Ether Side Chains Research Articles

Post-fabrication QAC-functionalized thermoplastic polyurethane for contact-killing catheter applications

The use of catheters is ubiquitous in medicine and the incidence of infection remains unacceptably high despite numerous advances in functional surfaces and drug elution. Herein we report the use of a thermoplastic polyurethane containing an allyl ether side-chain functionality (allyl-TPU) that allows for rapid and convenient surface modification with antimicrobial reagents, post-processing. This post-processing functionalization affords the ability to target appropriate TPU properties and maintain the functional groups on the surface of the device where they do not affect bulk properties. A series of quaternary ammonium thiol compounds (Qx-SH) possessing various hydrocarbon tail lengths (8–14 carbons) were synthesized and attached to the surface using thiol-ene “click” chemistry. A quantitative assessment of the amount of Qx-SH available on the surface was determined using fluorescence spectroscopy and X-ray photoelectron spectroscopy (XPS). Contact-killing assays note the Q8-SH composition has the highest antimicrobial activity, and a live/dead fluorescence assay reveals rapid contact-killing of Staphylococcus aureus (>75% in 5 min) and Escherichia coli (90% in 10 min) inocula. Scale-up and extrusion of allyl-TPU provides catheter prototypes for biofilm formation testing with Pseudomonas aeruginosa, and surface-functionalized catheters modified with Q8-SH demonstrate their ability to reduce biofilm formation.

Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.

The simulation of the capturing of sodium ions in a monolayer consisting of polythiophene functionalised with crown ether side chains

When polythiophene is substituted in its ‘3’ sites by 6‑oxygen atom crown ether (CE) rings it forms a monolayer on a water surface. The migration of Na+ ions from the aqueous layer to the CE is simulated by molecular dynamics and their complexation by the rings are studied. It is found that when electric fields (applied or local) overcome steric forces, the cations can access the CE rings and the formation of CE-Na+ complexes is investigated. It is shown that the cations occupy sites near the rings but cannot migrate along their common axes. By conducting molecular dynamics over a range of temperatures two activated steps are found – the accession of the cations into the monolayer region and their subsequent release from the CE rings. Activation energies are found for each of these steps.

Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A3 adenosine receptor.

Three A3 adenosine receptor (AR) antagonists (1-3) selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave us the chance to evaluate whether their higher lipophilicity, reduced conformational freedom and chirality might improve the potency towards the A3 AR. Racemic mixtures of 1-3 were resolved using chiral HPLC methods and the absolute configurations of the enantiomers were assigned by chiroptical spectroscopy and density functional theory calculations. We measured the affinity for human A1, A2A, A2B and A3 ARs of the racemic mixtures and the pure enantiomers of 1-3 by radioligand competition binding experiments. Cell-based assays of the most potent enantiomers confirmed their A3 AR antagonist profiles. Our research led to the identification of (S)-1 with high potency (0.5 nM) and selectivity as an A3 AR antagonist. Moreover we built a docking-model useful to design new pyrimidine derivatives.

Click Synthesis of Shape-Persistent Azodendrimers and their Orthogonal Self-Assembly to Nanofibres

The copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction has been efficiently utilized to synthesize a series of dendrons with amino functionalities. The aminodendrons successfully underwent azodimerization to furnish a series of pyridyl- and phenyl-based azodendrimers with peripheral alkyl or ether side chain substituents. The molecular structures of the azodendrimers were fully assigned using different spectroscopic techniques, such as 1H NMR and 13C NMR, and the molecular weights were determined using MALDI-TOF mass spectrometry. The molecular self-assembly of the azodendrimers was investigated by scanning electron microscopy and transmission electron microscopy, which revealed the formation of highly ordered and uniform self-assembled nanofibres.

Efficient Perovskite Solar Cells over a Broad Temperature Window: The Role of the Charge Carrier Extraction

AbstractThe mechanism behind the temperature dependence of the device performance in hybrid perovskite solar cells (HPSCs) is investigated systematically. The power conversion efficiency (PCE) of the reference cell using [60]PCBM as electron extraction layer (EEL) drops significantly from 11.9% at 295 K to 7% at 180 K. The deteriorated charge carrier extraction is found as the dominant factor causing this degradation. Temperature dependent spectroscopy and charge transport studies demonstrate that the poor electron transport in the [60]PCBM EEL at low temperature leads to inefficient charge carrier extraction. It is further demonstrated that the n‐type doping of [60]PCBM EEL or the use of an EEL (fulleropyrrolidine with a triethylene glycol monoethyl ether side chain) with higher electron transport capability is an effective strategy to achieve HPSCs working efficiently over a broad temperature range. The devices fabricated with these highly performing EELs have PCEs at 180 K of 16.7% and 18.2%, respectively. These results support the idea that the temperature dependence of the electron transport in the EELs limits the device performance in HPSCs, especially at lower temperatures and they also give directions toward further improvement of the PCE of HPSCs at realistic operating temperatures.

Solvation by aqueous solutions of imidazole-based ionic liquids: 2- A comparison between alkyl and alkoxy side-chains

Binary mixtures of ionic liquids (ILs) and molecular solvents are employed for practical reasons, e.g., reduction of solution viscosity and overcoming solubility/miscibility problems. We obtain information on solvation in these media from solvent properties, e.g., empirical polarity ET(probe) calculated from the spectra of solvatochromic probes. To evaluate the effect on solvation of the IL cation side-chain we studied the solvatochromic response of the polarity probe WB (2,6-dichloro-4-(2,4,6-triphenylpyridinium-1-yl)phenolate) dissolved in the following aqueous ILs: 1-R-3-methylimidazoliumAcO, where R = 1-heptyl, C7MeImAcO; and 3,6-dioxa-(1-heptyl), C5O2MeImAcO; AcO = acetate; in the temperature range 15–60 °C. The relative acidity of the imidazolium ring hydrogens bears on solvation. Consequently, we extended our study to aqueous solutions of 1-R′-1,2-dimethylimidazoliumAcO, R' = 1-butyl (C4Me2ImAcO) and methoxyethyl (C3OMe2ImAcO). Our results showed that the expected effect of the side-chain ether oxygen on ET(WB) is impaired by formation of intramolecular hydrogen bonding, e.g., with hydrogens of the imidazolium ring. We corroborated this conclusion by 1H NMR data, and theoretical calculations (molecular dynamics simulations; quantum chemistry calculations). Introducing second ether oxygen (C5O2MeImAcO) and replacing C2-H by C2-CH3 in the imidazolium ring (C3OMe2ImAcO) increased the difference in polarity between ILs with alkoxy and alkyl side-chains. For C7MeImAcO and C5O2MeImAcO the dependence of ET(WB) on the water mole fraction was treated according to a model that includes solvation by the complex solvent (IL⋅⋅⋅water); the latter is the most efficient solvent species present because it forms more hydrogen-bonds with the phenolate oxygen of WB.

2D Organic Superlattice Promoted via Combined Action of π-π Stacking and Dipole-Dipole Interaction in Discotic Liquid Crystals.

A series of discotic liquid crystals based on hexapentyloxytriphenylene (HAT5) have been investigated where one out of the six ether side chains of a triphenylene core was replaced by an ester side chain and named for 5a-5h. During the process of studying these compounds, the characteristic straight line defect of ordered columnar structure was identified by polarizing optical microscopy (POM) and liquid crystal state over a wide temperature range was obtained by differential scanning calorimetry (DSC). Basic phase structure and molecular arrangement were assigned by one-dimensional wide-angle X-ray diffraction (1D WAXD), small-angle X-ray scattering (SAXS), two-dimensional wide-angle X-ray diffraction (2D WAXD), and transmission electron microscope (TEM). Combined with sharp and regular dots in 2D WAXD patterns and characteristic peaks at small angle in SAXS pattern which indicated the existence of superlattice, we proved that 2D superlattice formed from self-assembly of discotic molecules with a polar group via π-π stacking and dipole-dipole interaction. In order to verify the effect of orientation on charge carrier mobility, their electron and hole mobilities were measured by time-of-flight (TOF) device, among which the charge carrier mobility could achieve almost twice as that of HAT5. The formation of superlattice no doubt improved their electronic properties and made them more attractive in organic electronics.

Synthesis of antithrombotic poly(carbonate-urethane)s through a sequential process of ring-opening polymerization and polyaddition facilitated by organocatalysts

We have first confirmed that an organic acid, diphenyl phosphate (DPP) is effective in a sequential process of ring-opening polymerization (ROP) of a cyclic carbonate and polyaddition with a diisocyanate. More potent triflic acid (TfOH) exhibited higher catalytic activities for both ROP and polyaddition than DPP and pairs of thiourea and basic catalysts such as cyclic amidines and sparteine. However, DPP-catalyzed ROP was more manageable than that using TfOH regarding control over the molar-mass dispersity of the resultant polycarbonates that matters to the final polyurethanes. As a consequence of DPP-catalyzed one-pot synthesis of poly(carbonate-urethane)s, we have obtained segmented polyurethanes comprising a poly(trimethylene carbonate) analog with ether side chains as a soft segment and hexamethylene diisocyanate as a hard segment. Although the whole reaction took a few days, high molecular weight over 50k was achieved for the resultant polyurethanes whose texture suggested improved physical properties. Nevertheless, the polyuretahnes maintained low platelet adhesion properties. This antithrombotic polyurethane became more promising as a candidate base material for resorbable artificial blood vessels. Furthermore, this sequential synthesis by single organocatalysts enables the efficient production of functionalized poly(carbonate-urethane)s.

Improved efficiency of NiOx-based p-i-n perovskite solar cells by using PTEG-1 as electron transport layer

We present efficient p-i-n type perovskite solar cells using NiOx as the hole transport layer and a fulleropyrrolidine with a triethylene glycol monoethyl ether side chain (PTEG-1) as electron transport layer. This electron transport layer leads to higher power conversion efficiencies compared to perovskite solar cells with PCBM (phenyl-C61-butyric acid methyl ester). The improved performance of PTEG-1 devices is attributed to the reduced trap-assisted recombination and improved charge extraction in these solar cells, as determined by light intensity dependence and photoluminescence measurements. Through optimization of the hole and electron transport layers, the power conversion efficiency of the NiOx/perovskite/PTEG-1 solar cells was increased up to 16.1%.

Supramolecular cation transporters alter root morphology in the Arabidopsis thaliana plant

Bibracchial (two-armed) 4,13-diaza-18-crown-6 lariat ether and tris(macrocycle) hydraphile synthetic amphiphiles alter root morphology in Arabidopsis thaliana plants. The effect on root structure and growth depends both on the hydraphile spacer chain length and lariat ether side chain length as well as the concentration of compound in the growth medium. In some cases a correlation to ion transport activity was apparent, but such a correlation is not always manifested. Surprisingly, planar bilayer conductance (BLM) studies showed that lariat ethers and lariat ether amides both exhibited well controlled membrane activity. Pore formation in soybean asolectin membranes occurred readily and the pores were stable and sustained. Low concentrations of active hydraphiles and lariat ethers altered the primary:lateral root density ratio, generally increasing it. The transporter-mediated alterations in lateral root density were suggestive of the activity of plant auxins such as indole-3-acetic acid and 2,4-dichlorophenoxyacetic acid, which are known to depend on cytosolic potassium ion concentrations. The hypothesis that the compounds interfere with the auxin pathway was tested and discounted by using auxin-resistant A. thaliana mutants. Rather than functioning directly as auxin mimics, ionophores affect the ion gradients producing an auxin-like effect on root development.

Helical Folding of Meta-Connected Aromatic Oligoureas.

Aromatic oligoureas composed of meta-linked residues bearing phenolic ether side chains are synthesized. The basic N,N'-diarylurea units adopt a trans,trans intramolecularly H-bonded conformation that is further strengthened by additional intermolecular H-bonding. Such basic units, in combination with meta-linked benzene residues, result in stably folded helical oligoureas in the highly polar DMF with up to four turns and with a small cylindrical inner pore that would be difficult to acquire.

Synthesis and evaluation of a novel pyrrolidinium-based zwitterionic additive with an ether side chain for ionic liquid electrolytes in high-voltage lithium-ion batteries

Ionic liquids (ILs) containing zwitterions were studied as electrolytes for lithium-ion batteries. The effect of a pyrrolidinium zwitterion with a long ether side chain on the thermal and electrochemical properties of an IL and the charge/discharge properties of Li/LiCoO2, Li/LiNi1/3Mn1/3Co1/3O2 (NMC), and graphite/Li cells with IL/zwitterion electrolytes was investigated. The melting temperature of the IL-based electrolyte composed of N-methyl-N-methoxymethylpyrrolidinium bis(fluorosulfonyl)amide ([Pyr1,1O1][FSA]) and lithium bis(fluorosulfonyl)amide (LiFSA) with 3-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-1-ium-1-yl)propane-1-sulfonate (OE2pyps) as the zwitterionic additive was about −18°C. The electrochemical window of [Pyr1,1O1][FSA]/LiFSA/OE2pyps was over 5V vs. Li/Li+. Li|electrolyte|LiCoO2 cells containing the [Pyr1,1O1][FSA]/LiFSA/OE2pyps electrolyte system exhibited high capacity values in the cut-off voltage range of 3.0–4.3V, even after 50 cycles. Moreover, increases of interfacial resistance between the electrolyte and cathode during cycling were suppressed. Li|electrolyte|NMC cells containing this electrolyte system also exhibited high capacities in a wide cut-off voltage range of 3.0–4.6V, even after 50 cycles. In the cyclic voltammograms of cells employing a graphite electrode, the intercalation/deintercalation of lithium ions was observed between 0 and + 0.4V vs. Li/Li+. Further, graphite|electrolyte|Li cells containing [Pyr1,1O1][FSA]/LiFSA/OE2pyps exhibited stable charge/discharge cycle behavior over 5 cycles.

Synthesis and Structure-Activity Relationships of Novel Benzylamine-Type Antifungals as Butenafine-Related Antimycotics.

Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting compounds was evaluated in an agar diffusion assay against the yeasts C. glabrata and Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte H. burtonii. The compounds were also tested in a microdilution assay against the yeast Candida glabrata and the dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against C. glabrata, comparable to terbinafine or clotrimazole.

Synthesis and Antimicrobial Activity of Novel 3,7-Disubstituted 2H-1- Benzopyran-2-Ones

2H-1-benzopyran-2-one (Coumarin), an important oxygen heterocyclic scaffold, widely distributed throughout the plant kingdom, displayed a wide range of potential biological activities such as anti-microbial, anti-inflammatory and antioxidant activities. In this paper, we have synthesized a novel class of 3,7-disubstituted 2H-1-benzopyran- 2-one derivatives (3aa-3hb) bearing a basic ether side chain at C-7 and a substituted phenyl ring at C-3 of the coumarin ring. These compounds have been evaluated for anti-microbial (antibacterial/antifungal) activities. Some of the compounds 3ac, 3ae, 3bb, 3bc have shown significant anti-fungal activities against selective strains. Compound 3ae and 3bc with the MIC values of 1.56 μg/mL displayed better antifungal activity than fluconazole against Trichophyton mentagrophytes.

Thermochromic Magnetic Ionic Liquids from Cationic Nickel(II) Complexes Exhibiting Intramolecular Coordination Equilibrium.

Among the various thermochromic materials, liquid thermochromic materials are comparatively rare. To produce functional thermochromic liquids, we have designed ionic liquids based on cationic nickel complexes with ether side chains, [Ni(acac)(Me2 NC2 H4 NR1 R2 )]Tf2 N ([1]Tf2 N: R1 =C3 H6 OEt, R2 =Me; [2]Tf2 N: R1 =C3 H6 OMe, R2 =Me; [3]Tf2 N: R1 =R2 =C3 H6 OMe), where acac=acetylacetonate and Tf2 N=(F3 CSO2 )2 N- . The side chains (R1 , R2 ) can moderately coordinate to the metal center, enabling temperature-dependent coordination equilibria in the liquid state. [1]Tf2 N is a liquid at room temperature. [2]Tf2 N is obtained as a solid (Tm =352.7 K) but remains liquid at room temperature after melting. [3]Tf2 N is a solid with a high melting point (Tm =422.3 K). These salts display thermochromism in the liquid state, appearing red at high temperatures and orange, light-blue, or bluish-green at lower temperatures, and exhibiting concomitant changes in their magnetic properties. This phenomenon is based on temperature-dependent equilibrium between a square-planar diamagnetic species and a paramagnetic species with intramolecular ether coordination.

The Effect of Lengthening Cation Ether Tails on Ionic Liquid Properties

Ionic liquids (ILs) are attractive alternative solvents in a variety of applications such as in supercapacitors, batteries, solar energy conversion and for the storage and clean-up of nuclear waste. However, their high viscosities impede their adoption in many large scale processes. Ether side chains have been shown to lower the viscosity of ILs. In this work, we have synthesized a series of ten pyrrolidinium ionic liquids and ten imidazolium ionic liquids bearing ether and alkyl side chains of varying lengths (4 to 10 atoms in length). Their physical properties, such as viscosity, conductivity and thermal profile were measured and compared. Results reveal a dramatic decrease in viscosity with the substitution of alkoxy (ether) side chains for alkyl side chains on the pyrrolidinium cation. However, as the length of the ether chain increases there is negligible change in the viscosity (of about 50 cP). In contrast, a consistent increase in the viscosity was observed as the length of the alkyl side chain increases. Preliminary results of the imidazolium series show a similar trend. These results provide significant insight on the choice of starting materials for researchers designing ILs for specific applications. The work at BNL was supported by the BNL Office of Educational Programs and the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences under contract DE- SC0012704.

The Effect of Lengthening Cation Ether Tails on Ionic Liquid Properties

In order to explore the effect of multiple ether functionalities on ionic liquid properties, a series of ten pyrrolidinium ionic liquids and ten imidazolium ionic liquids bearing ether and alkyl side chains of varying lengths (4 to 10 atoms in length) were prepared. Their physical properties, such as viscosity, conductivity and thermal profile were measured and compared. Consistent with earlier literature, a single ether substituent substantially decreases the viscosity of pyrrolidinium and imidazolium ILs compared to their alkyl congeners. Remarkably, as the number of ether units in the pyrrolidinium ILs increases there is hardly any increase in the viscosity, in contrast to alkylpyrrolidinium ILs where the viscosity increases steadily with chain length. Viscosities of imidazolium ether ILs increase with chain length but always remain well below their alkyl congeners. These results provide significant insight on the choice of starting materials for researchers designing ILs for specific applications.

Stimuli-responsive brush-shaped conjugated polymers with pendant well-defined poly(vinyl ether)s

For the synthesis of brush-shaped conjugated polymers consisting of a poly(phenylene butadiynylene) backbone and well-defined poly(vinyl ether) (polyVE) side chains, we designed polyVE-based macromonomers bearing a diethynyl benzene group at the terminus and applied them to the grafting through synthesis. The macromonomer (DE-PIBVE) was synthesized by living cationic polymerization of isobutyl VE (IBVE) using a functionalized initiator (TMS-DEVE-TFA) having a TMS protected diethynyl benzene moiety, followed by deprotection of the TMS groups. As a result, we succeeded in the synthesis of the target brush-shaped conjugated polymers [poly(DE-PIBVE)] by oxidative coupling reaction of the diethynyl benzene groups. We found that the solution of poly(DE-PIBVE) with a specific side chain length exhibited solvatochromism and thermochromism depending on the polarity of the media employed. This phenomenon was attributed to self-assembly in polar media due to the intermolecular π–π interaction between neighboring conjugated polymer backbones, where the self-assembly behavior would be closely related to the pendant polyVE structure. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 3318–3325

Abstract 4735: Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin

Abstract Background: Tubulysins are natural products isolated from myxobacterial species. They are potent mitotic poisons as they inhibit the polymerization of tubulin into microtubules. Structurally, tubulysins are linear tetrapeptides comprised of N-Me pipecolic acid (Mep), isoleucine (Ile), tubuvaline (Tuv) and tubutyrosine (Tut). All natural tubulysins possess an acid-, base-, and enzyme-sensitive N-acyloxymethyl substituent, as well as a labile acetate group. For the natural tubulysins, both of these functional groups are essential for their potent cytotoxicity. The focus of this presentation is on design and synthesis of chemically stable analogs of tubulysin with improved biological activity. Methods: To explore the influence of tubulysin's functional groups on its cytotoxicity, we designed novel analogs, incorporating ether, thioether, amide and carbamate-based side chains. We also suggested basic SAR-rules for the activity of these synthetic analogs. Results: Structural features, critical for the tubulysin's cytotoxicity, were investigated. e.g., changing the (R)-OAc group of Tuv to (S)-NHAc completely abolished cytotoxicity, while analogs possessing (R)-NHAc on the Tuv moiety still exhibited activity. On the other hand, exchange of Tuv's (R)-OAc group with (R)-OMe had no influence activity. Replacement of the O-acyl part of N-acyloxymethyl substituent (dotted circle) with an alkyl or alkylthiol group resulted in N,O-acetals or N,S-thioacetals possessing similar or higher activity. Tup and Tut are interchangeable in terms of the activities of their respective tubulysin analogs. Conclusion: We designed and synthesized tubulysin analogs which are less prone to degradation under acidic and basic conditions, as well as enzymic influences. Structural features, essential for the cytotoxicity of the tubulysin analogs, were established. Some of the new compounds, especially those with N,S-thioacetal side chains, have increased cytotoxicity in comparison to natural tubulysins. These novel tubulysin analogs were used as warheads for folate receptor(FR)-targeted therapy. Citation Format: Iontcho Vlahov, Fei You, Paul Kleindl, Marilynn Vetzel, Joseph Reddy, Christopher Leamon. Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4735.