Ethylene Spacer Research Articles

Bis-(1-(2-aminoethyl)piperidino), (2-(2-aminoethyl)pyridino) and (1-(2-aminoethyl)pyrrolidino)-substituted dicyanoquinodimethanes: consequences of flexible ethylene spacers with heterocyclic moieties and amine functionalities.

Heterocyclic building blocks possessing ethylene spacer and amine functionality such as 1-(2-aminoethyl)piperidine (1,2-AEPi), 2-(2-aminoethyl)pyridine (2,2-AEPy) and 1-(2-aminoethyl)pyrrolidine (1,2-AEPr) were reacted with tetracyanoquinodimethane (TCNQ) to give disubstituted compounds namely bis-(1-(2-aminoethyl)piperidino)dicyanoquinodimethane (1), bis-(2-(2-aminoethyl)pyridino)dicyanoquinodimethane (2) and bis-(1-(2-aminoethyl)pyrrolidino)dicyanoquinodimethane (3). Utilization of 1,2-AEPi, 2,2-AEPy and 1,2-AEPr as disubstituents on TCNQ has resulted in interesting crystal structures. Inter- and intramolecular hydrogen-bond mediated and expanded supramolecular structures were observed in the lattices of the crystals. Strong fluorescence was observed in solids and solutions. (2) showed a strong second harmonic generation (SHG) whereas (1) and (3) were found to be SHG inactive. All compounds possess good thermal stabilities.

Ligands with Two Different Binding Sites and O2 Reactivity of their Copper(I) Complexes

The synthesis of two new unsymmetric dinucleating ligand systems, L1, combining a bidentate binding site with a tridentate binding site linked through a dibenzofuran spacer, and L2, with two tridentate binding sites bridged by an ethylene spacer, is reported. The ligands L1 and L2 were used for the preparation of the dicopper(I) complexes [Cu2(L1)(NCCH3)3](X)2, {[Cu2(L1)Cl2]}n and [Cu2(L2)(NCCH3)2](Y)2 (X = PF6, BF4, OTf; Y = ClO4, PF6, BF4), in which the two respective copper ions possess two different coordination environments. All complexes reacted with O2, but in the case of the L1 series, no primary O2 adduct could be identified by UV/Vis spectroscopy. Reaction of the [Cu2(L2)(NCCH3)2](Y)2 complexes with pure oxygen led to the formation of an O2 adduct that proved rather unstable.

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.

Gemini Surfactants with Polymethylene Spacer: Supramolecular Structures at Solid Surface and Aggregation in Aqueous Solution

AbstractAggregation of α,ω‐bisammonium cationic gemini surfactants with a variable polymethylene spacer and two dodecyl chains has been studied on a solid surface and in aqueous solution. Scanning electron microscopy and dynamic light scattering with the time‐resolved fluorescence quenching technique were used for the experiments on the solid surface and in aqueous solution, respectively. As the results from the scanning electron microscopy indicate, the morphology of supramolecular structures of gemini surfactants at the solid surface depends on the spacer length. In aqueous solution, gemini surfactants with spacers consisting of 4, 6, 8, 10, and 12 CH2 groups form spherical micelles with diameters between 2 and 3.5 nm. Micelles of gemini surfactant with a short ethylene spacer show an increase in size up to 13 nm at the maximum concentration investigated. The aggregation number of micelles determined by time resolved fluorescence quenching was found to be in the range 14–25 for the spacer lengths from 6 to 12 CH2 groups with only a moderate increase with surfactant concentration. For micelles of gemini surfactants with the short ethylene spacer, the increase of the aggregation number up to 50 at the maximum concentration was observed. The findings support micellar growth of gemini surfactants with short ethylene spacer.

Polymer architecture effect on sodium ion transport in PSTFSI-based ionomers: A molecular dynamics study

In this study, we investigated the effect of polymer architecture on the ion dynamics and local structure to understand the factors that might lead to the design of highly conductive and mechanically robust polyelectrolytes. Molecular dynamic simulations were undertaken on the sodium poly[(4-styrenesulfonyl) (trifluoromethanesulfonyl) imide] P(STFSINa) homopolymer and its copolymers with either ether or styrene spacer groups to investigate the spacer length and polarity dependence of Na-ion transport. Using a scaled charge model, we observed a continuous ion aggregate network in the homopolymer, which facilitates the fast ion dynamics despite the rigid polymer matrix. The longest spacer groups disrupt this percolating ionic network differently, with the ether group being more disruptive than the styrene group, and leading to more discrete ionic aggregates. The copolymer with the ether spacer was also found to result in an alternative Na-ion diffusion mechanism.

N(ω)-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y1 Receptor Antagonists and a Radiolabeled Selective High-Affinity Molecular Tool ([(3)H]UR-MK299) with Extended Residence Time.

Analogues of the argininamide-type NPY Y1 receptor (Y1R) antagonist BIBP3226, bearing carbamoyl moieties at the guanidine group, revealed subnanomolar Ki values and caused depression of the maximal response to NPY (calcium assay) by up to 90% in a concentration- and time-dependent manner, suggesting insurmountable antagonism. To gain insight into the mechanism of binding of the synthesized compounds, a tritiated antagonist, (R)-N(α)-diphenylacetyl-N(ω)-[2-([2,3-(3)H]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([(3)H]UR-MK299, [(3)H]38), was prepared. [(3)H]38 revealed a dissociation constant in the picomolar range (Kd 0.044 nM, SK-N-MC cells) and very high Y1R selectivity. Apart from superior affinity, a considerably lower target off-rate (t1/2 95 min) was characteristic of [(3)H]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t1/2 3 min, Kd 2.0 nM). Y1R binding of [(3)H]38 was fully reversible and fully displaceable by nonpeptide antagonists and the agonist pNPY. Therefore, the insurmountable antagonism observed in the functional assay has to be attributed to the extended target-residence time, a phenomenon of relevance in drug research beyond the NPY receptor field.

Antioxidant properties comparative study of natural hydroxycinnamic acids and structurally modified derivatives: Computational insights

Density functional theory (DFT) and time-dependent formulation of DFT (TDDFT) have been used to explore the antioxidant and absorption properties, respectively of naturally occurring cinnamic acids, caffeic and ferulic acids, and some derivatives recently synthesized from a structural modification of the ethylenic spacer between the aromatic ring and the carboxylic functionality. The main mechanisms proposed in the literature for the antioxidant action of polyphenols as radical scavengers, that are hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), were discussed in details. From the outcomes the HAT mechanism results to be the most probable one for the antioxidant action of this class of compounds. The simulated UV–Vis spectra are characterized by a broad band centered around 340 and 380nm for naturally occurring and synthesized compounds, respectively, generated by a H→L electronic transition. The absorption spectra of natural antioxidants are in good agreement with the experimental counterpart, supporting the reliability of the spectra computed at TDDFT level of theory also for the derivatives. One of the derivative has been identified as the most promising candidate as antioxidant. Accordingly, our calculations encourage the synthesis of derivatives arising from ad-hoc structural modifications which could improve the antioxidant properties.

Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer

A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogs (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3–4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analog. Both 2 and 3 appeared to be 5′-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogs and will profoundly impact future design strategies for these agents.

Synthesis and Properties of Alkyl Dibenzyl Ether Quaternary Ammonium Gemini Surfactant

Abstract Three gemini surfactants with dibenzyl ether spacer (10-B-10, 12-B-12, and 14-B-14) were synthesized and characterized. The surface activity and thermodynamic properties of micellization were determined by surface tension, steady-state fluorescence microscopy, and conductivity methods. The thermodynamic parameters of micellization (ΔmicG0, ΔmicH0, and ΔmicS0) derived from the electrical conductivity measurement implied that the micellization of these surfactants was driven by enthalpy. The enthalpy–entropy compensation of micellization showed that the stability of micelles increased with increasing alkyl chain length. Finally, we evaluated the effects of alkyl chain length on the interfacial tension, foam ability, and the emulsion stability.

Dynamics of Precise Ethylene Ionomers Containing Ionic Liquid Functionality

This paper presents the first findings on the molecular dynamics of the remarkable new class of linear and precisely functionalized ethylene copolymers. Specifically, we utilize broadband dielectric relaxation spectroscopy to investigate the molecular dynamics of linear polyethylene (PE)-based ionomers containing 1-methylimidazolium bromide (ImBr) pendants on exactly every 9th, 15th, or 21st carbon atom, along with one pseudorandom analogue. We also employed FTIR spectroscopy to provide insight into local ionic interactions and the nature of the ordering of the ethylene spacers between pendants. Prior X-ray scattering experiments revealed that the polar ionic groups in these ionomers self-assemble into microphase-separated aggregates dispersed throughout the nonpolar PE matrix. We focus primarily on the dynamics of the segmental relaxations, which are significantly slowed down compared to linear PE due to ion aggregation. Relaxation times depend on composition, the presence of crystallinity, and microphas...

Study on metal nanoparticles synthesis and orientation of gemini surfactant molecules used as stabilizer

In the present study, we report the synthesis of gold (Au), silver (Ag), and gold–silver alloy (Au–Ag) nanoparticles (NPs) by seed-mediated method using gemini surfactant, containing diethyl ether spacer group as a stabilizer. As-synthesized NPs are found very much stable and have been characterized using UV–vis spectroscopy, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), and zeta potential techniques. The orientation of gemini surfactant molecules surrounding the metal NPs has been investigated exploiting twisted intramolecular charge transfer (TICT) fluorescence properties of a probe 4-(N,N-dimethylamino) cinnamaldehyde (DMACA). The quenching efficiencies of different NPs have been performed in the fluorescence of DMACA and are found to be different. This effect can be related to the location of DMACA as well as the electro-negativity of the metals as the extent of orientation of the surfactant molecules around NPs controls the location of DMACA in a bilayer. To support the location of DMACA, fluorescence quenching studies with cetylpyridinium chloride (CPC) as an external quencher have also been carried out.

A photoresponsive planar chiral azobenzene dopant with high helical twisting power

A planar chiral molecule as a photon-mode chiral switch was synthesized for the reversible control of self-assembled superstructures based on doped chiral nematic liquid crystals. The chiral switch is composed of bis-hexyl substituted diphenylnaphthalene and a photoisomerizing azobenzene unit connected by ethylene spacers in a cyclic manner. Bis-hexyl substitution to the mesogenic unit promoted the chirality transfer to the host LC medium resulting in a high initial helical twisting power (HTP) and a large change in HTP by photo-isomerization of the chiral dopant. At very low doping concentrations, both reversible tuning of RGB reflection colors and rotation motion control of micro glass rods on the cholesteric liquid crystal surface were achieved.

Hybrid pharmacophore-based drug design, synthesis, and antiproliferative activity of 1,4-dihydropyridines-linked alkylating anticancer agents

Two series of novel substituted 1,4-dihydropyridine derivatives incorporating nitrogen mustard pharmacophore hybrids without spacer DHP-M (4a–4d) and with ethyl spacer DHP-L-M (8a–8g) were designed and synthesized. They were subjected to in silico ADME prediction study to check their drug-like properties and evaluated for their cytotoxicity against: A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) human cancer cell lines in vitro using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against chlorambucil and docetaxel. Majority of the test compounds exhibited moderate to significant cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by DHP-M (4a). This may be due to the less steric hindrance offered by 4a.

Biotransformation and detectability of the designer drug 2,5-dimethoxy-4-propylphenethylamine (2C-P) studied in urine by GC-MS, LC-MS(n), and LC-high-resolution-MS(n).

2,5-Dimethoxy-4-propylphenethylamine (2C-P) is a hallucinogenic designer drug of the phenethylamine class, the so-called 2Cs, named according to the ethyl spacer between the nitrogen and the aromatic ring. The aims of the present work were to identify the phases I and II metabolites of 2C-P. In addition, the detectability of 2C-P and its metabolites in urine as proof of an intake in clinical or forensic cases was tested. According to the identified metabolites, the following pathways were proposed: N-acetylation; deamination followed by reduction to the corresponding alcohol and oxidation to carbonic acid; mono- and bis-hydroxylation at different positions; mono- and bis-O-demethylation, followed by glucuronidation, sulfation, or both; and combination of these steps. Proof of an intake of a common user's dose of 2C-P was possible by both standard urine screening approaches, the GC-MS as well as the LC-MS(n) approach.

Perylenediimide-Based Donor–Acceptor Dyads and Triads: Impact of Molecular Architecture on Self-Assembling Properties

Perylenediimide-based donor-acceptor co-oligomers are particularly attractive in plastic electronics because of their unique electro-active properties that can be tuned by proper chemical engineering. Herein, a new class of co-oligomers has been synthesized with a dyad structure (AD) or a triad structure (DAD and ADA) in order to understand the correlations between the co-oligomer molecular architecture and the structures formed by self-assembly in thin films. The acceptor block A is a perylene tetracarboxyl diimide (PDI), whereas the donor block D is made of a combination of thiophene, fluorene, and 2,1,3-benzothiadiazole derivatives. D and A blocks are linked by a short and flexible ethylene spacer to ease self-assembling in thin films. Structural studies using small and wide X-ray diffraction and transmission electron microscopy demonstrate that AD and ADA lamellae are made of a double layer of co-oligomers with overlapping and strongly π-stacked PDI units because the sectional area of the PDI is about half that of the donor block. These structural models allow rationalizing the absence of organization for the DAD co-oligomer and therefore to draw general rules for the design of PDI-based dyads and triads with proper self-assembling properties of use in organic electronics.

Micellization of gemini surfactant with dibenzyl ether spacer in water–organic mixed media

The aggregation behavior and thermodynamics of gemini surfactant N,N′-(((1,4-phenylenebis(methylene))bis(oxy)) bis(ethane-2,1-diyl))bis(N,N-dimethyldodecan-1-aminium) (12-B-12) in a binary mixed solvent of water and organic solvents [1,4-dioxane (DO) and ethylene glycol (EG)] within the temperature range of 25°C to 40°C were investigated by the conductivity method. Micellization was delayed with the addition of organic co-solvent; consequently, a progressive increase was observed in critical micelle concentration (cmc), Gibbs free energy of micellization (ΔGm0), and Gibbs free energy of transfer (ΔGtrans0). 12-B-12 was found to be more prone to micellization in EG–water than in DO–water because of the lower cmc, more significantly negative ΔGm0, and less significantly positive ΔGtrans0. Enthalpy–entropy compensation was also investigated.

TTF–fluorene dyads and their M(CN)2−(M = Ag, Au) salts designed for photoresponsive conducting materials

To explore photoresponsive conducting materials, we developed new tetrathiafulvalene (TTF)–fluorene D–A dyads with a σ-bonded thiomethylene spacer (1a–d) or a π-conjugated ethylene spacer (2a–b) and reported their synthesis, electrochemical and optical properties. Fluorescence studies suggested that the fluorescence from an excited fluorene part is quenched by an intramolecular electron transfer process from the electron-donating TTF part to the fluorene part, and the intramolecular interaction through the π-conjugated ethylene spacer is stronger and shows more suppression than the non-planar σ-bonded thiomethylene spacer. We also investigated photoelectric conversion functionality by a photoelectrochemical method using the thin films of dyads 1–2 spin-coated on ITO-coated glass substrates. We observed electric current generation that depends on the absorption spectra of thin films, suggesting that absorbed photons are converted to electric currents on the thin film/ITO electrode. Crystal structure analysis and measurement of photoconductivity of a single crystalline sample of molecule 1d having 4,5-bis(methylthio)-substituents suggest generation of photocurrents along the stacking direction of the TTF parts by the photoinduced intramolecular electron transfer and the resultant charge-separated state. Furthermore, we also reported the crystal structure analyses, photoconductivity and magnetic properties of the cation radical salts, 2b2M(CN)2 (M = Ag, Au), where 2b contains a 4,5-ethylenedithio-substituent. The Ag(CN)2 salt showed a semiconducting behaviour with a room temperature conductivity of 0.088 S cm−1 due to a half-filled Mott insulating band structure of this crystal that originates from a strongly dimerized intermolecular interaction. Upon photoirradiation, this salt showed a slight enhancement of conductivities of ca. 14%.

Tuning the Photophysical Properties of BODIPY Molecules by π‐Conjugation with Fischer Carbene Complexes

The synthesis, structure, and photophysical properties of novel BODIPY-Fischer alkoxy-, thio-, and aminocarbene dyads are reported. The BODIPY chromophore is directly attached to the carbene ligand by an ethylenic spacer, thus forming donor-bridge-acceptor π-extended systems. The extension of the π-conjugation is decisive in the equilibrium geometries of the dyads and is clearly reflected in the corresponding absorption and emission spectra. Whereas the BODIPY fragment is mainly isolated in aminocarbene complexes, it is fully conjugated in alkoxycarbene derivatives. The former thus exhibit the characteristic photophysical properties of BODIPY units, whereas complete suppression of the BODIPY fluorescence emission is observed in the latter, as a direct consequence of the strong electron-accepting character of the (CO)5M=C moiety. As the π-acceptor character of the metal-carbene group can be modified, the electronic properties of the conjugated BODIPY can be tuned. Density functional calculations have been carried out to gain insight into the photophysical properties.

Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents

In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2′,5′-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50=17–130nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.

The Novel [4,5-e][1,3]Diazepine-4,8-dione and Acyclic Carbamoyl Imino-Ureido Derivatives of Imidazole: Synthesis, Anti-Viral and Anti-Tumor Activity Evaluations

In the present paper, we report on the synthesis, and in vitro antiviral and cytostatic activities of a series of novel imidazole[4,5-e][1,3]diazepine-4,8-dione (compounds 9–11) and acyclic carbamoyl imino-ureido imidazole (compounds 12 and 13) derivatives. These new type of chemical entities showed no significant activity on the broad spectrum of DNA and RNA viruses. Results of antiproliferative assays performed on a panel of selected human tumor cell lines revealed that only compounds 1 and 5 showed moderate and selective cytostatic effect against HeLa cells (IC50 = 24 and 32 µM) with no concomitant cytotoxic effects on human normal fibroblasts (BJ). Importantly, an imidazole derivative containing a pyrrolidine moiety linked via an ethylenic spacer (3) showed a selective cytostatic effect toward cervical carcinoma (HeLa) cells (IC50 = 9.5 µM) with no apparent cytotoxicity on human normal fibroblasts (BJ). This compound can be therefore considered as a potential anti-tumor lead compound for further synthetic structure optimization.