Search Results (60)

Imidazoline I₂ receptors (I₂-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I₂-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I₂-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I₂-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives. Full article

In this study, the palladium-catalyzed aminocarbonylation of 1-iodoisoquinoline was accomplished in the presence of various amines. While the reactions with simple primary and secondary amines were carried out by using the well-known Pd(OAc)₂/PPh₃ catalyst, the application of amines with lower basicity (e.g., aromatic amines) or more difficult structures (e.g., amino acid methyl esters, nortropine, diethyl (α-aminobenzyl)phosphonate) required the use of bidentate XantPhos ligand to achieve complete conversion in short reaction time (2–8 h). In this way, several valuable isoquinoline-1-carboxamides were synthesized in chemoselective carbonylation and isolated in good to high yields (55–89%). Furthermore, the aminocarbonylation of the model compound in the presence of several amines was also investigated in three biomass-derived solvents (GVL, ethyl levulinate, and 2-MeTHF). After comparing the outcome of the reactions in DMF and the above green solvents, similar reactivity was observed, justifying that they could be considered a feasible alternative reaction medium. Full article

Background: Methylenebisphosphonic derivatives including hydroxy-methylenebisphosphonic species may be of potential biological activity, and a part of them is used in the treatment of bone diseases. Methods: Methylenebisphosphonates may be obtained by the Michaelis–Arbuzov reaction of suitably α-substituted methylphosphonates and trialkyl phosphites or phosphinous esters, while the hydroxy-methylene variations are prepared by the Pudovik reaction of α-oxophosphonates and different >P(O)H reagents, such as diethyl phosphite and diarylphosphine oxides. Results: After converting α-hydroxy-benzylphosphonates and -phosphine oxides to the α-halogeno- and α-sulfonyloxy derivatives, they were utilized in the Michaelis–Arbuzov reaction with trialkyl phosphites and ethyl diphenylphosphinite to afford the corresponding bisphosphonate, bis(phosphine oxide) and phosphonate–phosphine oxide derivatives. The Pudovik approach led to α-hydroxy-methylenebisphosphonic species and to their rearranged products. A part of the derivatives revealed a significant cytotoxic effect on pancreatic adenocarcinoma or multiple myeloma cells. Conclusions: The new families of compounds synthesized by our novel approaches may be of practical importance due to the significant cytotoxic activity on the cell cultures investigated. Compounds lacking hydroxy groups showed anti-myeloma activity or limited effect on pancreatic cancer (PANC-1) cells unless substituted with para-trifluoromethyl group. Hydroxy-containing bisphosphonates and their rearranged derivatives demonstrated varying effects depending on structural modifications. While myeloma (U266) cells indicated greater sensitivity overall, the most significant reductions in cell viability were observed in PANC-1 cancer cells, raising potential therapeutic applications of bisphosphonates beyond myeloma-associated bone disease, particularly for malignancies like pancreatic ductal adenocarcinoma. Full article

In the search for new bioactive molecules, a series of new molecules from the phosphonate family were synthesized via the Kabachnik–Fields reaction (phosphonate ester) and the Irani–Moedritzer reaction (phosphonic acids). Their structures were characterized by various spectroscopic methods, including IR and UV-vis. The synthesized compounds were screened for in vitro antimicrobial activity against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria, using the well method. The results also showed that all the products synthesized exhibited good activity with a zone of inhibition: D > 8, except one product against S. aureus bacteria. The three products were tested for their antifungal effects against three pathogenic fungal strains, namely Candida albicans, Aspergillus niger, and Penicillium notatum. The results show that the zones of maximum inhibition were observed against P. notatum (35.5 mm). Therefore, the biological tests showed that all the compounds studied exhibited high antibacterial and antifungal activities. Full article

Thiosemicarbazones (TSCs) with their modular character (thiosemicarbazides + carbonyl compound) allow broad variation of up to four substituents on the main R¹R²C=N(1)–NH–C(S)–N(4)R³R⁴ core and are thus interesting tools for the formation of conjugates or the functionalization of nanoparticles (NPs). In this work, di-2-pyridyl ketone was introduced for the coordination of metals and 9-anthraldehyde for luminescence as R¹ and R² to TSCs. R³ and R⁴ substituents were varied for the formation of conjugates. Amino acids were introduced at the N4 position to produce [R¹R²TSC–spacer–amino acid] conjugates. Further, functions such as phosphonic acid (R–P(O)(OH)₂), D-glucose, o-hydroquinone, OH, and thiol (SH) were introduced at the N4 position producing [R¹R²TSC–spacer–anchor group] conjugates for direct NP anchoring. Phenyl, cyclohexyl, benzyl, ethyl and methyl were used as spacer units. Both phenyl phosphonic acid TSC derivatives were bound on TiO₂ NPs as a first example of direct NP anchoring. [R¹R²TSC–spacer–end group] conjugates including OH, S–Bn (Bn = benzyl), NH–Boc (Boc = tert-butyloxycarbonyl), COOtBu, C≡CH, or N₃ end groups were synthesized for potential covalent binding to functional molecules or functionalized NPs through amide, ester, or triazole functions. The synthesis of the thiosemicarbazides H₂NNH–C(S)–NR₃R₄ starting from amines, including amino acids, SCCl₂ or CS₂, and hydrazine and their condensation with dipyridyl ketone and anthraldehyde led to 34 new TSC derivatives. They were synthesized in up to six steps with overall yields ranging from 10 to 85% and were characterized by a combination of nuclear magnetic resonance spectroscopy and mass spectrometry. UV-vis absorption and photoluminescence spectroscopy allowed us to easily trace the dipyridyl imine and anthracene chromophores. Full article

Recycling spent lithium-ion batteries (LIBs) is crucial to prevent environmental pollution and recover valuable metals. Traditional methods for recycling spent LIBs include hydrometallurgy and pyrometallurgy. Among these methods, solvent extraction can selectively extract valuable metals in spent LIB leachate. Meanwhile, spent LIBs that underwent pyrometallurgical treatment generate a so-called ‘black alloy’ of Ni, Co, Cu, and so on. These elements in the black alloy need to be separated by solvent extraction and there have been few studies on extracting valuable metals from black alloy. Therefore, it is necessary to examine the extraction behavior of elements in black alloy and optimize the solvent extraction process to recover valuable metals. In this paper, four types of organic extractants are used to extract metals from simulated black alloy leachate: di-(2ethylhexyl) phosphoric acid (D2EHPA), bis-(2,4,4-trimethylpentyl) phosphinic acid (Cyanex272), 2-ethylhexyl phosphonic acid mono-2-ethylhexyl ester (PC88A), and neodecanoic acid (Versatic acid 10). Based on the pH isotherms, D2EHPA would be the most reasonable for Mn extraction and impurity removal. Cyanex 272 would be more suitable for Co separation than PC88A, and Versatic acid 10 is preferred for Cu extraction over other metals. In conclusion, the optimal combination of extractants is suggested for the recovery of valuable metals. Full article

Conduits are plastic tubes extensively used to safeguard electrical cables, traditionally made from PVC. Recent safety guidelines seek alternatives due to PVC’s emission of thick smoke and toxic gases upon fire incidents. Polypropylene (PP) is emerging as a viable alternative but requires modification with suitable halogen-free additives to attain flame retardancy (FR) while maintaining high mechanical strength and weathering resistance, especially for outdoor applications. The objective of this study was to develop two FR systems for PP: one comprising a cyclic phosphonate ester and a monomeric N-alkoxy hindered amine adjuvant achieving V0, and another with hypophosphite and bromine moieties, along with a NOR-HAS adjuvant achieving V2. FR performance along with mechanical properties, physicochemical characterization, and dielectric behavior were evaluated prior to and after 2000 h of UV weathering or heat ageing. The developed FR systems set the basis for the production of industrial-scale masterbatches, from which further optimization to minimize FR content was performed via melt mixing with PP towards industrialization of a low-cost FR formulation. Accordingly, two types of corrugated conduits (ø20 mm) were manufactured. Their performance in terms of flame propagation, impact resistance, smoke density, and accelerated UV weathering stability classified them as Halogen Free Low Smoke (HFLS) conduits; meanwhile, they meet EU conduit standards without significantly impacting conduit properties or industrial processing efficiency. Full article

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. Full article

Breast cancer is the most common type of cancer and the leading cause of cancer mortality among women worldwide. Considering the limitations of the current treatments available, we analyzed the in vitro cytotoxic potential of ((4-Fluoro-phenyl)-{2-[(1-phenyl-9H-β-carboline-3-carbonyl)-amino]-ethylamino}-methyl)-phosphonic acid dibutyl ester (BCP-1) in breast cancer cells (MCF-7 and MDA-MB-231) and in a non-tumor breast cell line (MCF-10A). BCP-1 has an α-aminophosphonate unit linked to the β-carboline nucleus, and the literature indicates that compounds of these classes have high biological potential. In the present study, the mechanism of action of BCP-1 was investigated through methods of spectrofluorimetry, flow cytometry, and protein expression analysis. It was found that BCP-1 inhibited the proliferation of both cancer cell lines. Furthermore, it induced oxidative stress and cell cycle arrest in G2/M. Upregulation of apoptosis-related proteins such as Bax, cytochrome C, and caspases, as well as a decrease in the anti-apoptotic protein Bcl-2, indicated potential induction of apoptosis in the MDA-MB-231 cells. While in MCF-7 cells, BCP-1 activated the autophagic death pathway, which was demonstrated by an increase in autophagic vacuoles and acidic organelles, in addition to increased expression of LC3I/LC3II and reduced SQSTM1/p62 expression. Further, BCP-1 demonstrated antimetastatic potential by reducing MMP-9 expression and cell migration in both breast cancer cell lines. In conclusion, BCP-1 is a promising candidate for breast cancer chemotherapy. Full article

Phosphonic acids represent one of the most important categories of organophosphorus compounds, with myriad examples found in chemical biology, medicine, materials, and other domains. Phosphonic acids are rapidly and conveniently prepared from their simple dialkyl esters by silyldealkylation with bromotrimethylsilane (BTMS), followed by desilylation upon contact with water or methanol. Introduced originally by McKenna, the BTMS route to phosphonic acids has long been a favored method due to its convenience, high yields, very mild conditions, and chemoselectivity. We systematically investigated microwave irradiation as a means to accelerate the BTMS silyldealkylations (MW-BTMS) of a series of dialkyl methylphosphonates with respect to solvent polarity (ACN, dioxane, neat BTMS, DMF, and sulfolane), alkyl group (Me, Et, and iPr), electron-withdrawing P-substitution, and phosphonate–carboxylate triester chemoselectivity. Control reactions were performed using conventional heating. We also applied MW-BTMS to the preparation of three acyclic nucleoside phosphonates (ANPs, an important class of antiviral and anticancer drugs), which were reported to undergo partial nucleoside degradation under MW hydrolysis with HCl at 130–140 °C (MW-HCl, a proposed alternative to BTMS). In all cases, MW-BTMS dramatically accelerated quantitative silyldealkylation compared to BTMS with conventional heating and was highly chemoselective, confirming it to be an important enhancement of the conventional BTMS method with significant advantages over the MW-HCl method. Full article

We previously reported that Lys175 in the region of the active site of chymotrypsin (Csin) could be site-selectively modified by using an N-hydroxy succinimide (NHS) ester of the peptidyl derivative containing 1-amino-2-ethylphenylphosphonate diphenyl ester [NHS-Suc-Ala-Ala-Phe^P(OPh)₂]. In this study, the Lys175-selective modification method was expanded to incorporate functional groups into Lys 175 in Csin. Two types of peptidyl phosphonate derivatives with the dansyl group (Dan) as a functional molecule, Dan-β-Ala-[Asp(NHS) or Glu(NHS)]-Ala-Ala-(R)-Phe^P(OPh)₂ (DanD and DanE, respectively), were synthesized, and their action was evaluated when modifying Lys175 in Csin. Ion-exchange chromatography (IEC), fluorescence spectroscopy, and LC-MS/MS were used to analyze the products from the reaction of Csin with DanD or DanE. By IEC and LC-MS/MS, the results showed that DanE reacted with Csin more effectively than DanD to produce the modified Csin (DanMCsin) bearing Dan at Lys175. DanMCsin exhibited an enzymatic activity corresponding to 1/120 of Csin against Suc-Ala-Ala-Phe-pNA. In addition, an effect of Lys175 modification on the access of the proteinaceous Bowman–Birk inhibitor to the active site of DanMCsin was investigated. In conclusion, by using a peptidyl derivative containing 1-amino-2-ethylphenylphosphonate diphenyl ester, we demonstrated that a functional group could be incorporated into Lys175 in Csin. Full article

Polystyrene (PS) was modified by covalently binding P-, P-N- and/or N- containing fire-retardant moieties through co- or ter-polymerization reactions of styrene with diethyl(acryloyloxymethyl)phosphonate (DEAMP), diethyl-p-vinylbenzyl phosphonate (DEpVBP), acrylic acid-2-[(diethoxyphosphoryl)methylamino]ethyl ester (ADEPMAE) and maleimide (MI). In the present study, the condensed-phase and the gaseous-phase activities of the abovementioned fire retardants within the prepared co- and ter-polymers were evaluated for the first time. Pyrolysis–Gas Chromatography/Mass Spectrometry was employed to identify the volatile products formed during the thermal decomposition of the modified polymers. Benzaldehyde, α-methylstyrene, acetophenone, triethyl phosphate and styrene (monomer, dimer and trimer) were detected in the gaseous phase following the thermal cracking of fire-retardant groups and through main chain scissions. In the case of PS modified with ADEPMAE, the evolution of pyrolysis gases was suppressed by possible inhibitory actions of triethyl phosphate in the gaseous phase. The reactive modification of PS by simultaneously incorporating P- (DEAMP or DEpVBP) and N- (MI) monomeric units, in the chains of ter-polymers, resulted in a predominantly condensed-phase mode of action owing to synergistic P and N interactions. The solid-state ³¹P NMR spectroscopy, Scanning Electron Microscopy/Energy Dispersive Spectroscopy, Inductively-Coupled Plasma/Optical Emission Spectroscopy and X-ray Photoelectron Spectroscopy of char residues, obtained from ter-polymers, confirmed the retention of the phosphorus species in their structures. Full article

This study examines the synthesis of two geminal bisphosphonate ester-supported Ln³⁺ complexes [Ln(L3)₂(NO₃)₃] (Ln = Nd³⁺ (5), La³⁺ (6)) and optical properties of the neodymium(III) complex. These results are compared to known mono-phosphonate ester-based Nd³⁺ complexes [Nd(L1/L2)₃X₃]_n (X = NO₃⁻, n = 1; Cl⁻, n = 2) (1–4). The optical properties of Nd³⁺ compounds are determined by micro-photoluminescence (µ-PL) spectroscopy which reveals three characteristic metal-centered emission bands in the NIR region related to transitions from ⁴F_3/2 excited state. Additionally, two emission bands from ⁴F_5/2, ²H_9/2 → ⁴I_J (J = 11/2, 13/2) transitions were observed. PL spectroscopy of equimolar complex solutions in dry dichloromethane (DCM) revealed remarkably higher emission intensity of the mono-phosphonate ester-based complexes in comparison to their bisphosphonate ester congener. The temperature-dependent PL measurements enable assignment of the emission lines of the ⁴F_3/2 → ⁴I_9/2 transition. Furthermore, low-temperature polarization-dependent measurements of the transitions from R₁ and R₂ Stark sublevel of ⁴F_3/2 state to the ⁴I_9/2 state for crystals of [Nd(L3)₂(NO₃)₃] (5) are discussed. Full article

The development of new organophosphorus flame retardants for polymeric materials is spurred by relatively low toxicity, effectiveness, and demand for replacement of more traditional materials. To function, these compounds must decompose in a degrading polymer matrix to form species which promote modification of the solid phase or generate active radical moieties that escape to the gas phase and interrupt combustion propagating reactions. An understanding of the decomposition process for these compounds may provide insight into the nature of flame retardant action which they may offer and suggest parameters for the synthesis of effective new organophosphorus flame retardants. The thermal degradation of a series of organophosphorus esters varying in the level of oxygenation at phosphorus—alkyl phosphate, aryl phosphate, phosphonate, phosphinate—has been examined. Initial degradation in all cases corresponds to elimination of a phosphorus acid. However, the facility with which this occurs is strongly dependent on the level of oxygenation at phosphorus. For alkyl phosphates elimination occurs rapidly at relatively low temperature. The same process occurs at somewhat higher temperature for aryl phosphates. Elimination of a phosphorus acid from phosphonate or phosphinate occurs more slowly and at much higher temperature. Further, the acids formed from elimination rapidly degrade further to evolve volatile species. Full article

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97–99% inhibition) at 10–100 ng/mL but was more potent than TAF when compared at molar concentration. Full article