Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

The Application of Porous Organic Polymers as Metal Free Photocatalysts in Organic Synthesis.

Concerns about increasing greenhouse gas emissions and their effect on our environment highlight the urgent need for new sustainable technologies. Visible light photocatalysis allows the clean and selective generation of reactive intermediates under mild conditions. The more widespread adoption of the current generation of photocatalysts, particularly those using precious metals, is hampered by drawbacks such as their cost, toxicity, difficult separation, and limited recyclability. This is driving the search for alternatives, such as porous organic polymers (POPs). This new class of materials is made entirely from organic building blocks, can possess high surface area and stability, and has a controllable composition and functionality. This review focuses on the application of POPs as photocatalysts in organic synthesis. For each reaction type, a representative material is discussed, with special attention to the mechanism of the reaction. Additionally, an overview is given, comparing POPs with other classes of photocatalysts, and critical conclusions and future perspectives are provided on this important field.

Versatile Palladium-catalyzed intramolecular cyclization to access new luminescent azaphosphaphenalene motifs.

Using a straightforward sequence of diphosphonylation and a Pd-catalysed concerted-metalation-deprotonation (CMD), a synthetic strategy towards polyaromatic phosphorus containing heterocycles was developed. Herein, we report the synthesis and characterization of new azaphosphaphenalenes, using easily accessible palladium catalysts and starting materials. The key tetrahydroquinoline intermediates of the reaction were synthesised via a fast and effective procedure and could be isolated as such, or further reacted towards the target polyaromatic structures. The obtained products showed interesting luminescent properties and their emission, excitation and quantum yields were evaluated.

Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime?

Tumor-associated mesenchymal stem/stromal cells (TA-MSCs) have been recognized as attractive therapeutic targets in several cancer types, due to their ability to enhance tumor growth and angiogenesis and their contribution to an immunosuppressive tumor microenvironment (TME). In glioblastoma (GB), mesenchymal stem cells (MSCs) seem to be recruited to the tumor site, where they differentiate into glioblastoma-associated mesenchymal stem/stromal cells (GA-MSCs) under the influence of tumor cells and the TME. GA-MSCs are reported to exert important protumoral functions, such as promoting tumor growth and invasion, increasing angiogenesis, stimulating glioblastoma stem cell (GSC) proliferation and stemness, mediating resistance to therapy and contributing to an immunosuppressive TME. Moreover, they could act as precursor cells for cancer-associated fibroblasts (CAFs), which have recently been identified in GB. In this review, we provide an overview of the different functions exerted by GA-MSCs and CAFs and the current knowledge on the relationship between these cell types. Increasing our understanding of the interactions and signaling pathways in relevant models might contribute to future regimens targeting GA-MSCs and GB-associated CAFs to inhibit tumor growth and render the TME less immunosuppressive.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Drug discovery-based approach identifies new nitrification inhibitors.

Nitrogen (N) fertilization is crucial to sustain global food security, but fertilizer N production is energy-demanding and subsequent environmental N losses contribute to biodiversity loss and climate change. N losses can be mitigated be interfering with microbial nitrification, and therefore the use of nitrification inhibitors in enhanced efficiency fertilizers (EEFs) is an important N management strategy to increase N use efficiency and reduce N pollution. However, currently applied nitrification inhibitors have limitations and do not target all nitrifying microorganisms. Here, to identify broad-spectrum nitrification inhibitors, we adopted a drug discovery-based approach and screened 45,400 small molecules on different groups of nitrifying microorganisms. Although a high number of potential nitrification inhibitors were identified, none of them targeted all nitrifier groups. Moreover, a high number of new nitrification inhibitors were shown to be highly effective in culture but did not reduce ammonia consumption in soil. One archaea-targeting inhibitor was not only effective in soil, but even reduced - when co-applied with a bacteria-targeting inhibitor - ammonium consumption and greenhouse gas emissions beyond what is achieved with currently applied nitrification inhibitors. This advocates for combining different types of nitrification inhibitors in EEFs to optimize N management practices and make agriculture more sustainable.

Overview of N-Rich Antennae Investigated in Lanthanide-Based Temperature Sensing.

The market share of noncontact temperature sensors is expending due to fast technological and medical evolutions. In the wide variety of noncontact sensors, lanthanide-based temperature sensors stand out. They benefit from high photostability, relatively long decay times and high quantum yields. To circumvent their low molar light absorption, the incorporation of a light-harvesting antenna is required. This Review provides an overview of the nitrogen-rich antennae in lanthanide-based temperature sensors, emitting in the visible light spectrum, and discusses their temperature sensor ability. The N-rich ligands are incorporated in many different platforms. The investigation of different antennae is required to develop temperature sensors with diverse optical properties and to create a diverse offer for the multiple application fields. Molecular probes, consisting of small molecules, are first discussed. Furthermore, the thermometer properties of ratiometric temperature sensors, based on di- and polynuclear complexes, metal-organic frameworks, periodic mesoporous organosilicas and porous organic polymers, are summarized. The antenna mainly determines the application potential of the ratiometric thermometer. It can be observed that molecular probes are operational in the broad physiological range, metal-organic frameworks are generally very useful in the cryogenic region, periodic mesoporous organosilica show temperature dependency in the physiological range, and porous organic polymers are operative in the cryogenic-to-medium temperature range.

Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N-Heterocyclic Carbene) Complexes.

The use of weak and inexpensive bases has recently opened promising perspectives towards the simpler and more sustainable synthesis of Au(I)-aryl complexes with valuable applications in catalysis, medicinal chemistry, and materials science. In recent years, continuous manufacturing has shown to be a reliable partner in establishing sustainable and controlled process scalability. Herein, the first continuous flow synthesis of a range of Au(I)-aryl starting from widely available boronic acids and various [Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in unprecedentedly short reaction times and high yields is reported. Successful synthesis of previously non- or poorly accessible complexes exposed fascinating reactivity patterns. Via a gram-scale synthesis, convenient process scalability of the developed protocol was showcased.

Continuous Flow Synthesis of Metal-NHC Complexes*.

The use of weak bases and mild conditions is currently the most sustainable and attractive synthetic approach for the preparation of late-transition metal complexes, some of which are widely used in catalysis, medicinal chemistry and materials science. Herein, the use of cuprate, aurate or palladate species for a continuous flow preparation of CuI , AuI and PdII -NHC complexes is reported. All reactions examined proceed under extremely mild conditions and make use of technical grade acetone as solvent. The scalability of the process was exemplified in a multigram-scale synthesis of [Cu(IPr)Cl].

Learning Molecular Representations for Thermochemistry Prediction of Cyclic Hydrocarbons and Oxygenates.

Accurate thermochemistry estimation of polycyclic molecules is crucial for kinetic modeling of chemical processes that use renewable and alternative feedstocks. In kinetic model generators, molecular properties are estimated rapidly with group additivity, but this method is known to have limitations for polycyclic structures. This issue has been resolved in our work by combining a geometry-based molecular representation with a deep neural network trained on ab initio data. Each molecule is transformed into a probabilistic vector from its interatomic distances, bond angles, and dihedral angles. The model is tested on a small experimental dataset (200 molecules) from the literature, a new medium-sized set (4000 molecules) with both open-shell and closed-shell species, calculated at the CBS-QB3 level with empirical corrections, and a large G4MP2-level QM9-based dataset (40 000 molecules). Heat capacities between 298.15 and 2500 K are calculated in the medium set with an average deviation of about 1.5 J mol-1 K-1 and the standard entropy at 298.15 K is predicted with an average error below 4 J mol-1 K-1. The standard enthalpy of formation at 298.15 K has an average out-of-sample error below 4 kJ mol-1 on a QM9 training set size of around 15 000 molecules. By fitting NASA polynomials, the enthalpy of formation at higher temperatures can be calculated with the same accuracy as the standard enthalpy of formation. Uncertainty quantification by means of the ensemble standard deviation is included to indicate when molecules that are on the edge or outside of the application range of the model are evaluated.

Endocrine disrupting potency and toxicity of novel sophorolipid quaternary ammonium salts.

A new class of biosurfactants, namely quaternary ammonium sophorolipids (SQAS), suitable for pharmaceutical applications, was tested for the evaluation of their (anti)estrogenic and (anti)androgenic potency with the help of YES/YAS assays. Also their toxicity towards yeasts (Saccharomyces cerevisiae) and bacteria (Escherichia coli) was checked. The results achieved for SQAS, which can be regarded as potential micropollutants, were compared with those obtained for two well-known micropollutants diclofenac and 17α-ethinylestradiol subjected to the same testing procedures. This work demonstrated that acetylation of the hydroxyl group of the carbohydrate head of SQAS decreased the toxicity of this class of biosurfactants towards Saccharomyces cerevisiae. Furthermore, it contributed to the decrease of their endocrine disrupting potency. None of the SQAS studied showed clear agonist activity for female or male hormones. SQAS1 and SQAS2 revealed weak antiestrogenic and antiandrogenic potency. All of these properties were weaker, not only to the potency of the appropriate positive control in the antagonists bioassays, but also compared to the potency of other tested compounds, i.e. DCF and EE2. SQAS3 possessed most probably inhibitory activity towards male hormones. Moreover, cytotoxicity of two out of four studied SQAS at the highest concentrations towards the strains of Saccharomyces cerevisiae interfered with the endocrine disruption activity. It would be also worth studying it with the use of another endocrine activity test.

Quantifying the Likelihood of Structural Models through a Dynamically Enhanced Powder X-Ray Diffraction Protocol.

Structurally characterizing new materials is tremendously challenging, especially when single crystal structures are hardly available which is often the case for covalent organic frameworks. Yet, knowledge of the atomic structure is key to establish structure-function relations and enable functional material design. Herein, a new protocol is proposed to unambiguously predict the structure of poorly crystalline materials through a likelihood ordering based on the X-ray diffraction (XRD) pattern. Key of the procedure is the broad set of structures generated from a limited number of building blocks and topologies, which is submitted to operando structural characterization. The dynamic averaging in the latter accounts for the operando conditions and inherent temporal character of experimental measurements, yielding unparalleled agreement with experimental powder XRD patterns. The proposed concept can hence unquestionably identify the structure of experimentally synthesized materials, a crucial step to design next generation functional materials.

Design and visualization of second-generation cyanoisoindole-based fluorescent strigolactone analogs.

Strigolactones (SLs) are a family of terpenoid allelochemicals that were recognized as plant hormones only a decade ago. They influence a myriad of both above- and below-ground developmental processes, and are an important survival strategy for plants in nutrient-deprived soils. A rapidly emerging approach to gain knowledge on hormone signaling is the use of traceable analogs. A unique class of labeled SL analogs was constructed, in which the original tricyclic lactone moiety of natural SLs is replaced by a fluorescent cyanoisoindole ring system. Biological evaluation as parasitic seed germination stimulant and hypocotyl elongation repressor proved the potency of the cyanoisoindole strigolactone analogs (CISAs) to be comparable to the commonly accepted standard GR24. Additionally, via a SMXL6 protein degradation assay, we provided molecular evidence that the compounds elicit SL-like responses through the natural signaling cascade. All CISAs were shown to exhibit fluorescent properties, and the high quantum yield and Stokes shift of the pyrroloindole derivative CISA-7 also enabled in vivo visualization in plants. In contrast to the previously reported fluorescent analogs, CISA-7 displays a large similarity in shape and structure with natural SLs, which renders the analog a promising tracer to investigate the spatiotemporal distribution of SLs in plants and fungi.

Strongly Reducing (Diarylamino)benzene-Based Covalent Organic Framework for Metal-Free Visible Light Photocatalytic H2O2 Generation.

Photocatalytic reduction of molecular oxygen is a promising route toward sustainable production of hydrogen peroxide (H2O2). This challenging process requires photoactive semiconductors enabling solar energy driven generation and separation of electrons and holes with high charge transfer kinetics. Covalent organic frameworks (COFs) are an emerging class of photoactive semiconductors, tunable at a molecular level for high charge carrier generation and transfer. Herein, we report two newly designed two-dimensional COFs based on a (diarylamino)benzene linker that form a Kagome (kgm) lattice and show strong visible light absorption. Their high crystallinity and large surface areas (up to 1165 m2·g-1) allow efficient charge transfer and diffusion. The diarylamine (donor) unit promotes strong reduction properties, enabling these COFs to efficiently reduce oxygen to form H2O2. Overall, the use of a metal-free, recyclable photocatalytic system allows efficient photocatalytic solar transformations.

N-Rich Porous Polymer with Isolated Tb3+ -Ions Displays Unique Temperature Dependent Behavior through the Absence of Thermal Quenching.

The challenge of measuring fast moving or small scale samples is based on the absence of contact between sample and sensor. Grafting lanthanides onto hybrid materials arises as one of the most promising accurate techniques to obtain noninvasive thermometers. In this work, a novel bipyridine based porous organic polymer (bpyDAT POP) was investigated as temperature sensor after grafting with Eu(acac)3 and Tb(acac)3 complexes. The bpyDAT POP successfully showed temperature-dependent behavior in the 10-310 K range, proving the potential of amorphous, porous organic frameworks. We observed unique temperature dependent behavior. More intriguingly, instead of the standard observed change in emission as a result of a change in temperature for both Eu3+ and Tb3+ , the emission spectrum of Tb3+ remained constant. This work provides framework- and energy-based explanations for the observed phenomenon. The conjugation in the bpyDAT POP framework is interrupted, creating energetically isolated Tb3+ environments. Energy transfer from Tb3+ to Eu3+ is therefore absent, nor energy back transfer from Tb3+ to bpyDAT POP ligand (i.e. no thermal quenching) is detected.

Structural and Photophysical Properties of Various Polypyridyl Ligands: A Combined Experimental and Computational Study.

Covalent triazine frameworks (CTFs) with polypyridyl ligands are very promising supports to anchor photocatalytic complexes. Herein, we investigate the photophysical properties of a series of ligands which vary by the extent of the aromatic system, the nitrogen content and their topologies to aid in selecting interesting building blocks for CTFs. Interestingly, some linkers have a rotational degree of freedom, allowing both a trans and cis structure, where only the latter allows anchoring. Therefore, the influence of the dihedral angle on the UV-Vis spectrum is studied. The photophysical properties are investigated by a combined computational and experimental study. Theoretically, both static and molecular dynamics simulations are performed to deduce ground- and excited state properties based on density functional theory (DFT) and time-dependent DFT. The position of the main absorption peak shifts towards higher wavelengths for an increased size of the π-system and a higher π-electron deficiency. We found that the position of the main absorption peak among the different ligands studied in this work can amount to 271 nm; which has a significant impact on the photophysical properties of the ligands. This broad range of shifts allows modulation of the electronic structure by varying the ligands and may help in a rational design of efficient photocatalysts.

Single-molecule lamellar hydrogels from bolaform microbial glucolipids.

Lipid lamellar hydrogels are rare soft fluids composed of a phospholipid lamellar phase instead of fibrillar networks. The mechanical properties of these materials are controlled by defects, induced by local accumulation of a polymer or surfactant in a classical lipid bilayer. Herein we report a new class of lipid lamellar hydrogels composed of one single bolaform glycosylated lipid obtained by fermentation. The lipid is self-organized into flat interdigitated membranes, stabilized by electrostatic repulsive forces and stacked in micrometer-sized lamellar domains. The defects in the membranes and the interconnection of the lamellar domains are responsible, from the nano- to the micrometer scales, for the elastic properties of the hydrogels. The lamellar structure is probed by combining small angle X-ray and neutron scattering (SAXS, SANS), the defect-rich lamellar domains are visualized by polarized light microscopy while the elastic properties are studied by oscillatory rheology. The latter show that both storage G' and loss G'' moduli scale as a weak power-law of the frequency, that can be fitted with fractional rheology models. The hydrogels possess rheo-thinning properties with second-scale recovery. We also show that ionic strength is not only necessary, as one could expect, to control the interactions in the lamellar phase but, most importantly, it directly controls the elastic properties of the lamellar gels.

Fundamental Study on the Salt Tolerance of Oregano Essential Oil-in-Water Nanoemulsions Containing Tween 80.

This study provides fundamental information about the influence of salt on the physicochemical stability of oregano essential oil (EO) and its main components incorporated in a nanoemulsion delivery system containing Tween 80 (T80) emulsifier. The emulsion stability was found to be strongly correlated with the lipid phase composition and the type of salts. The oregano essential oil nanoemulsions remained stable for several weeks in the absence of salts. Moreover, they were insensitive to tetrabutylammonium bromide, whereas similar to carvacrol emulsions, they exhibited a rapid phase separation and oiling-off in the presence of sodium chloride. On the other hand, high oleic sunflower oil (HOSO) and p-cymene emulsions remained stable in the presence of NaCl. Addition of 70 and 80% HOSO to the lipid phase of oregano EO and carvacrol, respectively, was found to be sufficient for the formation of emulsions with a high stability to 1.7 M NaCl. Hereby, the morphology of the oregano EO emulsions after 30 days of storage in the presence of NaCl was visualized using a transmission electron microscope. The determination of the surface load and area per surfactant molecule by interfacial tension (IFT) measurements and quartz crystal microbalance with dissipation revealed the dehydration of the polyoxyethylene groups of T80 in the presence of salt. The thickness of the T80 adsorbed layer onto solid hydrophobic and hydrophilic surfaces was significantly lower (p < 0.05) in the presence of sodium chloride. It is hypothesized that a combination of Ostwald ripening and coalescence due to an IFT increase and dehydration was responsible for the instability of the emulsions containing the more polar oregano EO and carvacrol in the presence of salt. The results obtained in this study could be useful for the formulation of essential oil nanoemulsions in the presence of salts applicable in food, pharmaceutical, and personal care products.

Optical Properties of Isolated and Covalent Organic Framework-Embedded Ruthenium Complexes.

Heterogenization of RuL3 complexes on a support with proper anchor points provides a route toward design of green catalysts. In this paper, Ru(II) polypyridyl complexes are investigated with the aim to unravel the influence on the photocatalytic properties of varying nitrogen content in the ligands and of embedding the complex in a triazine-based covalent organic framework. To provide fundamental insight into the electronic mechanisms underlying this behavior, a computational study is performed. Both the ground and excited state properties of isolated and anchored ruthenium complexes are theoretically investigated by means of density functional theory and time-dependent density functional theory. Varying the ligands among 2,2'-bipyridine, 2,2'-bipyrimidine, and 2,2'-bipyrazine allows us to tune to a certain extent the optical gaps and the metal to ligand charge transfer excitations. Heterogenization of the complex within a CTF support has a significant effect on the nature and energy of the electronic transitions. The allowed transitions are significantly red-shifted toward the near IR region and involve transitions from states localized on the CTF toward ligands attached to the ruthenium. The study shows how variations in ligands and anchoring on proper supports allows us to increase the range of wavelengths that may be exploited for photocatalysis.

Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch.

Bromination reactions are crucial in today's chemical industry since the versatility of the formed organobromides makes them suitable building blocks for numerous syntheses. However, the use of the toxic and highly reactive molecular bromine (Br2) makes these brominations very challenging and hazardous. We describe here a safe and straightforward protocol for bromination in continuous flow. The hazardous Br2 or KOBr is generated in situ by reacting an oxidant (NaOCl) with HBr or KBr, respectively, which is directly coupled to the bromination reaction and a quench of residual bromine. This protocol was demonstrated by polybrominating both alkenes and aromatic substrates in a wide variety of solvents, with yields ranging from 78% to 99%. The protocol can easily be adapted for the bromination of other substrates in an academic and industrial environment.