Pillararenes as Promising Carriers for Drug Delivery.

Since their discovery in 2008 by N. Ogoshi and co-authors, pillararenes (PAs) have become popular hosts for molecular recognition and supramolecular chemistry, as well as other practical applications. The most useful property of these fascinating macrocycles is their ability to accommodate reversibly guest molecules of various kinds, including drugs or drug-like molecules, in their highly ordered rigid cavity. The last two features of pillararenes are widely used in various pillararene-based molecular devices and machines, stimuli-responsive supramolecular/host-guest systems, porous/nonporous materials, organic-inorganic hybrid systems, catalysis, and, finally, drug delivery systems. In this review, the most representative and important results on using pillararenes for drug delivery systems for the last decade are presented.

Polyaromatic Hydrocarbon (PAH)-Based Aza-POPOPs: Synthesis, Photophysical Studies, and Nitroanalyte Sensing Abilities.

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.

(1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-Bisfunctionalized 3- and 4-PEG: Synthesis and Photophysical Studies.

Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.

New Degradable Semiconducting Polymers for Photoacoustic Imaging of λ-Carrageenan-Induced Arthritis Mouse Model.

Semiconducting polymer has a high extinction coefficient and a long band absorption and can be used as a photoacoustic imaging contrast agent. However, nonbiodegradable semiconducting polymers may cause biosafety issues due to being retained in the body. Therefore, developing degradable semiconducting polymers is necessary for in vivo imaging. Herein, we developed three degradable semiconducting polymers with unique optical properties. We adjusted the optical properties of semiconducting polymers by designing the molecular structure of semiconducting polymers. Polymers with a donor-π-acceptor structure could easily improve the optical properties through adjusting the donor or acceptor units. Through adjusting the electron-donor and -acceptor units, three diketopyrrolopyrrole derivative polymers (DPPTz, DPPQu, and DPPWu) were synthesized and converted into nanosize particles. By introducing the degradable chemical groups in the main chain structure of semiconducting polymers, diketopyrrolopyrrole polymers could be degraded by ClO-. Among these nanosize particles, DPPTz NPs and DPPQu NPs were used to achieve the in vivo photoacoustic imaging of λ-carrageenan-induced arthritis mouse model. This work provides a novel design idea for the designing of red-shifted semiconducting polymer with degradable properties.

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.

Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads.

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.

Recent advances in the synthesis of fluorinated compounds via an aryne intermediate.

The development of new methodologies for the synthesis of fluorinated organic molecules is in high demand due to their wide applications in agriculture and pharmaceutical sciences. Various strategies have been employed for this purpose for a long time. Arynes are well known synthetic intermediates and have gained the attention of synthetic chemists for the synthesis of various functionalized organic molecules. Consequently, these synthetic intermediates have been successfully employed in the synthesis of fluorinated organic moieties. Various useful fluorinated aromatic and heterocyclic molecules have been synthesized employing aryne intermediates. In this review, we will discuss all these methodologies developed in the last decade via aryne intermediates.

Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process.

The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted aryne intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels-Alder products or 1,2,4-triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5 position of the 1,2,4-triazine core or in the aryne moiety. The structures of the key products were confirmed based on X-ray data. Based on the density functional theoretical (DFT) studies of the Diels-Alder transition state geometries, the influence of the nature of arynes on the direction of the 1,2,4-triazine transformation has been proposed.

Polymers and Polymer-Based Materials for the Detection of (Nitro-)explosives.

Methods for the remote detection of warfare agents and explosives have been in high demand in recent times. Among the several detection methods, fluorescence methods appear to be more convenient due to their low cost, simple operation, fast response time, and naked-eye-visible sensory response. For fluorescence methods, a large variety of fluorescent materials, such as small-molecule-based fluorophores, aggregation-induced emission fluorophores/materials, and supramolecular systems, have been reported in the literature. Among them, fluorescent (bio)polymers/(bio)polymer-based materials have gained wide attention due to their excellent mechanical properties and sensory performance, their ability to recognize explosives via different sensing mechanisms and their combinations, and, finally, the so-called amplification of the sensory response. This review provides the most up-to-date data on the utilization of polymers and polymer-based materials for the detection of nitroaromatic compounds (NACs)/nitro-explosives (NEs) in the last decade. The literature data have been arranged depending on the polymer type and/or sensory mechanism.

TM-Free and TM-Catalyzed Mechanosynthesis of Functional Polymers.

Mechanochemically induced methods are commonly used for the depolymerization of polymers, including plastic and agricultural wastes. So far, these methods have rarely been used for polymer synthesis. Compared to conventional polymerization in solutions, mechanochemical polymerization offers numerous advantages such as less or no solvent consumption, the accessibility of novel structures, the inclusion of co-polymers and post-modified polymers, and, most importantly, the avoidance of problems posed by low monomer/oligomer solubility and fast precipitation during polymerization. Consequently, the development of new functional polymers and materials, including those based on mechanochemically synthesized polymers, has drawn much interest, particularly from the perspective of green chemistry. In this review, we tried to highlight the most representative examples of transition-metal (TM)-free and TM-catalyzed mechanosynthesis of some functional polymers, such as semiconductive polymers, porous polymeric materials, sensory materials, materials for photovoltaics, etc.

Mechanosynthesis of Polyureas and Studies of Their Responses to Anions.

Polyureas (PUs) have already found wide practical applications, and various methods of their synthesis have been reported. In this manuscript, we wished to report the very first mechanochemical approach towards aromatic PUs via reactions between isomeric 2,2'-, 3,3'-, and 4,4'-diaminobiphenyls and triphosgene under solvent-free conditions following ball-milling. By using this synthetic approach, both PUs and azomethine-capped Pus were obtained. The fluorescence response of the above-mentioned PUs towards various anions in solutions were studied and selective fluorescence responses towards the hydroxyl and fluoride anions were observed.

Chichibabin-type condensation of cyclic ketones with 3-R-1,2,4-triazin-5(4H)-ones.

Reactions between substituted 1,2,4-triazines and ketones were investigated. General procedures for one-pot synthesis of hydrogenated derivatives of such polycyclic systems as benzo[c][1,2,4]triazino[1,6-a][2]azecine, [1,2,4]triazino[1,6-f]phenantridine, and dicyclopenta[b,d]pyrido[1,2-f][1,2,4]triazine are described.

Computer vision vs. spectrofluorometer-assisted detection of common nitro-explosive components with bola-type PAH-based chemosensors.

Computer vision (CV) algorithms are widely utilized in imaging processing for medical and personal electronics applications. In sensorics CV can provide a great potential to quantitate chemosensors' signals. Here we wish to describe a method for the CV-assisted spectrofluorometer-free detection of common nitro-explosive components, e.g. 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), by using polyaromatic hydrocarbon (PAH, PAH = 1-pyrenyl or 9-anthracenyl) - based bola-type chemosensors. The PAH components of these chemical bolas are able to form stable, bright emissive in a visual wavelength region excimers, which allows their use as extended matrices of the RGB colors after imaging and digital processing. In non-polar solvents, the excimers have poor chemosensing properties, while in aqueous solutions, due to the possible micellar formation, these excimers provide "turn-off" fluorescence detection of DNT and TNT in the sub-nanomolar concentrations. A combination of these PAH-based fluorescent chemosensors with the proposed CV-assisted algorithm offers a fast and convenient approach for on-site, real-time, multi-thread analyte detection without the use of fluorometers. Although we focus on the analysis of nitro-explosives, the presented method is a conceptual work describing a general use of CV for quantitative fluorescence detection of various analytes as a simpler alternative to spectrofluorometer-assisted methods.

Marine biomaterials: Biomimetic and pharmacological potential of cultivated Aplysina aerophoba marine demosponge.

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.

Fluorescent Detection of 2,4-DNT and 2,4,6-TNT in Aqueous Media by Using Simple Water-Soluble Pyrene Derivatives.

Pyrene-containing water-soluble probes for the fluorescent detection of nitroaromatic compounds (NACs), such as explosive components (2,4-DNT and 2,4,6-TNT) and herbicides (2,4-dinitrocresol, 2,4-DNOC), in aqueous media are reported. In the probes, the introduction of surface-active hydrophilic "heads" at the periphery of lipophilic (i.e., hydrophobic) pyrene "tails" resulted in the formation of highly fluorescent micelle-like aggregates/pre-associates in aqueous solutions at concentrations of ≤10(-5) m. The enhanced fluorescence quenching of the herein reported architectures is achieved in the presence of ultra-trace amounts of TNT or 2,4-DNT with values of Stern-Volmer quenching constant close to 1×10(5) m(-1) and a detection limit as low as 182 ppb. The most hydrophilic probes demonstrated higher response to 2,4-DNT over TNT. Filter paper test strips impregnated with 1×10(-5) m solutions of the probes were able to detect TNT, 2,4-DNT, and other NACs at levels as low as 50 ppb in water.