Search Results (348)

Vanadyl octa-(4-tert-butylphenyl)phthalocyanine (VOPc(t-BuPh)₈) and vanadyl octa-(4-tert-butylphenyl)tetrapyrazinoporphyrazine (VOTPyzPz(t-BuPh)₈) complexes were synthesized for the first time and confirmed by IR and UV-Vis spectroscopy and MALDI-TOF spectrometry. The method of synthesis of their precursors, 4,5-bis(4-tert-butylphenyl)phthalonitrile ((t-BuPh)₂PN) and 5,6-bis(4-tert-butylphenyl)pyrazine-2,3-dicarbonitrile ((t-BuPh)₂PDC), was modified, resulting in higher yields. For the vanadyl complexes, the basic properties were studied, and it was found that the red shift in the Q band in the first protonation step is approximately two times greater than that of previously known complexes. An electrochemical study showed the influence of aza-substitution on the redox properties and on the energies of the frontier orbitals of all the compounds presented. For all four considered compounds, quantum chemical calculations of the molecular structure, IR spectra, and electronic absorption spectra were carried out using density functional theory (DFT) and time-dependent density functional theory (TDDFT and simplified sTDDFT) approaches. According to the DFT calculations, vanadyl macrocyclic complexes have dome-shaped distorted structures. Experimental and theoretical IR and electronic absorption spectra were compared and interpreted. Full article

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE’s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug–membrane and drug–solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics. Full article

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, ^99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for ^99mTc have been described; however, the development of effective delivery systems for this isotope to the area of interest is a complex research task. The use of tumor-targeting molecules as carriers for radioactive tracers is an effective strategy that has enabled the development of many novel radiopharmaceuticals for cancer imaging. Background: To date, a number of studies have shown tumorotropicity of tetrapyrrole compounds to tumor tissues, in particular derivatives of natural chlorophyll A. Methods: Purification was performed using solid-phase extraction. Assessment of radiochemical yield and purity was performed via radio-ITLC. The in vitro tumor cell accumulation was assessed using SKOV-3 and A-431 cell lines. Dose-dependent biodistribution was evaluated in Nu/J mice bearing epidermoid carcinoma (A-431) xenografts. Results: In this work, we obtained complexes with ^99mTc based on water-soluble carboxylate chlorin e₆ derivatives in order to evaluate their potential for use as SPECT radiopharmaceuticals. We performed radiolabelling optimization of a series of the novel chlorins and primary preclinical studies, including an assessment of the effect of their lipophilicity and charge on tumor uptake. Conclusions: Modification of the periphery of the chlorin macrocycle with chelating groups allows for complexing a wide range of metals, including ^99mTc, which can be used for targeted delivery of the radionuclide to the area of interest. Full article

Antimicrobial resistance remains a critical global health challenge, and was intensified by the COVID-19 pandemic. To address this growing threat, novel antibacterial agents targeting unconventional mechanisms are urgently needed. One promising strategy involves inhibiting bacterial riboswitches—RNA elements that regulate gene expression. Unlike most riboswitches that respond to small-molecule metabolites, the T-box riboswitch uniquely binds non-aminoacylated tRNA and is predominantly found in Gram-positive bacteria, making it an attractive target due to its conserved sequences and regulatory role over essential genes. This study explored oxazolidinone- and triazole-based compounds as potential inhibitors of the T-box riboswitch. Prior investigations into tricyclic oxazolidinones revealed an allosteric modulator that effectively inhibited T-box riboswitch transcriptional readthrough in vitro, though it showed limited disruption of the isolated tRNA–antiterminator complex. To enhance RNA-binding affinity and stereoselectivity, a macrocyclic oxazolidinone scaffold was designed, incorporating a strategic substituent to expand the interaction footprint. A synthetically viable candidate was identified, and computational docking studies suggested that one of the designed compounds may interfere with tRNA-induced transcription by forming π–π stacking interactions with G5 in the antiterminator region. These findings support the potential of targeting the T-box riboswitch with structurally optimized small molecules as a novel antibacterial strategy. Full article

The first systematic chemical investigation on Sinularia mollis resulted in the isolation and identification of 36 seven-membered cembranolides, including 14 new compounds named sinumollolides A–N (1–14) and 22 known analogs (15–36) by HSQC-based small molecule accurate recognition technology (SMART). Their structures were characterized by spectroscopic methods (1D/2D NMR and UV), HRESIMS, quantum chemical calculations (DP4+ analysis and ECD calculations), and X-ray diffraction analysis. In zebrafish assays, compounds 1, 2, 4, and 5 exhibited anti-inflammatory activity at 20 μM by inhibiting the number of macrophages around the neuromasts, with inhibition rates ranging from 30.4% to 45.6%. Moreover, the two most bioactive and less toxic compounds, 1 and 5, featuring a 14-membered macrocyclic lactone scaffold with several hydroxyl groups and a seven-membered α, β-unsaturated lactone moiety, can inhibit inflammation by suppressing the secretion of inflammatory cytokines at 10 μM in LPS-stimulated BV-2 cells. Full article

For decades, dendrimers have attracted the great interest of researchers, and continue to do so to this day. These compounds found a wide variety of applications in such areas as medicine, catalysis, and electronics. However, their synthesis is very expensive, and purification and isolation are difficult. In addition, dendrimers are often highly toxic. Toxic properties are significantly dependent on the generation and terminal group features. For the toxicity, decreasing the modification of dendrimer structure is widely used. This review discusses some examples of constructing dendrimers based on macrocyclic compounds—cyclophanes (pillararenes, resorcinarenes, and (thia)calixarenes). Preparation of these hybrids is not very difficult, and due to the presence of a hydrophobic macrocyclic platform, they acquire a number of practically useful properties that are not available to traditional dendrimers, such as additional opportunities for encapsulating substrates. Moreover, dendrimers acquire amphiphilic and chiral properties. This review is devoted to the features of the synthesis and properties of macrocyclic dendrimers based on cyclophanes. The review also demonstrates the prospects of using the resulting dendrimers for medicine, sensorics, catalysis and alternative energy sources. Full article

Pyrogallol[4]arenes are polyhydroxylated compounds obtained by condensation between pyrogallol and different aldehydes. Depending on both the type of aldehyde (aromatic or aliphatic) and the reaction time, these compounds can be obtained in different conformations, the most common being the crown and chair conformations. Using the conventional synthesis method, it is possible to obtain, in addition to the chair or crown conformers, other molecular associations, such as dimer capsules. The research in this study focuses on the synthesis products obtained from the condensation between pyrogallol and propanal. These products were characterized using spectroscopic methods, revealing that it is possible to obtain, in addition to the crown conformation, the dimer capsule of the macrocycle. Finally, the volumetric properties of these conformers were evaluated in dimethyl sulfoxide (DMSO) solution at several temperatures. Full article

Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain–penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg/kg of [D-Phe⁴]CJ-15,208, 4, and 30 mg/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208. Full article

Antimicrobial resistance has emerged as one of the most critical public health challenges of the 21st century, threatening to undermine the foundations of modern medicine. In 2019, bacterial infections accounted for 13.6% of all global deaths, with more than 7.7 million fatalities directly attributable to 33 bacterial pathogens, most prominently Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Resistance mechanisms are multifactorial, encompassing enzymatic degradation, target modification, efflux pump overexpression, reduced membrane permeability, and biofilm formation, often in combination, leading to multidrug-resistant, extensively drug-resistant, and pandrug-resistant phenotypes. Alarmingly, projections estimate that by 2050 AMR could result in over 10 million deaths annually. This comprehensive review synthesizes global epidemiological data, insights into bacterial resistance mechanisms, and emerging therapeutic solutions, including novel antibiotics such as lasso peptides and macrocyclic peptides (e.g., zosurabalpin), naturally derived compounds (e.g., corallopyronin, clovibactin, chlorotonil A), and targeted inhibitors (e.g., Debio 1453 for Neisseria gonorrhoeae). Addressing the AMR crisis requires coordinated international efforts, accelerated drug discovery, and the integration of innovative non-antibiotic approaches to preserve the efficacy of existing therapies and ensure preparedness against future bacterial threats. Full article

Background: Poor water solubility is a major limitation for the therapeutic use of many anticancer drugs. In this study, we report the design and development of two halloysite-based hybrid nanomaterials for the encapsulation and delivery of hydrophobic and positively charged drugs. Methods: A novel multicavity platform was obtained by covalently grafting calix[5]arene macrocycles onto the external surface of halloysite nanotubes (HNTs), combining lumen encapsulation with supramolecular host–guest recognition. PB4, a planar and hydrophobic pyridinium salt with significant antiproliferative activity, was selected as a model compound. Both PB4-loaded HNTs (HNTs/PB4) and calixarene-functionalized HNTs (HNTs-Calix/PB4) were incorporated into Laponite^®-based thixotropic hydrogels to obtain injectable and biocompatible systems. Results: The nanomaterials were thoroughly characterized, and their loading efficiency, release behavior, and aqueous dispersibility were evaluated. Antiproliferative tests on MCF-7 cells demonstrated that both hydrogels retained PB4 activity, with distinct release profiles: the pristine HNTs allowed faster drug availability, while calix[5]arene-functionalized systems promoted sustained release. Conclusions: This work introduces the first example of covalently calixarene-functionalized halloysite and presents a versatile drug delivery platform adaptable to different therapeutic contexts and combination strategies. Full article

The alarming increase in infections caused by antimicrobial-resistant bacteria is increasingly posing a critical threat to public health. For this reason, the scientific community is focusing on alternative therapeutic strategies, such as antimicrobial photodynamic therapy (aPDT). This review examined the use of natural photosensitizers (PSs) in aPDT, emphasizing how they may produce high yields of reactive oxygen species when activated by light and consequently inactivate a wide range of pathogens, including bacteria embedded in biofilms, efficiently. The main methodologies and several strategies of incorporation into cutting-edge nanotechnological delivery systems of the most prevalent natural PSs (curcuminoids, perylenequinones, tetrapyrrolic macrocycles, and flavins) have been analyzed. Although natural PSs have benefits in terms of environmental sustainability and biocompatibility, their clinical use is frequently constrained by low bioavailability and solubility, issues that are being addressed more and more through novel formulations and dual-mode treatments. Studies conducted both in vitro and in vivo highlight these compounds’ strong antibacterial and wound-healing properties. In conclusion, natural molecule-based aPDT is a flexible and successful strategy for combating antimicrobial resistance, deserving of more translational study and clinical advancement. Full article

Macrocyclic organic nanostructures have emerged as crucial components of functional supramolecular materials owing to their unique structural and chemical features, such as their distinctive “infinite” cyclic topology and tunable topology-dependent properties, attracting significant recent attention. However, the controlled synthesis of macrocyclic compounds with well-defined compositions and geometries remains a formidable challenge. On-surface synthesis, capable of constructing nanostructures with atomic precision on various substrates, has become a frontier technique for exploring novel macrocyclic architectures. This review summarizes the recent advances in the on-surface synthesis of macrocycles. It focuses on analyzing the synthetic mechanisms and conformational characterization of macrocycles formed through diverse bonding interactions, including both covalent and non-covalent linkages. This review elucidates the intricate interplay between the thermodynamic and kinetic factors governing macrocyclic structure formation across these bonding types and clarifies the critical influence of the reaction temperature and external conditions on the cyclization efficiency. Ultimately, this study offers design strategies for the precise on-surface synthesis of larger and more flexible macrocyclic compounds. Full article

The article describes a simple and scalable preparation of 2-monothiacalix[4]arene 7, the simplest representative of the mixed-bridged (CH₂ and S) calix[4]arenes. The synthesis is based on the condensation of linear building blocks (bisphenols), which are relatively readily available, and allows, depending on the conditions, the use of two alternative reaction routes that provide macrocycle 7 in high yield. The dynamic behavior of the basic macrocyclic skeleton was investigated using NMR spectroscopy at variable temperatures. High-temperature measurements showed that compound 7 undergoes a cone–cone equilibrium with activation free energy ΔG^# of the inversion process of 63 kJ·mol⁻¹. Interestingly, the same barrier for the oxidized sulfone derivative 14 shows a value of 60 kJ·mol⁻¹, indicating weakened hydrogen bonds at the lower rim of the calixarene. The same was also confirmed at low temperatures, when barriers to changing the direction of the cyclic hydrogen bond arrays (flip-flop mechanism) were determined (compare ΔG^# = 44 kJ·mol⁻¹ for 7 vs. ΔG^# = 40 kJ·mol⁻¹ for 14). Full article

Porphyrins play an extremely important role in both photodynamic (PDT) and sonodynamic therapy (SDT). These techniques, which have a lot in common, are largely based on the interaction between the sensitizer and light or ultrasounds (US), respectively, resulting in the formation of reactive oxygen species (ROS) that have the ability to destroy target cells. SDT requires the use of an appropriate frequency of US waves that are able to excite the chemical compound used. In this study, five porphyrin complexes were used: free-base meso-tetra(N-methyl-pyridinium-4-yl)porphyrin (TMPyP) and its transition metal complexes containing zinc(II), palladium(II), copper(II), and chloride-iron(II). The sonodynamic activity of these compounds was studied in vitro. The obtained results confirm the significant relationship between the chemical structure of the macrocycle and its stability and ability to generate ROS. The highest efficiency in ROS generation and high stability were demonstrated by non-metalated compound and its complex with zinc(II), while complex with copper(II), although less stable, were equally effective in terms of ROS production. Antibacterial activity tests showed the unique properties of the tested compounds, including a reduction in the number of both planktonic and biofilm antibiotic-resistant microorganisms above 5 log, which is rare among sonosensitizers. Full article

Vitamins are chemical compounds, or a group of closely related compounds known as vitamers, which are crucial for an organism’s metabolic functions. Vitamins are categorized as either water-soluble or fat-soluble, with this second group composed of vitamins A, D, E, and K. The low aqueous solubility of these compounds often necessitates the use of pharmaceutical excipients to benefit from their medicinal efficiency. A successful example of this is the formation of the inclusion complexes with cyclodextrins (CDs), a group of cyclic oligosaccharides, composed of glucose subunits forming a macrocyclic ring. CD complexes with fat-soluble vitamins have been consistently utilized to accomplish diverse objectives, with CDs predominantly employed as solubilizers and absorption enhancers. This article examines studies detailing the synthesis and the biological, physicochemical, and structural characteristics of the inclusion complexes formed between fat-soluble vitamins and different cyclodextrins. This research demonstrates that although the fat-soluble vitamins form stable complexes with various CDs, the kind of CDs employed significantly influences the resultant properties of the complex formed. Full article