Cytotoxic activity of distinct families of phosphonic acid derivatives - A chemocentric approach to assess their molecular action.

Phosphorus containing small molecules (particularly α-aminophosphonates, α-hydroxyphosphonates and bisphosphonates) represent a unique chemical space among the biologically active compounds. We selected 35 diverse compounds that showed remarkable cytotoxicity effects on various cancer cell lines. However, the exact mechanism of action often requires further investigations, in vitro or in silico target identification even though many target-based activity data were gathered for the above cluster of compounds.

Molecularly Imprinted Polymeric Nanoparticles as Drug Delivery System for Tenofovir, an Acyclic Nucleoside Phosphonate Antiviral.

A molecularly imprinted polymer of Tenofovir (1), an FDA-approved acyclic nucleoside phosphonate with antiviral activity, was synthesized using a non-covalent approach. A pre-polymerization complex was formed between (1) and DMAEMA and in-house synthetic N1-[(2-methacryloyloxy)ethyl] thymine, with EGDMA as a cross-linker in an MeCN/H2O (9:1, 1:1) mixture as a porogen, giving an imprinting factor (IF) of 5.5 at 2.10-5 mol/L. Binding parameters were determined by the Freundlich-Langmuir model, Qmax and Ka, and well as the particle morphology for MIP and NIP. Finally, the release profiles, for MIP and NIP, were obtained at 25 °C and 37 °C, which is body temperature, in a phosphate buffer saline, pH 7.4, mimicking the blood pH value, to determine the potential sustained release of our polymeric materials.

Dissolved Organic Phosphorus Bond-Class Utilization by Synechococcus.

Dissolved organic phosphorus (DOP) contains compounds with phosphoester, phosphoanhydride, and phosphorus-carbon bonds. While DOP holds significant nutritional value for marine microorganisms, the bioavailability of each bond-class to the widespread cyanobacterium Synechococcus remains largely unknown. This study evaluates bond-class specific DOP utilization by Synechococcus strains from open and coastal oceans. Both strains exhibited comparable growth rates when provided phosphate, a phosphoanhydride (3-polyphosphate, 45-polyphosphate), or a DOP compound with both phosphoanhydride and phosphoester bonds (adenosine 5'-triphosphate). Growth rates on phosphoesters (glucose-6-phosphate, adenosine 5'-monophosphate, bis(4-methylumbelliferyl) phosphate) were variable, and neither strain grew on selected phosphorus-carbon compounds. Both strains hydrolyzed 3-polyphosphate, then adenosine 5'-triphosphate, and lastly adenosine 5'-monophosphate, exhibiting preferential enzymatic hydrolysis of phosphoanhydride bonds. The strains' exoproteomes contained phosphorus hydrolases, which combined with enhanced cell-free hydrolysis of 3-polyphosphate and adenosine 5'-triphosphate under phosphate deficiency, suggests active mineralization of phosphoanhydride bonds by these exoproteins. Synechococcus alkaline phosphatases presented broad substrate specificities, including activity towards the phosphoanhydride 3-polyphosphate, with varying affinities between strains. Collectively, these findings underscore the potentially significant role of compounds with phosphoanhydride bonds in Synechococcus phosphorus nutrition and highlight varied growth and enzymatic responses to molecular diversity within DOP bond-classes, thereby expanding our understanding of microbially-mediated DOP cycling in marine ecosystems.

Importance of iron complexation and floc formation towards phosphonate removal with Fe-electrocoagulation.

Phosphonates are widely used scale inhibitors, but the residual phosphonates in drainage are challenging to remove because of their chelating capacity and resistance to biodegradation. Here, we reported a highly efficient and robust Fe-electrocoagulation (Fe-EC) system for phosphonate removal. Surprisingly, we found for the first time that phosphonates like NTMP were more efficiently removed under anoxic conditions (80% of total soluble phosphorus (TSP) in 4 min) than oxic conditions (0% of TSP within 6 min) in NaCl solution. A similar phenomenon was observed when other phosphonates, such as EDTMP and DTPMP, were removed, highlighting the importance of iron complexation and floc formation toward phosphonate removal with Fe-EC. We also showed that the removal efficiency of NTMP by electrochemically in-situ formed flocs (97%) was much higher than post-adsorption systems (ex-situ, 40%), revealing that the growth of flocs consumed the active site for NTMP adsorption. Beyond the removal of TSP, 10 % of NTMP-P was also degraded after the electrolysis phase, evidenced by the evolution of phosphate-P. However, this did not happen in anoxic or chemical coagulation processes, which confirms the formation of reactive oxygen species via Fe(II) oxidation in the oxic Fe-EC system. The primary removal mechanism of phosphonates is due to their complexation with iron (hydr)oxide generated in the Fe-EC system by forming a Fe-O-P bond. Encouragingly, the Fe-EC system exhibits comparable or even better performance in treating phosphonate-laden wastewater (i.e., cooling water). Our preliminary cost calculation suggests the proposed system (€ 0.009/m3) has a much lower OPEX under oxic conditions than existing approaches. This study sheds light on the removal mechanism of phosphonate and the treatment of phosphonate-laden wastewater by playing with the iron complexion and flocs formation in classical Fe-EC systems.

Bis(2,2,2 trifluoroethyl) Phosphonate as a Convenient Precursor for the Synthesis of H-Phosphonates.

A microwave-assisted synthesis of dialkyl and cyclic H-phosphonates via bis(2,2,2 trifluoroethyl) phosphonate (BTFEP) is described. This method enables the synthesis of various cyclic H-phosphonates and hetero-substituted dialkyl H-phosphonates by simple alcoholysis under non-inert and additive-free conditions. Short reaction times and the requirement for only stoichiometric amounts of alcohol render this method attractive for synthetic applications.

Inhibition of human mevalonate kinase by allosteric inhibitors of farnesyl pyrophosphate synthase.

Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target.

Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes.

Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs2 onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment.

Synthesis and characterization of nitrogen-doped-MWCNT@cobalt oxide for nerve agent simulant detection.

Organophosphorus nerve agents are toxic compounds that disrupt neuromuscular transmission by inhibiting the neurotransmitter enzyme, acetylcholinesterase, leading to rapid death. A hybrid composite was synthesized using a hydrothermal process for the early detection of dimethyl methyl phosphonate (DMMP), a simulant of the G-series nerve agent, sarin. Quartz crystal microbalance (QCM) and surface acoustic wave (SAW) sensors were used as detectors. Nitrogen-doped multiwalled carbon nanotubes (N-MWCNTs), cobalt oxide (Co3O4), and N-MWCNT@Co3O4 were compared to detect DMMP concentrations of 25-150 ppm. At 25 ppm, the differential frequencies (Δf) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors were 5.8, 2.3, and 99.5 Hz, respectively. The selectivity results revealed a preference for the DMMP rather than potential interference. The coefficients of determination (R2) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 25-150 ppm DMMP were 0.983, 0.986, and 0.999, respectively. The response times of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 100 ppm DMMP were 25, 27, and 34 s, respectively, while the corresponding recovery times were 85, 105, and 181 s. The repeatability results revealed the reversible adsorption and desorption phenomena for the fixed DMMP concentration of 100 ppm. These unique findings show that synthesized materials can be used to detect organophosphorus nerve agents.

Genome sequence of the bialaphos producer Streptomyces sp. DSM 41527 and two putative phosphonate antibiotic producers Streptomyces sp. DSM 41014 and DSM 41981 from the DSMZ strain collection.

Streptomyces sp. DSM 41014, DSM 41527, and DSM 41981 are three strains from the DSMZ strain collection. Here, we present the draft genome sequences of DSM 41014, DSM 41527, and DSM 41981 with a size of 9.09 Mb, 8.45 Mb, and 9.23 Mb, respectively.

Biogenic Phosphonate Utilization by Globally Distributed Diatom Thalassiosira pseudonana.

Phosphonates are a class of organic phosphorus (P) compounds that contribute ~25% of dissolved organic P. Recent studies reveal the important role of phosphonates mediated by prokaryotes in the marine P redox cycle. However, its bioavailability by eukaryotic phytoplankton is under debate. 2-Aminoethylphosphonic acid (2-AEP) and 2-amino-3-phosphonopropionic acid (2-AP3) are two biogenic phosphonates in the marine environment. Here, Thalassiosira pseudonana, a common diatom species in the ocean, is able to recover growth from P starvation when provided with 2-AEP and 2-AP3. Moreover, 2-AEP cultures exhibited a more similar growth rate at 12 °C than at 25 °C when compared with inorganic P cultures. The cellular stoichiometry of 2-AEP groups was further determined, the values of which are in-between the P-depleted and DIP-replete cultures. This study provides evidence that biogenic phosphonates could be adopted as alternative P sources to support diatom growth and may provide physiological adaptation.

A novel chitosan/cellulose phosphonate composite hydrogel for ultrafast and efficient removal of Pb(II) and Cu(II) from wastewater.

Developing green and high-performance adsorbents to separate heavy metals from wastewater is a challenging task. Biomass hydrogel has the advantages of low cost, renewability, and biodegradability, but it has the problem of low adsorption efficiency. Herein, a novel chitosan/cellulose phosphonate composite hydrogel(CS/MCCP) is fabricated by two steps of reactions including the Phosphorylation reaction and the Mannich reaction. As an excellent chelating group, the phosphonate group greatly enhances the adsorption efficiency of the biomass hydrogel. The CS/MCCP shows ultrafast adsorption rate and excellent adsorption capacity for Pb(II) and Cu(II). The saturated adsorption capacity of Pb(II) and Cu(II) is 211.42 and 74.29 mg·g-1, respectively. The adsorption equilibration time is only 10 min. The adsorption performance of the CS/MCCP is superior to that of the reported cellulose/chitosan hydrogels. Besides, an in-depth analysis of the adsorption mechanism is conducted using X-ray photoelectron spectroscopy(XPS) combined with Density Functional Theory(DFT) calculation. The results reveal that the adsorption mechanism is electrostatic attraction and surface complexation, and there is a synergistic coordination between the phosphonate groups and the amino groups.

Novel electrocatalytic capacitive deionization with catalytic electrodes for selective phosphonate degradation: Performance and mechanism.

Phosphonate is becoming a global interest and concern owing to its environment risk and potential value. Degradation of phosphonate into phosphate followed by the recovery is regarded as a promising strategy to control phosphonate pollution, relieve phosphorus crisis, and promote phosphorus cycle. Given these objectives, an anion-membrane-coated-electrode (A-MCE) doped with Fe-Co based carbon catalyst and cation-membrane-coated-electrode (C-MCE) doped with carbon-based catalyst were prepared as catalytic electrodes, and a novel electrocatalytic capacitive deionization (E-CDI) was developed. During charging process, phosphonate was enriched around A-MCE surface based on electrostatic attraction, ligand exchange, and hydrogen bond. Meanwhile, Fe2+ and Co2+ were self-oxidized into Fe3+ and Co3+, forming a complex with enriched phosphonate and enabling an intramolecular electron transfer process for phosphonate degradation. Additionally, benefiting from the stable dissolved oxygen and high oxygen reduction reaction activity of C-MCE, hydrogen peroxide accumulated in E-CDI (158 µM) and thus hydroxyl radicals (·OH) were generated by activation. E-CDI provided an ideal platform for the effective reaction between ·OH and phosphonate, avoiding the loss of ·OH and triggering selective degradation of most phosphonate. After charging for 70 min, approximately 89.9% of phosphonate was degraded into phosphate, and phosphate was subsequently adsorbed by A-MCE. Results also showed that phosphonate degradation was highly dependent on solution pH and voltage, and was insignificantly affected by electrolyte concentration. Compared to traditional advanced oxidation processes, E-CDI exhibited a higher degradation efficiency, lower cost, and less sensitive to co-existed ions in treating simulated wastewaters. Self-enhanced and selective degradation of phosphonate, and in-situ phosphate adsorption were simultaneously achieved for the first time by a E-CDI system, showing high promise in treating organic-containing saline wastewaters.

Impact of Single Acyclic Phosphonate Nucleotide (ZNA) Modifications on DNA Duplex Stability.

An acyclic phosphonate-linked nucleic acid backbone (ZNA) demonstrated the capability to support duplex formation and propagate genetic information in vivo, unveiling its potential for evolution into a synthetic genetic system (XNA). To determine the structural impact of such modification, modified Dickerson Drew DNA dodecamers (DDDs) were prepared by solid phase synthesis, each containing either an (R) or (S) isomeric form of a cytosine ZNA nucleotide. While the DDD is known to adopt a stable duplex, both duplex and hairpin forms were simultaneously observed for both modified oligonucleotides by NMR spectroscopy over a broad temperature range (5-65 °C). Diffusion-ordered spectroscopy (DOSY) experiments allowed to separate duplex and hairpin signals based on the different diffusion constants of both conformational states. For the oligomer containing (R)-ZNA, only the duplex form occurred at 5 °C, while it was not possible to determine by NMR a single hairpin conformation at higher temperatures. In the case of the (S)-ZNA nucleoside modified oligomer, both hairpin and duplex forms were observable at 0 °C, while a single hairpin conformation was detected at 37 °C, suggesting a higher destabilizing effect on dsDNA.

Gold and Silver Nanoparticles as Biosensors: Characterization of Surface and Changes in the Adsorption of Leucine Dipeptide under the Influence of Substituent Changes.

Early detection of diseases can increase the chances of successful treatment and survival. Therefore, it is necessary to develop a method for detecting or sensing biomolecules that cause trouble in living organisms. Disease sensors should possess specific properties, such as selectivity, reproducibility, stability, sensitivity, and morphology, for their routine application in medical diagnosis and treatment. This work focuses on biosensors in the form of surface-functionalized gold (AuNPs) and silver nanoparticles (AgNPs) prepared using a less-time-consuming, inexpensive, and efficient synthesis route. This allows for the production of highly pure and stable (non-aggregating without stabilizers) nanoparticles with a well-defined spherical shape, a desired diameter, and a monodisperse distribution in an aqueous environment, as confirmed by transmission electron microscopy with energy-dispersive X-ray spectroscopy (TEM-EDS), X-ray diffraction (XRD), photoelectron spectroscopy (XPS), ultraviolet-visible (UV-VIS) spectroscopy, and dynamic light scattering (DLS). Thus, these nanoparticles can be used routinely as biomarker sensors and drug-delivery platforms for precision medicine treatment. The NPs' surface was coated with phosphonate dipeptides of L-leucine (Leu; l-Leu-C(R1)(R2)PO3H2), and their adsorption was monitored using SERS. Reproducible spectra were analyzed to determine the orientation of the dipeptides (coating layers) on the nanoparticles' surface. The appropriate R2 side chain of the dipeptide can be selected to control the arrangement of these dipeptides. This allows for the proper formation of a layer covering the nanoparticles while also simultaneously interacting with the surrounding biological environment, such as cells, tissues, and biological fluids.

Synthesis of LAVR-289, a new [(Z)-3-(acetoxymethyl)-4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug with pronounced antiviral activity against DNA viruses.

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC50 0.0035 µM, SI 740) and for thymidine kinase VZV deficient strains (EC50 0.018 µM, SI 145), with a low morphological toxicity in cell culture at 100 µM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC50 0.021 µM) and VV (EC50 0.050 µM), as well as against HSV-1 (TK-) (EC50 0.0085 µM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.

Fertilisation of agricultural soils with municipal biosolids: Glyphosate and aminomethylphosphonic acid inputs to Québec field crop soils.

Municipal biosolids (MBS) are suggested to be abundant, sustainable, inexpensive fertilisers, rich in phosphorus and nitrogen. However, MBS can also contain glyphosate and phosphonates that can degrade to AMPA. Glyphosate-based herbicides (GBH) are used in field crops all over the world. Most glyphosate generally degrades within a few weeks, mainly as aminomethylphosphonic acid (AMPA). AMPA is more persistent than glyphosate, and can accumulate from one crop year to the next. AMPA is phytotoxic even to glyphosate-resistant crops. The aims of this study were to assess whether MBS applications constitute: 1) an additional source of glyphosate and AMPA to agricultural soils with respect to GBH, 2) a significant source of trace metals, and 3) a partial replacement of mineral fertilisation while maintaining similar yields. To this end, four experimental agricultural sites were selected in Québec (Canada). Soil samples (0-20 cm) were collected to estimate the as yet unmeasured contribution of MBS application to glyphosate and AMPA inputs in agricultural soils. MBS applied in 2021 and 2022 had mean concentrations of 0.69 ± 0.53 µg glyphosate/dry g and 6.26 ± 1.93 µg AMPA/dry g. Despite the presence of glyphosate and AMPA in MBS, monitoring of these two compounds in corn and soybean crops over two years showed no significant difference between plots treated with and without MBS applications. For the same site, yields measured at harvest were similar between treatments. MBS application could thus represent a partial alternative to mineral fertilisers for field crops, while limiting the economic and environmental costs associated with their incineration and landfilling. It is also an economic advantage for agricultural producers given the possibility of using fewer mineral fertilisers and therefore reducing the environmental impact of their use.

Synthesis of novel organophosphorus compounds via reaction of substituted 2-oxoindoline-3-ylidene with acetylenic diesters and triphenylphosphine or triphenyl phosphite.

An efficient reaction between triphenylphosphine or triphenyl phosphite and 2-oxoindoline-3-ylidene derivatives in the presence of acetylenic esters leads to functionalized 2-oxoindoline-3-ylidene containing phosphorus ylieds or phosphonate esters. All compounds obtained in these reactions are stable and have good yields.

Bromide triggers efficient peroxymonosulfate activation for phosphonate degradation.

Phosphonates have received a widespread attention in wastewater treatment due to their potential threat to the water environment. Advanced oxidation processes (AOPs) are feasible methods to degrade phosphonates, and most of the coexisting substances in water show a negative factor during their oxidation. However, the effect of bromide (Br-) on the degradation of phosphonates in peroxymonosulfate (PMS) activation is still unclear. Herein, using 1-hydroxyethane 1,1-diphosphonic acid (HEDP) as a target phosphonate, Br- could remarkably enhance the degradation of HEDP in PMS activation compared to the PMS alone. Under the condition of pH = 7.0, the optimal degradation efficiency of HEDP is 84.8% in the PMS/Br- process after 30-min reaction, whereas no significant oxidation is obtained in the PMS/I- and PMS/Cl- processes. Multiple experiments (i.e., electron paramagnetic resonance (EPR), radical quenching experiments and chemical probs) confirm that free bromine, SO4•- and HO• paly a minor role in HEDP removal, and bromine radical species make a dominant responsible for HEDP oxidation. Additionally, NO3-, SO42-, Cl-, and HCO3- have a little effect on the degradation of HEDP, but the HEDP removal is greatly inhibited in the presence of humic acid (HA). However, the degradation efficiency of HEDP using PMS/Br- process in river and sewage is a much higher than UV/persulfate (PDS) and UV/H2O2 processes. This study provides a new sight into the effect of Br- on the degradation phosphonates in PMS activation process.

Determination of the total antioxidant capacity of the Chinese tea based on a novel "peroxidase/zirconium phosphonate"composite electrochemical sensor.

In this work, a novel zirconium phosphonate (ZrPR1R2) was prepared by decorating both the aminoethoxy- group (R1) and the carboxypropyl- group (R2) on the zirconium phosphate layers in order to manipulate further the immobilization of the peroxidase (POD), and an antioxidant biosensor with higher sensitivity was constructed by dropping the POD/ZrPR1R2 composite onto the glassy carbon electrode surface. The activity of the POD/ZrPR1R2 composite was detected by Uv-vis spectra. The direct electrochemical behavior, the electrocatalytic response to dissolved oxygen and hydrogen peroxide, as well as the ability to detect total antioxidant capacity in tea sample were investigated by the methods of cyclic voltammetry. The results indicated that the immobilization of POD in ZrPR1R2 nanosheets matrix enhanced the enzymatic activity, and achieved the fast and direct electron transfer between POD and glassy carbon electrode. Moreover, the POD/ZrPR1R2 composite modified electrode show the electrocatalytic response to hydrogen peroxide in the linear range of 8.8×10-8 to 8.8×10-7 mol L-1, with the detection limit of 3.3×10-8 mol L-1. Attributing to the sensitive response to dissolved oxygen, the total antioxidant capacity can be detected directly in the real tea water by this POD/ZrPR1R2 composite modified electrode.

Multi-Functional Spirobifluorene Phosphonate Based Exciplex Interface Enables Voc Reaching 95% of Theoretical Limit for Perovskite Solar Cells.

Metal halide perovskite solar cells (PSCs) show significant advancements in power conversion efficiency (PCE). However, the open-circuit voltage (VOC) of PSCs is limited by interfacial factors such as defect-induced recombination, energy band mismatch, and non-intimate interface contact. Here, an exciplex interface is first developed based on the strategically designed and synthesized two spirobifluorene phosphonate molecules to mitigate VOC loss in PSCs. The exciplex interface constructed by the intimate contact between the multi-functional molecules and hole transport layer takes the roles to promote the hole extraction by donor-acceptor interaction, passivate coordination-unsaturated Pb2+ defects by equipped phosphonate groups, and optimize the energy level alignment. As a result, a record VOC of 1.26 V with a perovskite bandgap of 1.61 eV is achieved, representing over 95% of theoretical limit. This advancement leads to an increase in PCE from 21.29% to 24.12% and improved stability. The exciplex interface paves the way for addressing the long-standing challenge of VOC loss and promotes the wider application of PSCs.