RESUMEN
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.
Asunto(s)
Antineoplásicos , Compuestos Heterocíclicos , Organofosfonatos , Organofosfonatos/química , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Compuestos Aza/química , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , AnimalesRESUMEN
An acyclic phosphonate-linked nucleic acid backbone (ZNA) demonstrated the capability to support duplex formation and propagate genetic information inâ 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.
Asunto(s)
ADN , Conformación de Ácido Nucleico , Nucleótidos , Organofosfonatos , ADN/química , Organofosfonatos/química , Nucleótidos/química , Oligonucleótidos/química , Espectroscopía de Resonancia Magnética , Temperatura , Técnicas de Síntesis en Fase SólidaRESUMEN
ß-Aminophosphonates obtained by the Michael addition of primary amines to the double bond of diethyl vinylphosphonate proved to be suitable starting materials (amine components) in the Kabachnik-Fields reaction with formaldehyde and dialkyl phosphites or secondary phosphine oxides to afford N-phosphonylmethyl- and N-phosphinoylmethyl-ß-aminophosphonates. On the other hand, the starting aminophosphonates were modified by N-acylation using acid chlorides. The N-acyl products were found to exist in a dynamic equilibrium of two conformers as suggested by the broad NMR signals. At 26 °C, there may be rotation around the N-C axis of the acylamide function. At the same time, low-temperature NMR measurements at -5 °C revealed the presence of two distinct rotamers that could be characterized by 31P, 13C and 1H NMR data. The modified ß-aminophosphonic derivatives were subjected to a comparative structure-activity analysis on MDA-MB-231, PC-3, A431 and Ebc-1 tumor cell lines, and in a few cases, significant activity was detected.
Asunto(s)
Antineoplásicos , Organofosfonatos , Organofosfonatos/química , Organofosfonatos/farmacología , Organofosfonatos/síntesis química , Humanos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Aminas/química , Aminas/farmacología , Aminas/síntesis químicaRESUMEN
Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.
Asunto(s)
Antivirales , Coronavirus Humano 229E , Diseño de Fármacos , Subtipo H1N1 del Virus de la Influenza A , Simulación del Acoplamiento Molecular , Organofosfonatos , Pirimidinonas , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Humanos , Pirimidinonas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-Actividad , Organofosfonatos/farmacología , Organofosfonatos/química , Organofosfonatos/síntesis química , Coronavirus Humano 229E/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismoRESUMEN
A novel series of sulfonamide-incorporated bis(α-aminophosphonates) acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. The synthesized bivalent ligands were tested against five human (h) isoforms, hCA I, hCA II, hCA VII, hCA IX, and hCA XIII. Such derivatives showed high activity and selectivity against the cancer-related, membrane-bound isoform hCA IX, and among them, compound 5h, tetraisopropyl (1,3-phenylenebis{[(4-sulfamoylphenyl)amino]methylene})bis(phosphonate) showed a KI of 15.1 nM, being highly selective against this isoform over all other investigated ones (hCA I/IX = 42; hCA II/IX = 6, hCA VII/IX = 3, hCA XIII/IX = 5). Therefore, compound 5h could be a potential lead for the development of selective anticancer agents. The newly developed sulfonamides were also found effective inhibitors against the cytosolic hCA XIII isoform. Compound 5i displayed the best inhibition against this isoform with a KI of 17.2 nM, equal to that of the well-known inhibitor acetazolamide (AAZ), but significantly more selective over all other tested isoforms (hCA I/XIII = 239; hCA II/XIII = 23, hCA VII/XIII = 2, hCA IX/XIII = 3) compared to AAZ.
Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Diseño de Fármacos , Sulfonamidas , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Humanos , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Relación Estructura-Actividad , Anhidrasas Carbónicas/metabolismo , Cristalografía por Rayos X , Estructura Molecular , Isoenzimas/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Organofosfonatos/farmacología , Organofosfonatos/química , Organofosfonatos/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Aminoácidos , Ésteres , Herbicidas , Organofosfonatos , Herbicidas/síntesis química , Herbicidas/química , Organofosfonatos/química , Organofosfonatos/síntesis química , Aminoácidos/química , Ésteres/química , Ésteres/síntesis químicaRESUMEN
In this research, we explore the synthesis of and characterize α-aminophosphonates derived from anthraquinone and benzanthrone, focusing on their fluorescence properties and potential applications in confocal laser scanning microscopy (CLSM). The synthesized compounds exhibit notable solvatochromic behavior, emitting fluorescence from green to red across various solvents. Spectroscopic analysis, including 1H-, 13C-, and 31P-NMR, FTIR, and mass spectrometry, confirms the chemical structures. The compounds' toxicity is evaluated using etiolated wheat sprouts, revealing varying degrees of impact on growth and oxidative damage. Furthermore, the study introduces these α-aminophosphonates for CLSM imaging of the parasitic flatworm Opisthorchis felineus, demonstrating their potential in visualizing biological specimens. Additionally, an X-ray crystallographic study of an anthraquinone α-aminophosphonate provides valuable structural insights.
Asunto(s)
Benzo(a)Antracenos , Opisthorchis , Organofosfonatos , Animales , Cristalografía por Rayos X , Organofosfonatos/química , Espectroscopía de Resonancia Magnética , Microscopía Confocal/métodos , AntraquinonasRESUMEN
The co-occurrence of glyphosate (GLP) and aminomethylphosphonic acid (AMPA) in contaminated water, soil, sediment and plants is a cause for concern due to potential threats to the ecosystem and human health. A major route of exposure is through contact with contaminated soil and consumption of crops containing GLP and AMPA residues. However, clay-based sorption strategies for mixtures of GLP and AMPA in soil, plants and garden produce have been very limited. In this study, in vitro soil and in vivo genetically modified corn models were used to establish the proof of concept that the inclusion of clay sorbents in contaminated soils will reduce the bioavailability of GLP and AMPA in soils and their adverse effects on plant growth. Effects of chemical concentration (1-10 mg/kg), sorbent dose (0.5%-3% in soil and 0.5%-1% in plants) and duration (up to 28 days) on sorption kinetics were studied. The time course results showed a continuous GLP degradation to AMPA. The inclusion of calcium montmorillonite (CM) and acid processed montmorillonite (APM) clays at all doses significantly and consistently reduced the bioavailability of both chemicals from soils to plant roots and leaves in a dose- and time-dependent manner without detectable dissociation. Plants treated with 0.5% and 1% APM inclusion showed the highest growth rate (p ≤ 0.05) and lowest chemical bioavailability with up to 76% reduction in roots and 57% reduction in leaves. Results indicated that montmorillonite clays could be added as soil supplements to reduce hazardous mixtures of GLP and AMPA in soils and plants.
Asunto(s)
Bentonita , Bioacumulación , Herbicidas , Organofosfonatos , Contaminantes del Suelo , Zea mays , Humanos , Bentonita/química , Arcilla/química , Ecosistema , Herbicidas/análisis , Herbicidas/química , Herbicidas/farmacocinética , Suelo/química , Contaminantes del Suelo/análisis , Contaminantes del Suelo/farmacocinética , Zea mays/química , Zea mays/fisiología , Organofosfonatos/análisis , Organofosfonatos/química , Organofosfonatos/farmacocinética , Plantas Modificadas Genéticamente/química , Plantas Modificadas Genéticamente/fisiología , Bioacumulación/fisiología , GlifosatoRESUMEN
Phosphonate natural products, with their potent inhibitory activity, have found widespread use across multiple industries. Their success has inspired development of genome mining approaches that continue to reveal previously unknown bioactive scaffolds and biosynthetic insights. However, a greater understanding of phosphonate metabolism is required to enable prediction of compounds and their bioactivities from sequence information alone. Here, we expand our knowledge of this natural product class by reporting the complete biosynthesis of the phosphonoalamides, antimicrobial tripeptides with a conserved N-terminal l-phosphonoalanine (PnAla) residue produced by Streptomyces. The phosphonoalamides result from the convergence of PnAla biosynthesis and peptide ligation pathways. We elucidate the biochemistry underlying the transamination of phosphonopyruvate to PnAla, a new early branchpoint in phosphonate biosynthesis catalyzed by an aminotransferase with evolved specificity for phosphonate metabolism. Peptide formation is catalyzed by two ATP-grasp ligases, the first of which produces dipeptides, and a second which ligates dipeptides to PnAla to produce phosphonoalamides. Substrate specificity profiling revealed a dramatic expansion of dipeptide and tripeptide products, while finding PnaC to be the most promiscuous dipeptide ligase reported thus far. Our findings highlight previously unknown transformations in natural product biosynthesis, promising enzyme biocatalysts, and unveil insights into the diversity of phosphonopeptide natural products.
Asunto(s)
Productos Biológicos , Organofosfonatos , Streptomyces , Productos Biológicos/metabolismo , Productos Biológicos/química , Streptomyces/metabolismo , Streptomyces/genética , Organofosfonatos/metabolismo , Organofosfonatos/químicaRESUMEN
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.
Asunto(s)
Electrodos , Organofosfonatos , Catálisis , Organofosfonatos/química , Contaminantes Químicos del Agua/química , Oxidación-ReducciónRESUMEN
Developing flame retardant cotton fabrics (CF) is crucial for minimizing the harm caused by fires to people. To improve the flame retardancy of CF, this paper has synthesized a novel flame retardant called diboraspiro tetra phosphonate ammonium salt (N-PDBDN). The structure of N-PDBDN has been analyzed using FT-IR and NMR. Treating CF with N-PDBDN can increase the limiting oxygen index (LOI) to 36.2 % with a weight gain of 10.1 %. Moreover, even after undergoing 50 laundering cycles (LCs), the LOI remains at 27.1 %, indicating good flame retardancy and durability. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) show the presence of P and N elements on N-PDBDN treated CF, suggesting successful bonding between N-PDBDN and cellulose. Thermogravimetric analysis (TGA) results demonstrate that the addition of N-PDBDN significantly enhances the thermal stability and carbon formation ability of CF. Furthermore, cone calorimetry tests reveal reduced heat release rates (HRR), prolonged time to ignition (TTI), and 38 % lower total heat release (THR) in CF treated with N-PDBDN compared with pure cotton. Finally, a potential flame retardant mechanism involving N-PDBDN is proposed. These findings indicate that incorporating an ammonium phosphate group into CF can effectively improve the flame retardancy and durability.
Asunto(s)
Fibra de Algodón , Retardadores de Llama , Textiles , Nitrógeno/química , Fósforo/química , Espectroscopía Infrarroja por Transformada de Fourier , Organofosfonatos/química , TermogravimetríaRESUMEN
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.
Asunto(s)
Hierro , Organofosfonatos , Hierro/química , Organofosfonatos/química , Adsorción , Contaminantes Químicos del Agua/química , Electrocoagulación , Fósforo/química , Purificación del Agua/métodosRESUMEN
Phosphonate natural products have a history of commercial success across numerous industries due to their potent inhibition of metabolic processes. Over the past decade, genome mining approaches have successfully led to the discovery of numerous bioactive phosphonates. However, continued success is dependent upon a greater understanding of phosphonate metabolism, which will enable the prioritization and prediction of biosynthetic gene clusters for targeted isolation. Here, we report the complete biosynthetic pathway for phosphonoalamides E and F, antimicrobial phosphonopeptides with a conserved C-terminal l-phosphonoalanine (PnAla) residue. These peptides, produced by Bacillus, are the direct result of PnAla biosynthesis and serial ligation by two ATP-grasp ligases. A critical step of this pathway was the reversible transamination of phosphonopyruvate to PnAla by a dedicated transaminase with preference for the forward reaction. The dipeptide ligase PnfA was shown to ligate alanine to PnAla to afford phosphonoalamide E, which was subsequently ligated to alanine by PnfB to form phosphonoalamide F. Specificity profiling of both ligases found each to be highly specific, although the limited acceptance of noncanonical substrates by PnfA allowed for in vitro formation of products incorporating alternative pharmacophores. Our findings further establish the transaminative branch of phosphonate metabolism, unveil insights into the specificity of ATP-grasp ligation, and highlight the biocatalytic potential of biosynthetic enzymes.
Asunto(s)
Bacillus , Organofosfonatos , Bacillus/metabolismo , Organofosfonatos/metabolismo , Organofosfonatos/química , Vías Biosintéticas , Aminoácidos/metabolismo , Aminoácidos/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Familia de Multigenes , Especificidad por Sustrato , Ligasas/metabolismoRESUMEN
The action of calix[4]arenes C-424, C-425 and C-1193 has been investigated on suspended cholesterol/egg phosphatidylcholine lipid bilayer in a voltage-clamp mode. Comparative analysis with the membrane action by calix[4]arene-bis-α-hydroxymethylphosphonic acid (C-99) has shown that the substitution of bridge carbons for sulphur and addition of another methyl group to two alkyl tales in the lower rim of former dipropoxycalix[4]arene C-99 transformed mobile carrier that C-99 created in lipid bilayer (Shatursky et al., 2014) into a transmembrane pore as exposure of the bilayer membrane to sulphur-containing derivative dibutoxythiocalix[4]arene C-1193 resulted in microscopic transmembrane current patterns indicative of a channel-like mode of facilitated diffusion. Within all calix[4]arenes tested a net steady-state voltage-dependent transmembrane current was readily achieved only after addition of calix[4]-arene C-1193. In comparison with the membrane action of C-99 the current induced by calix[4]-arene C-1193 exhibited a much weakened anion selectivity passing slightly more current at positive potentials applied from the side of bilayer membrane to which the calix[4]-arene was added. Testing C-1193 for the membrane action against smooth muscle cells of rat uterus or swine myometrium and synaptosomes of rat brain nerve terminals revealed an increase in intracellular concentration of Ca2+ with reduction of the effective hydrodynamic diameter of the smooth muscle cells and enhanced basal extracellular level of neurotransmitters (glutamate and γ-aminobutyric acid) after C-1193-induced depolarization of the nerve terminals.
Asunto(s)
Calixarenos , Membrana Dobles de Lípidos , Transmisión Sináptica , Animales , Calixarenos/química , Calixarenos/farmacología , Transmisión Sináptica/efectos de los fármacos , Membrana Dobles de Lípidos/química , Contracción Muscular/efectos de los fármacos , Canales Iónicos/metabolismo , Azufre/química , Ratas , Femenino , Organofosfonatos/química , Masculino , Fenoles/química , Ratas WistarRESUMEN
An unprecedented study of the application of planar chiral compounds in antiviral pesticide development is reported. A class of multifunctional planar chiral ferrocene derivatives bearing α-amino phosphonate moieties was synthesized. These compounds, exhibiting superior optical purities, were subsequently subjected to antiviral evaluations against the notable plant pathogen potato virus Y (PVY). The influence of the absolute configurations of the planar chiral compounds on their antiviral bioactivities was significant. A number of these enantiomerically enriched planar chiral molecules demonstrated superior anti-PVY activities. Specifically, compound (Sp, R)-9n displayed extraordinary curative activities against PVY, with a 50% maximal effective concentration (EC50) of 216.11 µg/mL, surpassing the efficacy of ningnanmycin (NNM, 272.74 µg/mL). The protective activities of compound (Sp, R)-9n had an EC50 value of 152.78 µg/mL, which was better than that of NNM (413.22 µg/mL). The molecular docking and defense enzyme activity tests were carried out using the planar chiral molecules bearing different absolute configurations to investigate the mechanism of their antiviral activities against PVY. (Sp, R)-9n, (Sp, R)-9o, and NMM all showed stronger affinities to the PVY-CP than the (Rp, S)-9n. Investigations into the mechanisms revealed that the planar chiral configurations of the compounds played pivotal roles in the interactions between the PVY-CP molecules and could augment the activities of the defense enzymes. This study contributes substantial insights into the role of planar chirality in defending plants against viral infections.
Asunto(s)
Antivirales , Simulación del Acoplamiento Molecular , Organofosfonatos , Enfermedades de las Plantas , Potyvirus , Solanum tuberosum , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Enfermedades de las Plantas/virología , Organofosfonatos/farmacología , Organofosfonatos/química , Organofosfonatos/síntesis química , Solanum tuberosum/virología , Solanum tuberosum/química , Potyvirus/efectos de los fármacos , Relación Estructura-Actividad , Estereoisomerismo , Estructura MolecularRESUMEN
A method for introducing a range of phosphonates into oligopeptides through a Michael addition reaction between dehydroalanine and phosphite is presented. The method offers a mild, cheap, and straightforward approach to peptide phosphorylation that has potential applications in chemical biology and medicinal chemistry. Moreover, the introduction of a phosphonate group into short antibacterial peptides is described to demonstrate its utility, leading to the discovery of phosphonated antibacterial peptides with potent broad-spectrum antibacterial activity.
Asunto(s)
Alanina , Antibacterianos , Oligopéptidos , Organofosfonatos , Fosfitos , Organofosfonatos/química , Organofosfonatos/síntesis química , Oligopéptidos/química , Fosfitos/química , Estructura Molecular , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Alanina/química , Alanina/análogos & derivados , Pruebas de Sensibilidad Microbiana , FosforilaciónRESUMEN
A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M - HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33-80 µM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 µM), demonstrated good activity (IC50 = 17 µM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 µM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.
Asunto(s)
Acetilglucosamina , Antineoplásicos , Antioxidantes , Simulación del Acoplamiento Molecular , Organofosfonatos , Humanos , Organofosfonatos/química , Organofosfonatos/farmacología , Organofosfonatos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Acetilglucosamina/química , Acetilglucosamina/farmacología , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Proliferación Celular/efectos de los fármacosRESUMEN
A novel Fe(III) complex, Fe-tBPCDTA, was synthesized and explored as a potential contrast agent for MRI. Compared to established agents like Fe-EDTA and Fe-tCDTA, Fe-tBPCDTA exhibited moderate relaxivity (r1 = 1.17 s-1·mmol-1) due to its enhanced second-sphere mechanism. It also displayed improved kinetic inertness, lower cytotoxicity, and enhanced redox stability. In vivo studies demonstrated its function as an extracellular fluid agent, providing tumor contrast comparable to that of Gd-DTPA at a higher dosage. Complete renal clearance occurred within 24 h. These findings suggest Fe-tBPCDTA as a promising candidate for further development as a safe and effective extracellular MRI contrast agent.
Asunto(s)
Medios de Contraste , Quelantes del Hierro , Imagen por Resonancia Magnética , Organofosfonatos , Medios de Contraste/química , Medios de Contraste/síntesis química , Imagen por Resonancia Magnética/métodos , Animales , Humanos , Organofosfonatos/química , Organofosfonatos/síntesis química , Quelantes del Hierro/química , Quelantes del Hierro/farmacología , Quelantes del Hierro/síntesis química , Compuestos Férricos/química , Ratones , Línea Celular Tumoral , Quelantes/química , Quelantes/síntesis químicaRESUMEN
Mpox virus has wildly spread over 108 non-endemic regions in the world since May 2022. DNA replication of mpox is performed by DNA polymerase machinery F8-A22-E4, which is known as a great drug target. Brincidofovir and cidofovir are reported to have broad-spectrum antiviral activity against poxviruses, including mpox virus in animal models. However, the molecular mechanism is not understood. Here we report cryogenic electron microscopy structures of mpox viral F8-A22-E4 in complex with a DNA duplex, or dCTP and the DNA duplex, or cidofovir diphosphate and the DNA duplex at resolution of 3.22, 2.98 and 2.79 Å, respectively. Our structural work and DNA replication inhibition assays reveal that cidofovir diphosphate is located at the dCTP binding position with a different conformation to compete with dCTP to incorporate into the DNA and inhibit DNA synthesis. Conformation of both F8-A22-E4 and DNA is changed from the pre-dNTP binding state to DNA synthesizing state after dCTP or cidofovir diphosphate is bound, suggesting a coupling mechanism. This work provides the structural basis of DNA synthesis inhibition by brincidofovir and cidofovir, providing a rational strategy for new therapeutical development for mpox virus and other pox viruses.
Asunto(s)
Antivirales , Cidofovir , Citosina , Replicación del ADN , Organofosfonatos , Replicación Viral , Cidofovir/farmacología , Cidofovir/química , Organofosfonatos/farmacología , Organofosfonatos/química , Citosina/análogos & derivados , Citosina/farmacología , Citosina/química , Replicación del ADN/efectos de los fármacos , Humanos , Antivirales/farmacología , Antivirales/química , Replicación Viral/efectos de los fármacos , ADN Viral , Modelos MolecularesRESUMEN
Integrating lipid conjugation strategies into the design of nucleoside monophosphate and monophosphonate prodrugs is a well-established approach for discovering potential therapeutics. The unique prodrug design endows nucleoside analogues with strong lipophilicity and structures resembling lysoglycerophospholipids, which improve cellular uptake, oral bioavailability and pharmacological activity. In addition, the metabolic stability, pharmacological activity, pharmacokinetic profiles and biodistribution of lipid prodrugs can be finely optimized by adding biostable caps, incorporating transporter-targeted groups, inserting stimulus-responsive bonds, adjusting chain lengths, and applying proper isosteric replacements. This review summarizes recent advances in the structural features and application fields of lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs. This collection provides deep insights into the increasing repertoire of lipid prodrug development strategies and offers design inspirations for medicinal chemists for the development of novel chemotherapeutic agents.