Search Results (1,065)

Chiral supramolecular polymers offer a versatile platform for constructing dynamic functional materials, yet their development in aqueous media remains challenging due to weak host–guest interactions and limited chiral macrocyclic systems. Herein, we report a water-soluble chiral luminescent supramolecular polymer assembled from a pair of chiral macrocycle ((R)-/(S)-C[4]B) and an achiral bis-thiazole orange guest. The ultrahigh binding affinity between the host and guest enables stable one-dimensional polymerization in water. Efficient chirality transfer from the macrocyclic host to the achiral luminophore gives rise to pronounced circular dichroism (CD) and circularly polarized luminescence (CPL). The resulting polymer exhibits red emission (625 nm) with a luminescence dissymmetry factor of 8.5 × 10⁻³. This work provides an effective strategy for the development of aqueous CPL-active supramolecular polymers through ultrastrong host–guest recognition. Full article

The limitations of conventional inorganic electrodes call for organic alternatives for advanced energy storage. Metal–covalent organic frameworks (MCOFs) integrate the metal active sites of metal–organic frameworks (MOFs) with the high chemical stability imparted by strong covalent bonds in covalent organic frameworks (COFs) while retaining the high specific surface area and tunable porosity of both material classes. Among these, MCOFs constructed from porphyrin and phthalocyanine building units have emerged as a research hotspot in electrochemical energy storage owing to their inherent 18π-conjugated macrocyclic electronic systems, well-defined M–N₄ coordination sites, and potential bipolar charge storage characteristics. This review systematically summarizes recent advances in this class of materials. First, from the perspective of metal center introduction timing, three core synthetic strategies—pre-metallation, simultaneous metallation, and post-metallation—are categorized and evaluated in terms of coordination precision, synthetic efficiency, and scalability potential. Second, the regulatory effects of two-dimensional layered and three-dimensional interpenetrated structures on charge transport pathways and structural stability are elucidated. Subsequently, the applications of porphyrin/phthalocyanine-based MCOFs in lithium-based batteries, zinc-based batteries, sodium/potassium-ion batteries, and supercapacitors are reviewed in detail, with emphasis on the key roles of metal active sites in catalytic conversion, chemical anchoring/confinement, interface stabilization, and pseudocapacitive contribution. Finally, future directions to address key performance and mechanistic bottlenecks are discussed. This review aims to provide a systematic reference for the rational design and energy storage applications of high-performance porphyrin/phthalocyanine-based MCOFs. Full article

Enlicitide (MK-0616) is an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the treatment of hypercholesterolemia. We conducted the first systematic review and meta-analysis evaluating the efficacy and safety of enlicitide across randomized controlled trials enrolling adults with hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). The primary outcome was the baseline-to-endpoint percentage change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], and safety. Four randomized controlled trials involving 3894 participants were included. Enlicitide achieved a substantial reduction in LDL-C (mean difference [MD]: −55.78 percentage points; 95% confidence interval [CI]: −61.15 to −50.42; p < 0.0001; I² = 99.58%), with sustained efficacy demonstrated in the newly available 52-week Phase 3 CORALreef data. Significant reductions were also observed in ApoB (MD: −47.95 pp; 95% CI: −51.22 to −44.67), non-HDL-C (MD: −49.42 pp; 95% CI: −54.23 to −44.60), and Lp(a) (MD: −22.70 pp; 95% CI: −28.62 to −16.78). The pooled incidence of any adverse event was not statistically significant (event rate: 0.21; p = 0.087), and treatment discontinuation due to adverse events was uncommon (event rate: 0.007). Enlicitide demonstrated substantial lipid-lowering efficacy with an acceptable safety profile. The ongoing CORALreef Outcomes trial will determine whether these lipid improvements translate into reductions in major adverse cardiovascular events. Full article

Reversed-phase chromatography stationary phases (such as C18) are widely used in commercial high-performance liquid chromatography (HPLC). However, when dealing with complex mixtures, they often exhibit limited separation capabilities and peak tailing phenomena. To address this problem, two novel HPLC stationary phases based on polyamine macrocycles were developed. A trianglamine macrocyclic stationary phase (TRI-Sil) was first prepared using chlorinated silica gel as the support, which can effectively separate a variety of aromatic compounds, but with limited selectivity for positional isomers such as phenylenediamine. To further improve the separation selectivity, a polyamine-silica macrocyclic stationary phase (CPAM-Sil) was synthesized by introducing a branched-chain-containing monomer. Under optimized conditions, CPAM-Sil achieved baseline separation of phenylenediamine and phenylenediol positional isomers and improved the separation of terphenyl isomers, with favorable asymmetry factors and high column efficiency compared with the commercial C18 column. Molecular docking confirmed multiple interactions such as electrostatic interactions and hydrogen bonding between the polyamine macrocycle (CPAM) and analytes. The CPAM-Sil column also exhibited good reproducibility and stability, showing promising potential for industrial application in chromatographic separation. Full article

1,2-Dichloroethane was found to stabilize the lattice of chloride anions associated with the protonated porphyrin of formula [C₄₄H₃₂N₄]Cl₂·4C₂H₄Cl₂. The synthesis and X-ray characterization of this compound are reported and compared with analogous solvates. The porphyrin macrocycle displays a distorted saddle conformation, with chloride anions positioned above and below the mean plane of the ring, further surrounded by two dichloroethane molecules that stabilize the crystal packing. The Second-Harmonic Generation response was evaluated using the Kurtz–Perry powder technique with a ND:YAG laser (1064 nm). Full article

Small-molecule kinase inhibitors offer a compelling therapeutic strategy for glioblastoma, yet their clinical efficacy remains severely limited by blood–brain barrier penetration and active efflux transporter extrusion. This review evaluates current medicinal chemistry approaches and translational paradigms to overcome these drug delivery and biological constraints. A critical analysis of the literature reveals that direct structural optimization faces a multidimensional balancing act; next-generation design must prioritize macrocyclization, structural rigidification, and bioisosteric capping to lower polar surface area and evade P-glycoprotein and BCRP efflux. Furthermore, carrier-mediated prodrugs targeting the LAT1 transporter provide a viable rescue strategy for highly potent scaffolds. Reviewing recent clinical failures, such as paxalisib and osimertinib, underscores that single-node monotherapies fail due to compensatory pathway hyperactivation and clonal heterogeneity, whereas multi-targeted agents or rational dual-node combinations prevent rapid tumor adaptation. Additionally, combining kinase inhibitors with DNA damage repair inhibitors, immune checkpoint modulation, or MR-guided focused ultrasound could provide powerful synergistic networks. Finally, bridging the translational gap requires complementing conventional serum-cultured cell lines with patient-derived glioma stem cells and orthotopic xenografts to better recapitulate the cellular architecture of the disease. Ultimately, overcoming the therapeutic challenges in glioblastoma demands a fundamental pivot toward rigorous neuro-pharmacological design and multi-lineage network oncology. Full article

Background/Objectives: An evaluation of the sensitizing properties of chloroindium(III) phthalocyanine complex (InPc) bearing 4-sulfonylphenoxy groups was performed. Methods: The ability to form singlet oxygen under light exposure was assessed, and the quantum yield Φ_Δ was calculated to be 0.82 ± 0.04. Under ultrasound exposure of the sensitizer (1 MHz, 3 W, 40% duty cycle), significant 1,3-diphenylisobenzofuran decomposition was observed. Results: Moreover, the macrocycle was assigned to be a moderate–high photo- and sonostable sensitizer. Density functional theory studies supported experimental results, suggesting the InPc to be a good photochemical agent. From the global reactivity parameters analysis, it can be suggested that InPc would interact easily with electron-excess species, such as various free radicals, in the solution phase, and should also be able to interact with electrophilic species. Conclusions: Studied InPc revealed high photodynamic antimicrobial activity and reached >4 log₁₀ reduction in microbial growth against methicillin-resistant Staphylococcus aureus, and 4.08 ± 0.29 log₁₀ against Candida albicans resistant to fluconazole (for dosimetry of 100 μM and 50 J/cm²). Interestingly, the photosensitizer studied was inactive against extended-spectrum β-lactamase-producing Escherichia coli. Full article

Background: Produced by indoor Stachybotrys and Trichoderma spp., macrocyclic trichothecenes (MTs), a type of cytotoxic respirable molecule (<0.01–0.03 µm), inhibit protein/DNA/RNA production, damage mitochondria, and induce apoptosis. Dust-bound MTs remain toxic despite remediation/disinfection. Inhaled MTs easily cross tissue barriers, potentially reaching the placenta and the unborn. Methods: Retrospective medical record abstraction of pregnant females and offspring cohort exposed to indoor MTs, Stachybotrys, or Trichoderma to correlate professional indoor testing, exposure variables, mold species, environmental MTs, medical symptomatology, outcomes, and urine/milk MTs excretion. Results: In eight women from seven MT/mold-contaminated homes, with 21 pregnancies, complications occurred in 19 (90%) pregnancies, including miscarriages (38%) and premature labor (33%). Placental abnormalities in two women (25%) from the same home (calcification, chronic villitis, placental infarcts, double placenta, gritty membranitis). Birth defects in infants (38%) included renal hypertrophy, levocardia, patent foramen ovale, ventriculoseptal defect, ptosis, teeth, and “goosebump” black/grey skin discoloration. Later abnormalities included developmental delay, oropharyngeal hypotonic dysphagia, refractory eczema, and refractory perirectal rash progressing to intussusception. Lactation difficulties included grey-black oronasal drainage, thrush, projectile vomiting, choking, oropharyngeal neurologic damage, apnea, and respiratory arrest. Aspergillus +/− Penicillium exposure was documented in all, Stachybotrys (75%), Chaetomium (62%), Trichoderma (38%), and indoor MT contamination exposure (75%). Conclusions: In-utero indoor MTs and Stachybotrys exposure correlate strongly with adverse gestational, neonatal complications (miscarriage, congenital defects, and placental abnormalities). Exposure timing and severity correlate with adverse outcomes. Breastfeeding with indoor exposure appears hazardous. Environmental/human MTs testing appears useful for identifying MT contaminaion and/or exposure. Full article

Mononuclear nonheme iron(IV)–oxo species supported by mixed nitrogen–sulfur (N/S) ligands remain scarce, despite the prevalence of sulfur donors in biological iron sites and their expected impact on ferryl reactivity and catalyst design. In this work, a seven-coordinate iron(II) complex, [(N₃S₂)Fe^II(ClO₄)₂], bearing a rigid 15-membered N₃S₂ macrocycle, is shown to rapidly generate a mononuclear nonheme Fe^IV=O intermediate upon reaction with m-chloroperbenzoic (m-CPBA) acid in acetonitrile. The Fe^IV=O species forms within ≤2 s and is thermally persistent (t₁/₂ = 4.3 h at 25 °C), albeit in partial yield (~39% Fe^IV=O by Mössbauer spectroscopy), placing it in an intermediate regime between highly reactive but short-lived ferryl species and more inert, long-lived analogues. The intermediate is characterized by Mössbauer spectroscopy (δ = 0.35 mm s⁻¹, ΔE_Q = 0.90 mm s⁻¹, Γ_FWHM = 0.30 mm s⁻¹, relative area = 39.4%), EPR silence, a UV–vis absorption band at 428 nm, and cryogenic high-resolution ESI–MS (m/z 223.510, (N₃S₂)Fe^IV=O²⁺). Stopped-flow kinetic studies reveal saturation behavior that is well described by a pre-equilibrium oxidant-association model and subsequent O–O bond activation, with apparent activation parameters of ΔH^‡ = 17.7 kJ mol⁻¹ and ΔS^‡ = −155 J mol⁻¹ K⁻¹, indicating a highly ordered transition state within the seven-coordinate N₃S₂ framework under the conditions employed. Functionally, the Fe^IV=O species mediates clean oxygen-atom transfer to triphenylphosphine (k₂ = 8.1 × 10⁻² M⁻¹ s⁻¹) with an effective turnover number of ~12 after correction for the Fe^IV=O yield, establishing that this mixed N/S platform is catalytically competent under mild conditions, though less reactive than state-of-the-art all-nitrogen systems. Collectively, these findings identify the seven-coordinate N₃S₂ macrocycle as a mixed-donor platform that moderately extends ferryl lifetime while retaining measurable oxo-transfer reactivity, providing mechanistic guidance for the development of nonheme iron oxidation catalysts that incorporate sulfur donors. Full article

Carbapenem-resistant Acinetobacter baumannii (CRAB) is classified by the World Health Organization among the critical-priority pathogens, reflecting high mortality, near-ubiquitous nosocomial spread, and a depleted therapeutic pipeline. No antibiotic chemical class with a genuinely novel target and activity against A. baumannii reached patients for more than fifty years, and current options—sulbactam–durlobactam, cefiderocol, polymyxins, high-dose ampicillin–sulbactam and tetracyclines—are constrained by toxicity, inconsistent efficacy, or emerging resistance. Against this background, zosurabalpin (RG6006), the first member of the tethered macrocyclic peptide (MCP) class, represents a potentially important conceptual advance. Identified through whole-cell phenotypic screening of nearly 45,000 macrocyclic peptides and optimized into a zwitterionic clinical candidate, zosurabalpin inhibits the LptB₂FGC complex, the inner-membrane ATP-binding-cassette transporter that initiates lipopolysaccharide (LPS) export. By trapping LPS within the transporter, the drug causes lethal accumulation of the molecule at the inner membrane. This mechanism is structurally distinct from that of every clinically used antibiotic and, in preclinical studies, is not affected by the major currently recognized CRAB resistance mechanisms. Zosurabalpin shows potent, narrow-spectrum activity essentially restricted to the Acinetobacter baumannii–calcoaceticus complex, retaining activity in vitro against isolates resistant to cefiderocol and last-line agents; its clinical efficacy in patients, however, remains to be established. Here we review the discovery, structural mechanism, microbiological spectrum, and clinical development of zosurabalpin, and we situate it within a broader revival of pathogen-specific (narrow-spectrum) antibiotic development, discussing the diagnostic, stewardship, and economic implications of this paradigm. Full article

Cucurbiturils (CB[n]) are rigid glycoluril-based macrocycles possessing well-defined hydrophobic cavities capable of forming stable host–guest complexes in water. Owing to these properties, CB[n]-containing supramolecular polymer gels have attracted increasing attention as functional composite materials in modern materials science. This review summarizes recent progress in the development of cucurbituril-based supramolecular gels, with particular attention to synthetic approaches, network design, and emerging applications. Both conventional acid-catalyzed methods and more sustainable synthetic strategies for cucurbituril preparation and functionalization are discussed. We further consider the role of CB[n] macrocycles as reversible crosslinking units in polymer networks and analyze how host–guest interactions influence the mechanical properties, self-healing behavior, and stimuli responsiveness of the resulting materials. Recent applications in biomedical engineering, soft electronics, and environmental remediation are also highlighted, demonstrating how molecular-level supramolecular interactions can determine the macroscopic performance of these composite systems. The review concludes with perspectives on scalable synthesis, processing integration, and future directions in supramolecular composite materials. Full article

(1) Background: This study examines the toxicologic effects of gadolinium in the context of the growing number of industrial and medical applications that use gadolinium compounds. Furthermore, understanding the cellular effects on aquatic organisms is a growing concern regarding emerging pollutants, as gadolinium is found in aquatic environments and drinking water as a pollutant. (2) Methods: The microplate-based experiments were designed to assess lethal effects (LC₅₀) and analyze the cytological mechanisms in the larval stages of Artemia. Two gadolinium-containing compounds were comparatively analyzed: gadoteric acid (GA), an ionic compound, and gadoteridol (GD), a nonionic compound. Fluorescence analysis enabled detailed imaging and observations of the dynamics of the processes. Three fluorochromes were used for labeling: acridine orange (nuclear configuration), neutral red (lysosomal inclusions), and fluorescein isothiocyanate-labeled (cytoskeleton). (3) Results show that the effects became evident after more than 48 h of exposure. Cytotoxicity was higher for the nonionic macrocyclic compound GD (LC₅₀ = 60 µmol/mL ± 0.00462 compared with GA (LC₅₀ = 170 µmol/mL ± 0.01. The altered phenotype demonstrates the interference of the tested compounds at both the nuclear level (chromatin fragmentation, pyknotic nuclei) and the cytoplasmic level (enlarged lysosomal vesicles), as well as disorganized or condensed cytoskeleton. (4) Conclusions: Both compounds have effects on larvae, affecting their overall morphology and viability in 24–72 h after exposure. Identifying effects at the nuclear and cytoplasmic levels, as well as disruptions in cytoskeletal polymerization, helps to determine the factors that influence larval survival in an environment contaminated with such rare metals and to understand the cellular mechanisms induced by gadolinium compound poisoning. Full article

Teixobactin is a promising antibiotic that targets cell wall biosynthesis in Gram-positive bacteria and displays a low propensity for resistance; however, its structural complexity presents challenges for analogue development and optimisation. In this study, we investigated the effects of macrocycle size and replacement of the native depsipeptide linkage with an amide bond on antibacterial activity using a simplified Leu₁₀-teixobactin scaffold. An amide-based macrocyclisation strategy was developed for efficient lactam formation using readily accessible amino acid building blocks, avoiding reliance on synthetically demanding modified diamino acids employed in other approaches. Two complementary synthetic routes provided access to a series of ten analogues, comprising linear and macrocyclised variants with systematic variation at position 8. Antibacterial activity was evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant clinical isolates. While linear analogues exhibited weak or no measurable antibacterial activity, macrocyclised analogues retained measurable antibacterial activity, indicating that macrocyclisation is essential within this scaffold, whereas moderate expansion of the macrocycle was tolerated. The structure–activity relationships identified here demonstrate the suitability of a simplified Leu₁₀-teixobactin framework and provide a platform for further optimisation of teixobactin-inspired antibiotics. Full article

The majority of disease-associated proteins are considered “undruggable” due to the absence of well-defined binding pockets, the presence of extended interaction surfaces, and intrinsic structural disorder, which collectively limit the effectiveness of conventional small molecules and biologics. Representative examples include KRAS, p53, and c-MYC. Peptide therapeutics, particularly macrocyclic peptides, occupy a unique chemical space capable of targeting such recalcitrant protein–protein interactions (PPIs) where small molecules often fail. However, traditional peptide discovery, which relies heavily on high-throughput screening, is labor-intensive and frequently yields candidates with suboptimal pharmacological properties. The integration of artificial intelligence has begun to transform peptide discovery from a largely empirical process into a rational and design-driven paradigm. Modern deep learning approaches, including diffusion-based generative models, enable the de novo design of peptide binders with high affinity and structural precision, even for disordered or previously intractable targets. In this perspective, we highlight key structural and biological challenges associated with undruggable proteins and consider how peptide-based modalities are beginning to overcome these longstanding barriers. We further explore how advances in artificial intelligence and computational modeling may reshape the rational design of next-generation peptide therapeutics and propose an integrated experimental–computational framework to facilitate the development of clinically actionable candidates. Full article

Background/Objectives: mRNA display technology has emerged as a powerful platform for discovering macrocyclic peptides against intractable proteins. However, direct screening against the “undruggable” transcription factor MYC using this approach remains largely unexplored. In this study, we aimed to integrate tyrosinase-mediated cyclization with mRNA display to identify novel macrocyclic peptide inhibitors targeting MYC. Methods: We performed mRNA display combined with tyrosinase-mediated cyclization to generate macrocyclic peptides targeting MYC. Antiproliferative activity was assessed in MYC-dependent tumor cells using CCK8 assay. C-terminal fusions with a TAT-derived cell-penetrating peptide were generated to enhance cell membrane permeability. Binding affinities were measured by bio-layer interferometry (BLI). MYC transcriptional activity was evaluated by RNA sequencing (RNA-seq) analysis of canonical MYC target genes. Results: The identified macrocyclic peptides exhibited potent antiproliferative activity against MYC-dependent tumor cells, with half-maximal inhibitory concentration (IC₅₀) values in the micromolar range. Fusion with the TAT peptide improved antiproliferative potency, yielding IC₅₀ values of 1–3 μM in MYC-dependent cell lines. BLI assays confirmed dose-dependent binding of the peptides to MYC, with dissociation constants (Kd) in the micromolar range. Furthermore, RNA-seq analysis revealed significant downregulation of canonical MYC target genes upon treatment with the TAT-fusion macrocyclic peptide, indicating specific suppression of MYC transcriptional activity. Conclusions: This work establishes the feasibility of using mRNA display to target the “undruggable” protein MYC and identifies a panel of macrocyclic peptides as promising lead candidates for further optimization toward targeted therapies for MYC-driven cancers. Full article