to introduce an IR-active rhenium tricarbonyl entity, affording the four corresponding heterobimetallic neutral Pt^II/Re^I complexes, as well as a cationic Pt^II/Re^I derivative. X-ray crystallographic studies showed that distortion of the organic platform occurred to accommodate the coordination geometry of both metal centers. No ligand exchange or transchelation occurred upon incubation of the Pt^II complexes in aqueous environment or in the presence of Fe^III, respectively. The antiproliferative activity of the ligand and complexes was first screened on the triple-negative breast cancer cell line MDA-MB-231. Then, the IC₅₀ values of the most active candidates were determined on a wider panel of human cancer cells (MDA-MB-231, MCF-7, and A2780), as well as on a nontumorigenic cell line (MCF-10A). Low micromolar activities were reached for the complexes carrying a DMSO ligand, making them the first examples of highly active, but hydrolytically stable, Pt^II complexes. Finally, the characteristic mid-IR signature of the {Re(CO)₃} fragment in the Pt/Re heterobimetallic complexes was used to quantify their uptake in breast cancer cells.     

Scalable Total Syntheses and Structure–Activity Relationships of Haouamines A,B, and Their Derivatives as Stable Formate Salts

Haouamines A, B, and their derivatives were synthesized via Suzuki–Miyaura coupling and three key cyclization reactions as follows: the newly developed palladium(0)-catalyzed arylative cyclization of phenylalanine-derived alkyne–aldehydes with 2-bromoarylboronic acid (an “anti-Wacker”-type cyclization); BF₃ ⋅ OEt₂-promoted Friedel–Crafts-type cyclization of symmetrical electron-rich aromatic rings adjacent to a tertiary allylic alcohol leading to the indeno-tetrahydropyridine skeleton; and (cyanomethyl)trimethylphosphonium iodide-mediated macrocyclization of amino alcohols to afford aza-paracyclophane precursors. The palladium-catalyzed reduction of mono- and di-triflate intermediates in the later stages enabled the alteration of both the position and number of hydroxyl groups on the C-ring. The instability of haouamine B was dramatically improved by salt formation with formic acid. An unambiguous evaluation of the cytotoxicity of the prepared haouamine derivative formates with and without hydroxyl groups at different positions on the C-ring indicated that the catechol structure in haouamine B produced weak cytotoxicity.     

Rapid Discrimination of Crystal Handedness by X-ray Natural Circular Dichroism (XNCD) Mapping

An original method for determining the handedness of individual non-centrosymmetric crystals in a mixture using a tightly-focused, circularly polarized X-ray beam is presented. The X-ray natural circular dichroism (XNCD) spectra recorded at the metal K-edge on selected crystals of [Δ-M(en)₃](NO₃)₂ and [Λ-M(en)₃](NO₃)₂ (M=Co^II, Ni^II) show extrema at the metal pre-edge (7712 eV for Co, 8335 eV for Ni). A mapping of a collection of some 220 crystals was performed at the respective energies by using left and right circular polarizations. The difference in absorption for the two polarizations, being either negative or positive, directly yielded the handedness of the crystal volume probed by the beam. By using this technique, it was found that the addition of l -ascorbic acid during the synthesis of [Co(en)₃](NO₃)₂ resulted in an enantiomeric enrichment of the Λ-isomer of 67±13 %, whereas the Ni analogue was similarly, but conversely, enriched in the Δ-isomer (65±22 %).     

Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells

Although lipids contribute to cancer drug resistance, it is challenging to target diverse range of lipids. Here, we show enzymatically inserting exceedingly simple synthetic lipids into membranes for increasing membrane tension and selectively inhibiting drug resistant cancer cells. The lipid, formed by conjugating dodecylamine to d -phosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. The micelles effectively inhibit a drug resistant glioblastoma cell (T98G) or a triple-negative breast cancer cell (HCC1937), without inducing acquired drug resistance. Moreover, the enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g., endoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, in which for the first time membrane tension is increased to inhibit cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets.