Ether Conjugate Research Articles

Synthesis and Cytotoxic Activities of Novel Ether Conjugates ofDihydroartemisinin and Zerumbone: Evidenced by Intergrating Network Pharmacology and In Vitro Assay.

O-alkylation of the hydroxy compounds, including acetaminophen, starting compounds for the synthesis of the drug, and natural compounds with the bromides of dihydroartemisinin (DHA) and zerumbone, produced twenty novel ether conjugates 15a-j and 16a-j, respectively. Their structures were elucidated by 1D-, 2D-NMR, and HRMS data. Their in vitro cytotoxic activity was screened using three cancer cell lines: HepG2, HeLa, and PC-12. The results showed that eight out of ten conjugates in series 15a-j containing DHA skeleton exhibited activity against the tested cell lines, with IC50 values ranging from 4.26-47.37 µM. Notably, all conjugates in series 16a-j containing zerumbone scaffolds inhibited the growth of HepG2, HeLa, and PC12 with IC50 in the range of 4.46-35.07 µM. Using network pharmacology and molecular docking to target anti-liver cancer in the above 20 synthetic compounds, 271 intersection targets were discovered, including 5 targets with high degree values (EGFR, ESR1, AKT1, MDM2, and NFKB1). Artemisinin derivative 15i gave the highest binding energy for targets AKT1, EGFR, and NFKB1, while zerumbone-murrayafoline A ether 16g in the remaining series also gave the highest energy for proteins EGFR, AKT1, and NFKB1.

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer’s disease therapy

A series of scutellarein 7-l-amino acid carbamate-4′-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer’s disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ1–42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood–brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Decoration, Characterization and Antimicrobial Activity Evaluation of Novel Nano‐Based 1,2‐Phenylenediamine Functionalized Maleic Anhydride‐Allylphenyl Ether Conjugate

Abstract1,2‐Phenylenediamine (o‐PDA) is a well‐known fluorescent dye that enables the decoration of next‐generation chemotherapeutics. A novel o‐PDA‐functionalized maleic anhydride‐allyl phenyl ether (poly(MA‐alt‐APE)/o‐PDA conjugate) was successfully synthesized according to the Ringsdorf model, which is the starting point for macromolecular prodrugs. Functional polymeric‐carriers were prepared by free‐radical polymerization in butyl acetate with azobisisobutyronitrile (AIBN) radical‐initiator at 70 °C. The conjugation was carried out at 40 °C in N,N‐dimethylformamide (DMF) using triethylamine (Et3N) as the conjugation catalyst. Characterization was performed by Attenuated Total Reflectance‐Fourier Transform Infrared (ATR‐FTIR), Nuclear Magnetic Resonance (1H‐NMR), UV‐Vis and Fluorescence Spectroscopy. Weight average molecular weight (Mw), number average molecular weight (Mn) and polydispersity index (PDI) (Mw/Mn) were calculated using gel permeation chromatography (GPC). The surface morphology was also elucidated by Transmission Electron Microscopy (TEM). Evaluation of antimicrobial activity against two Gram‐positive bacteria (Staphylococcus aureus, Bacillus cereus), two Gram‐negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and one yeast Candida albicans was performed using the broth microdilution method according to Clinical Laboratory Standards Institute (CLSI) criteria. Interestingly, S. aureus was found to be more sensitive to polymer‐based samples and, in particular, the minimum inhibitory concentration (MIC) of the conjugate was lower than that of ciprofloxacin used as a control compound.

Multi-detection method for the fast screening of bisphenol A diglycidyl ether conjugates in the can-coating material

Multi-detection method for the fast screening of bisphenol A diglycidyl ether conjugates in the can-coating material

Synthesis and Biological Evaluation of 5'-O-Fatty Acyl Ester Derivatives of 3'-Fluoro-2',3'-dideoxythymidine as Potential Anti-HIV Microbicides.

A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC50 values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC50 values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines.

UV/enzyme dual responsive photosensitizer‐loaded 4‐(Phenylazo)benzoic Acid‐mPEG nanosystem for enhanced photodynamic insecticide efficacy

AbstractTo improve photostability and enhance utilization rate and reduce pest resistance, a new strategy based on the combination of photodynamic insecticide action and stimulus‐responsive polymer micelles is developed. 4‐(phenylazo)benzoic acid (PBA)‐modified poly(ethylene glycol) monomethyl ether (mPEG) conjugate is prepared by the esterification reaction of mPEG and PBA, and followed by self‐assembly in aqueous solution to obtain polymeric nanoparticles. TEM shows that the nanoparticles have a core‐shell structure and an average diameter of 78 nm. DLS shows that the nanoparticles are stability in water solution but can change their structure in response to UV light and/or esterase stimulation. The photodegradation of Protoporphyrin IX (PpIX) encapsulated in the nanoparticles can be effectively inhibited because of aggregation‐caused quenching effect, whose maximum photodegradation rate is about 20.54% after 8 h exposure to daylight compared with the complete photodegradation of free PpIX. UV light and/or esterase stimulus can trigger PpIX release and result in a high photodynamic activity. Compared with free PpIX, the PpIX‐loaded nanoparticles show a higher phototoxicity to insect cells and the daylight pretreatment has little influence on the phototoxicity.

On the Search of a Silver Bullet for the Preparation of Bioinspired Molecular Electrets with Propensity to Transfer Holes at High Potentials.

Biological structure-function relationships offer incomparable paradigms for charge-transfer (CT) science and its implementation in solar-energy engineering, organic electronics, and photonics. Electrets are systems with co-directionally oriented electric dopes with immense importance for CT science, and bioinspired molecular electrets are polyamides of anthranilic-acid derivatives with designs originating from natural biomolecular motifs. This publication focuses on the synthesis of molecular electrets with ether substituents. As important as ether electret residues are for transferring holes under relatively high potentials, the synthesis of their precursors presents formidable challenges. Each residue in the molecular electrets is introduced as its 2-nitrobenzoic acid (NBA) derivative. Hence, robust and scalable synthesis of ether derivatives of NBA is essential for making such hole-transfer molecular electrets. Purdie-Irvine alkylation, using silver oxide, produces with 90% yield the esters of the NBA building block for iso-butyl ether electrets. It warrants additional ester hydrolysis for obtaining the desired NBA precursor. Conversely, Williamson etherification selectively produces the same free-acid ether derivative in one-pot reaction, but a 40% yield. The high yields of Purdie-Irvine alkylation and the selectivity of the Williamson etherification provide important guidelines for synthesizing building blocks for bioinspired molecular electrets and a wide range of other complex ether conjugates.

Design and Synthesis of Supramolecular Phosphatases Formed from a Bis(Zn2+‐Cyclen) Complex, Barbital‐Crown‐K+ Conjugate and Cu2+ for the Catalytic Hydrolysis of Phosphate Monoester

AbstractThe development of artificial mimics of natural enzymes such as hydrolases and phosphatases is one of the great challenges in bioorganic and bioinorganic chemistry and related sciences. Supramolecular strategies are one of the useful methods to construct artificial catalysts as mimics of natural enzymes and to understand their reaction mechanisms. Herein, we report on the formation of amphiphilic supramolecular phosphatases by the 2 : 2 : 2 self‐assembly of a bis(Zn2+‐cyclen) complex (cyclen=1,4,7,10‐teraazacyclododecane) containing a 2,2′‐bipyridyl (bpy) linker and one long alkyl chain (Zn2L3), 5,5‐diethylbarbituric acid (Bar) derivative functionalized with 1‐aza‐18‐crown‐6 ether and Cu2+ in a two‐phase solvent system (CHCl3/H2O). We hypothesized that crown ether moiety of the Bar‐crown ether conjugate would form complexes with alkaline ions and other metal ions such as Li+, Na+, K+, Rb+, Mg2+ and La3+ in organic phase to mimic the Mg2+ found as the third metal ion in the active site of alkaline phosphatase (AP). The results indicate that the 2 : 2 : 2 : 4 complexes of Zn2L3, a Bar block equipped with the 18‐crown‐6 ether, Cu2+ and alkaline metal are constructed in a two‐phase solvent system. The resulting complexes have a higher hydrolysis activity for mono(4‐nitrophenyl)phosphate (MNP) in the presence of K+ than that in the presence of Li+, Na+, Rb+, Mg2+ and La3+ and a greater hydrolysis activity than our previous supermolecules having no crown ether part, suggesting that crown ether‐K+ complex located in close proximity to the Cu2(μ‐OH)2 core contributes to the acceleration of the MNP hydrolysis.

Synthesis and characterization of a porphyrin-crown ether conjugate as a potential intermediate for drug delivery application

The development of synthetic strategies for functional building units plays a central role in supramolecular chemistry. Both porphyrin and crown ethers have attracted the attention of researchers worldwide owing to their unique properties. It is envisioned that the integration of the two molecules will result in hybrid materials with potential applications in many fields. In the present study, a new porphyrin derivative 3 appended with four 18-crown-6 (18C6) ether moieties was synthesized through the Suzuki-Miyaura coupling of boronic ester porphyrin 1 and 4-bromobenzo-18-crown-6 2 in 80% yield. Porphyrin 3 was fully characterized by 1H/[Formula: see text]C NMR spectroscopy and high resolution mass spectrometry. The tendency of the 18C6 to form host-guest complexes with ammonium cations was exploited to assemble cation responsive hybrid material of porphyrin 3 and ammonium immobilized mesoporous silica nanoparticles (MSNs). Furthermore, the potential application of the 3/MSNs conjugate as a cation-responsive drug delivery vehicle was investigated in solution by UV-vis and fluorescence spectroscopies.

Monofunctionalized Bambus[6]urils and Their Conjugates with Crown Ethers for Liquid-Liquid Extraction of Inorganic Salts.

Bambusurils are a growing family of macrocyclic anion receptors. In this Letter, we present the first syntheses of monofunctionalized bambusurils and their use for the preparation of heteroditopic bambusuril-crown ether conjugates suitable for the extraction of ion pairs from water to chloroform.

Synthesis, molecular docking simulation, and biological evaluation studies of novel amide and ether conjugates of 2,3‐diaryl‐1,3‐thiazolidin‐4‐ones

AbstractWith an aim to develop potent lead molecules as a novel class of reverse transcriptase (RT) inhibitors, we have synthesized amide and ether conjugates of 2,3‐diaryl‐1,3‐thiazolidin‐4‐one derivatives. The compounds 9a and 9f exhibited IC50 values of 0.21113 ± 0.013μM and 12.6804 ± 0.062μM respectively from the in vitro human immunodeficiency virus type 1 (HIV‐1) RT assay. None of the compounds showed toxicity towards peripheral blood mononuclear cells (PBMC). Structure‐activity relationship (SAR) studies were performed for the synthesized compounds in order to estimate the effect of the substitution pattern on the RT inhibition potency. In silico docking studies revealed that two or more interactions are necessary for significant activity.

Evaluation of Oleic Acid and Polyethylene Glycol Monomethyl Ether Conjugate (PEGylated Oleic Acid) as a Solubility Enhancer of Furosemide

Poor aqueous solubility limits the therapeutic efficacy of many marketed and investigational drugs. Synthesis of new drugs with improved solubility is challenging due to time constraint and expenses involved. Therefore, finding the solubility enhancers for existing drugs is an attractive and profitable strategy. In this study, PEGylated oleic acid (OA-mPEG5000), a conjugate of oleic acid and mPEG5000 was synthesized and evaluated as a solubilizer for furosemide. OA-mPEG5000 was evaluated as a nanocarrier for furosemide by formulating polymersomes. Solubility of furosemide in milli-Q water and aqueous OA-mPEG5000 solution was determined using shake flask method. At 37 °C, the solubility of furosemide in OA-mPEG5000 (1% w/w) and milli-Q water was 3404.7 ± 254.6 µg/mL and 1020.2 ± 40.9 µg/mL, respectively. Results showed there was a 3.34-fold increase in solubility of furosemide in OA-mPEG5000 compared to water at 37 °C. At 25 °C, there was a 3.31-fold increase in solubilization of furosemide in OA-mPEG5000 (1% w/w) (90.0 ± 1.45 µg/mL) compared to milli-Q water (27.2 ± 1.43 µg/mL). Size, polydispersity index and zeta potential of polymersomes ranged from 85–145.5 nm, 0.187–0.511 and −4.0–12.77 mV, respectively. In-vitro release study revealed a burst release (71%) within 1 h. Significant enhancement in solubility and formation of polymersomes suggested that OA-mPEG5000 could be a good solubilizer and nanocarrier for furosemide.

A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic.

Reactions that form sec-sec ethers are well known, but few lead to compounds with dense functionality around the O-linkage. Replacement of the α-glucopyranosyl unit of adenophostin A, a potent d-myo-inositol 1,4,5-trisphosphate (IP3R) agonist, with a d-chiro-inositol surrogate acting substantially as a pseudosugar, leads to "d-chiro-inositol adenophostin". At its core, this cyclitol-nucleoside trisphosphate comprises a nucleoside sugar linked via an axial d-chiro-inositol 1-hydroxyl-adenosine 3'-ribose ether linkage. A divergent synthesis of d-chiro-inositol adenophostin has been achieved. Key features of the synthetic strategy to produce a triol for phosphorylation include a new selective mono-tosylation of racemic 1,2:4,5-di-O-isopropylidene-myo-inositol using tosyl imidazole; subsequent conversion of the product into separable camphanate ester derivatives, one leading to a chiral myo-inositol triflate used as a synthetic building block and the other to l-5-O-methyl-myo-inositol [l-(+)-bornesitol] to assign the absolute configuration; the nucleophilic coupling of an alkoxide of a ribose pent-4-ene orthoester unit with a structurally rigid chiral myo-inositol triflate derivative, representing the first sec-sec ether formation between a cyclitol and ribose. Reaction of the coupled product with a silylated nucleobase completes the assembly of the core structure. Further protecting group manipulation, mixed O- and N-phosphorylation, and subsequent removal of all protecting groups in a single step achieves the final product, avoiding a separate N6 protection/deprotection strategy. d-chiro-Inositol adenophostin evoked Ca2+ release through IP3Rs at lower concentrations than adenophostin A, hitherto the most potent known agonist of IP3Rs.

Synthesis and evaluation of novel coumarin-oxime ethers as potential anti-tubercular agents: Their DNA cleavage ability and BSA interaction study

As a contribution to the development of novel coumarin-oxime ether conjugates with therapeutically interesting properties, a series of coumarin-oxime ether (1a–1j) was synthesised using SN2 reaction of bromomethyl coumarins with butane-2,3-dione monoxime. Invitro anti-tuberculosis activityagainstMTBH37Rv strain was established for the coumarin-oxime ether (1a–1j). Most of the compounds exhibited significant activity with minimum inhibitory concentration (MIC)in the range of 0.04–3.12 μg mL−1. Compound (1h) was identified as a hit candidate exhibiting MIC of 0.04 μg mL−1, closer to the MIC value of Isoniazid (0.02 μg mL−1), a commercially available drug for the treatment of tuberculosis. Compound 1h also displayed a low level of toxicity in Vero cells along with a good safety profile in vitro. Compounds that showed potent anti-tubercular activity were also found to cleave DNA more efficiently and thereby exhibit nuclease activity. The most active compound (1h) was further studied to deduce the mode of interaction with model serum protein, bovine serum albumin (BSA).

Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin–morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin–piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.

Efficient Synthesis of Ditopic Polyamide Receptors for Cooperative Ion Pair Recognition in Solution and Solid States.

Following a late-stage functionalization strategy, a series of heteroditopic cryptand receptors were prepared in three steps only from 1,4-dioxane. As evidenced by 1 H NMR spectroscopic and solid state analyses, these polyamide-crown ether conjugates present general ion pair binding capacity towards salts of monovalent cations and linear triatomic anions.

Supramolecular tuning of energy transfer efficiency and direction in a bis(styryl) dye–crown ether conjugate

The control of the energy transfer (FRET) in a novel bischromophoric styryl(pyridinium) dye bearing two different crown ether residues is presented. Complexation of the dye with metal cations allows to tune the FRET efficiency without changing the transfer direction or to switch the FRET off, whereas protonation launches the FRET process in the opposite direction relative to the molecular structure.

Efficient Self-Assembly of mPEG End-Capped Porous Silica as a Redox-Sensitive Nanocarrier for Controlled Doxorubicin Delivery.

Porous nanosilica (PNS) has been regarded as a promising candidate for controlled delivery of anticancer drugs. Unmodified PNS-based nanocarriers, however, showed a burst release of encapsulated drugs, which may limit their clinical uses. In this report, PNS was surface conjugated with adamantylamine (ADA) via disulfide bridges (-SS-), PNS-SS-ADA, which was further modified with cyclodextrin-poly(ethylene glycol) methyl ether conjugate (CD-mPEG) to form a core@shell structure PNS-SS-ADA@CD-mPEG for redox triggered delivery of doxorubicin (DOX), DOX/PNS-SS-ADA@CD-mPEG. The prepared PNS-SS-ADA@CD-mPEG nanoparticles were spherical in shape with an average diameter of 55.5 ± 3.05 nm, a little larger than their parentally PNS nanocarriers, at 49.6 ± 2.56 nm. In addition, these nanoparticles possessed high drug loading capacity, at 79.2 ± 3.2%, for controlled release. The release of DOX from DOX/PNS-SS-ADA@CD-mPEG nanoparticles was controlled and prolonged up to 120 h in PBS medium (pH 7.4), compared to less than 40 h under reducing condition of 5 mM DTT. Notably, the PNS-SS-ADA@CD-mPEG was a biocompatible nanocarrier, and the toxicity of DOX was dramatically reduced after loading drugs into the porous core. This redox-sensitive PNS-SS-ADA@CD-mPEG nanoparticle could be considered a potential candidate with high drug loading capacity and a lower risk of systemic toxicity.

Formation of organometallic species from complexes of N-phenylaza-crown ether conjugates with lead cations in CID-MS/MS conditions

Gas phase decomposition of the ions [M+PbNO3]+ (M stands for fluoro-substituted N-nitrophenylaza-crown ether conjugate), has been studied by the electrospray ionization-collision induced dissociation-tandem mass spectrometry (ESI-CID-MS/MS). The conjugates containing hydrogen atom at ortho position to the crown moiety, form abundant fragment ions which can be assigned as complexes of deprotonated conjugates and lead cation, thus the ions [M−H+Pb]+ (fragment ions formed as a result of HNO3 loss). Interaction between the nitro group (present at the second ortho position to the crown moiety) and the metal cation affects the formation of fragment ion [M−H+Pb]+ (but does not prevent its formation). Ions [M−H+Pb]+ are very rare example of the organometallic species (containing metal-carbon bond), in which metal cation is also complexed by crown ether moiety.

Scorpionate complexes of aza-18-crown-6 containing fluoronitrophenyl substituents as studied by electrospray ionization mass spectrometry.

Coordination of a metal cation by a nitro group is rare and the interaction between them is usually weak. Examples of complexes in which such an interaction takes place are metal complexes of cyclams containing nitrophenyl or nitrobenzyl substituents. It seemed to be interesting to check if in the complexes of the respective crown ether conjugates the interaction can also take place. We synthesized the respective conjugates of aza-18-crown-6, namely fluoro-substituted N-nitrophenylaza-18C6 conjugates. Their complexes with alkali and alkali earth metal cations were generated in the gas phase by electrospray ionization mass spectrometry (ESI-MS). Both collision-induced dissociation 'in-source' and collision-induced dissociation tandem mass spectrometry (ESI-CID-'in-source' and ESI-CID-MS/MS) were used to study the gas-phase stabilities of the generated complexes. The gas-phase decomposition of the studied complexes indicated that the complexes formed by the conjugates containing a nitro group at the ortho position are more stable than those formed by the conjugates with a nitro group at the para position. This indicates that a metal cation complexed by crown ether ring is additionally coordinated by a nitro group in the scorpionate mode. To the best of our knowledge, our finding provide the first example of a complex in which a metal cation complexed by a crown ether ring is additionally coordinated by a nitro group.