Spacers Of Different Lengths Research Articles

The effect of the molecular structures of dicyanomethylene compounds on their supramolecular assembly, photophysical and electrochemical properties

Two series of flexible dicyanomethylene compounds, specifically, class 1 and class 2 compounds, have been designed and synthesised. In class 1 compounds, the dicyanomethylene groups are separated by glycol chain spacers of different lengths, whereas, in class 2 compounds, the spacers are alkyl linkers of different lengths. The notion underlying the design of these compounds is that in class 1 molecules, the spacers contain donor oxygen atoms that could not only form hydrogen bonds during the course of crystal packing but also promote withdrawing effects that modify the photophysical and electrochemical properties of these molecules in solution; in contrast, these effects would be absent for class 2 molecules. However, this study revealed that, with respect to crystal packing, the size of the spacers and their even and odd numbers of atoms are more important than their chemical nature. All of the synthesised compounds exhibited blue emission in the solid state and in CH2Cl2 solutions. The photophysical and electrochemical properties of these compounds in solution were not significantly affected by the type and length of the spacer that was used in each molecule. In the solid state, however, the compound with the shortest spacer showed the highest Stokes shift. The electronic transitions for the synthesized compounds in solution were explained by density functional theory and time-dependent density functional theory calculations, which indicated that the methylene moieties control the properties of both classes of compounds and that the spacers do not conjugate with the end groups. These two series of flexible dicyanomethylene compounds could be utilised as molecular building blocks for the development of new solids with novel properties.

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).

Tuning the interaction between carbon nanotubes and dipole switches: the influence of the change of the nanotube–spiropyran distance

The non-covalent functionalization of carbon nanotubes with spiropyran molecules, serving as optically addressable dipole switches, is reported. Two kinds of pyrene–spiropyran-based dyads with spacers of different lengths resulting in different switch–tube distances were investigated. While both surfactants were able to form stable carbon nanotube suspensions, the different distances between the switch and the tube affected both of the components’ optical properties. In the case of the shorter spacer, the nanotubes’ luminescence as well as the merocyanine absorption band were red-shifted and furthermore, the rate of the merocyanine → spiropyran thermal back isomerization was decreased.

One-step template-directed synthesis of acridine-based rigid cyclophanes

Cyclo-bisintercalands are macrocyclic systems containing aromatic subunits, which are commonly used as hosts for aromatic molecules and as DNA intercalators. In this article, a step-by-step synthesis of a series of cyclo-bisintercalands containing 3,6-diaminoacridines as aromatic units, and connected by rigid spacers of different lengths, is reported. In addition, we describe herein a more efficient synthetic alternative, involving single-step template-directed processes. The new routes allow the easy synthetic access to these macrocyclic systems with acceptable yields. The synthesized cyclo-bisintercalands and their precursors have been structurally characterized by UV–visible and NMR methods. Preliminary biological activity assays performed on the bisintercalands and cyclo bisintercalands revealed interesting cytotoxic properties against different tumor cell lines, especially in the case of the bisintercalands, highlighting their potential as cancer chemotherapeutic agents.

Structure of p73 DNA-binding domain tetramer modulates p73 transactivation

The transcription factor p73 triggers developmental pathways and overlaps stress-induced p53 transcriptional pathways. How p53-family response elements determine and regulate transcriptional specificity remains an unsolved problem. In this work, we have determined the first crystal structures of p73 DNA-binding domain tetramer bound to response elements with spacers of different length. The structure and function of the adaptable tetramer are determined by the distance between two half-sites. The structures with zero and one base-pair spacers show compact p73 DNA-binding domain tetramers with large tetramerization interfaces; a two base-pair spacer results in DNA unwinding and a smaller tetramerization interface, whereas a four base-pair spacer hinders tetramerization. Functionally, p73 is more sensitive to spacer length than p53, with one base-pair spacer reducing 90% of transactivation activity and longer spacers reducing transactivation to basal levels. Our results establish the quaternary structure of the p73 DNA-binding domain required as a scaffold to promote transactivation.

Evidence for Directed Evolution of Larger Size Motif inArabidopsis thalianaGenome

Transcription control of gene expression depends on a variety of interactions mediated by the core promoter region, sequence specific DNA-binding proteins, and their cognate promoter elements. The prominent group of cis acting elements in plants contains an ACGT core. The cis element with this core has been shown to be involved in abscisic acid, salicylic acid, and light response. In this study, genome-wide comparison of the frequency of occurrence of two ACGT elements without any spacers as well as those separated by spacers of different length was carried out. In the first step, the frequency of occurrence of the cis element sequences across the whole genome was determined by using BLAST tool. In another approach the spacer sequence was randomized before making the query. As expected, the sequence ACGTACGT had maximum occurrence in Arabidopsis thaliana genome. As we increased the spacer length, one nucleotide at a time, the probability of its occurrence in genome decreased. This trend continued until an unexpectedly sharp rise in frequency of (ACGT)N25(ACGT). The observation of higher probability of bigger size motif suggests its directed evolution in Arabidopsis thaliana genome.

Hydrogels with well-defined peptide-hydrogel spacing and concentration: impact on epithelial cell behavior

The spacing of peptides away from a hydrogel matrix dramatically impacts their availability and subsequent interactions with cells. Peptides were synthesized with monodisperse poly(ethylene glycol) spacers of different lengths that separate the peptide from the monomeric functionality which reacts during hydrogel polymerization. Specifically, bioactive RGD ligands were conjugated to PEG(5), PEG(11) or PEG(27) spacers via solid phase techniques and then functionalized with an acryloyl end group. These acryloyl-PEGx-RGD conjugates were then copolymerized with PEGDA to form an inert hydrogel network decorated with RGD ligands for cell interactions. As the PEG spacer length increases, the RGD concentration required to support cell attachment and spreading decreases. The competitive detachment of hTCEpi cells in the presence of soluble linear RGD also shows non-linear dependence on the PEG spacer length, as more cells remained attached and spread on gels functionalized with longer PEG-RGD conjugates in comparison to the shorter PEG-RGD conjugates. The strategy and synthetic techniques developed here allow for reproducible control over peptide-hydrogel spacing and peptide concentration, and may be extended for incorporation of multiple peptides and to other hydrogel platforms.

Conformational Analysis of Bivalent Estrogen Receptor Ligands: From Intramolecular to Intermolecular Binding

The estrogen receptor binding affinities of bivalent raloxifene ligands tethered by flexible spacers of different lengths have been evaluated in vitro. Two bivalent binding modes, intra- and intermolecular, were hypothesized to explain their different binding properties. The binding affinities of these bivalent ligands in an aqueous environment are influenced by their conformations, which can be determined by 2D NMR and UV spectral methods. Moreover, computer modeling and simulations were performed to explain the binding modes of these bivalent ligands and to estimate the conformational entropy difference between their unbound and bound states. It was found that bivalent ligands tethered by long spacers had weaker binding affinities because of the shielding of the binding moieties that results from their folded conformations; those tethered by short spacers had stronger affinities because they exposed their ligands to the receptor.

Synthesis and characterization of DMAP-modified NPY Y1 receptor antagonists as acyl-transfer catalysts

Starting from the working hypothesis that specific chemical labelling may be an attractive approach to detect and study G protein-coupled receptors (GPCRs) we synthesized catalytically active antagonists of the neuropeptide Y1 receptor (Y1R). An argininamide-type Y1R antagonist scaffold was combined with a DMAP moiety via spacers of different length and chemical nature. These hybrid compounds have Y1R affinities in the two-digit nanomolar range and are capable of catalysing acyl-transfer reaction to surrogates of bionucleophiles, as demonstrated in the absence of cells by using esters of fluorescent dyes as substrates in buffer. By contrast, selective staining of Y1Rs on living MCF-7 cells was not achieved due to significant non-catalysed (Y1R ligand independent) reaction with biomolecules and the limited density of Y1R on the cell surface. Although this may also depend on insufficient selectivity of the staining reagents, the results of this study suggest that the general applicability of catalytic staining to GPCRs has to be reconsidered, as this approach is hampered by a very low portion of receptor of interest compared to the total amount of membrane proteins.

Influence of the photo-active azo cross-linker spacer on the opto-mechanics of polysiloxane elastomer actuators

Nematic liquid single crystal elastomers (LSCEs) that contain azobenzenes as cross-linkers have a clear application in the field of light-controlled actuators. They are able to modify their macroscopic dimensions upon irradiation with UV light and furthermore relax back thermally or by irradiation with visible light. Many efforts have been put forward to improve the photo-mechanical effect. However, there are no previous studies about the role of the length of the photo-active cross-linker spacer on the opto-mechanics of light-controlled actuators. In this way, we have prepared several photo-active side-chain nematic polysiloxane LSCEs that contain 4,4′-dialkoxyazobenzenes as cross-linkers, which bear spacers of different lengths. The opto-mechanical behaviour of the different LSCEs prepared has been analyzed. The use of photo-active cross-linkers with long spacers yields actuators with higher mechanical responses under irradiation with UV light. Neither the irradiation nor the thermal relaxation time of the actuator depends on the spacer length.

Adsorption of Gemini Surfactants with Dodecyl Side Chains and Different Spacers, Including Partially Fluorinated Spacers, on Different Surfaces: Neutron Reflectometry Results

Neutron reflectometry has been used to study the adsorption of two symmetrical cationic (dimethyl ammonium bromide) gemini surfactants with two C(12)H(25) chains and different partially fluorinated spacers at three different surfaces: air/water, hydrophilic silica/water, and hydrophobic (octadecyltricholorosilane (OTS))/water. In addition, the adsorption of purely hydrocarbon geminis with the same side chains and spacers of different lengths has been studied at the same two solid surfaces. The limiting close-packed areas for the two fluorocarbon geminis, C(12)-C(3)fC(6)C(3)-C(12) and C(12)-C(4)fC(4)C(4)-C(12), are 92 and 72 ± 4 at the hydrophilic silica surface, 81 and 89 ± 4 at OTS, and 137 and 106 ± 4 Å(2) at the air/water interface with decreases of 38 and 24% from air/water to the average solid value, respectively. These changes suggest that the packing at the air/water interface is inefficient, and this allows the extra hydrophobicity of the chain environment at the two solid surfaces to promote much more efficient packing. At the air/water interface, the fluorocarbon spacers are on average the fragments furthest away from the underlying water, further out than in the nearest comparable hydrocarbon gemini, C(12)-C(12)-C(12). This is the probable explanation of the much lower value of the area per molecule at the air/water interface of C(12)-C(4)fC(4)C(4)-C(12) compared to that of C(12)-C(12)-C(12). It is also the probable cause of the inefficient packing of the hydrocarbon side chains. At the more hydrophobic OTS surface the situation is reversed and the fluorocarbon spacers are now the furthest from the hydrophobic surface, further out than the spacer in C(12)-C(12)-C(12). This is an unusually large structural change that must be associated with the greatly improved packing at the OTS surface. The efficiency of the packing is also high for the hydrophilic surface, no doubt because the hydrocarbon chains can interact favorably in the adsorbed bilayer core. The values of the area per molecule obtained for the series of hydrocarbon geminis at the air/water, OTS/water and silica/water interfaces are respectively 139, 104, and 98 ± 4 Å(2) for C(12)-C(12)-C(12), 114, 106, and 94 ± 4 Å(2) for C(12)-C(10)-C(12), 104, 84, and 85 ± 4 Å(2) for C(12)-C(6)-C(12), and 78, 66, and 70 ± 3 Å(2) for C(12)-C(3)-C(12). The area per molecule is also about 20% less on average at the two solid surfaces than at the air/water interface. This can also be attributed to more efficient packing caused by the more favorable hydrophobic interactions possible at these two surfaces than at the air/water interface, again showing that the packing at the air/water interface is inefficient and probably resulting from the competition between spacer and chains, which will be most pronounced for the C(12) spacer.

Extreme bending of composite insulators on 750 kV compact transmission lines

In designing and constructing the first 750 kV double-circuit compact transmission line, much pioneering work is necessitated in the choice of tower, insulator strings and phase-to-phase spacers. In this paper the mechanical characteristics of three possible phase-to-phase composite spacers for such compact transmission lines are considered in respect of very large bending of the spacer. A large deflection theory is introduced to calculate the lateral deflections and longitudinal compressions caused by applied axial loads and these are compared with the results of tests on three spacers of different lengths and diameters. Agreement between calculation and test results was good and the necessity for the larger diameter demonstrated. No permanent damage due to the extreme bending was found and two of the spacer samples were found to be suitable for use in the compact transmission lines with a good safety margin in respect of such bending.

Dimeric liquid crystalline thermosets from azo-containing diglycidyl ether cured by anhydride

A series of dimeric liquid crystalline (LC) epoxy monomers containing azobenzene group with central spacers of different lengths were synthesized and structurally characterized by 1H NMR, 13C NMR, and elemental analysis. The mesogenic behavior of these monomers was measured by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and X-ray diffraction (XRD). Like other dimeric LC epoxy monomers, the melting points, clear points, and mesophase of these compounds are influenced by the carbon numbers of central spacers. Anhydride was employed to cure the monomers and LCTs with nematic phase were obtained. Thermal properties, dynamic mechanical properties and UV–Vis spectra of the LCTs were studied. The decomposition of the LCTs occurred near 220 °C and followed three stages. The LCTs also had the natural absorbance bonds of azo compounds.

Peptide modified nanocarriers for selective targeting of bombesin receptors

The present work describes new supramolecular aggregates obtained by co-assembling two different amphiphilic molecules, one containing the bioactive bombesin peptide (BN), or a scramble sequence, and the other, the DOTA chelating agent, (C18)(2)DOTA, capable of forming stable complexes with the radioactive (111)In(III) isotope. The peptide in the amphiphilic monomer is spaced by the lipophilic moiety through ethoxylic spacers of different length: a shorter spacer with five units of dioxoethylene moieties in (C18)(2)L5-peptide, or a longer spacer consisting of a Peg3000 residue in (C18)(2)Peg3000-peptide. Structural characterization by SANS and DLS techniques indicates that, independently from the presence of the peptide containing monomer in the final composition, the predominant aggregates are liposomes of similar shape and size with a hydrodynamic radius R(h) around 200 nm and bilayer thickness, d, of 4 nm. In vitro data show specific binding of the (111)In-(C18)(2)DOTA/(C18)(2)L5-[7-14]BN 90:10 liposomes in receptor expressing cells. However, the presence of the Peg3000 unit on the external liposomal surface, could hide the peptide and prevent the receptor binding. In vivo experiments using (111)In-(C18)(2)DOTA/(C18)(2)L5-[7-14]BN show the expected biological behavior of aggregates of such size and molecular composition, moreover there is an increase in concentration of the GRPR targeting aggregate in the tumors compared to control at the 48 h time point evaluated (2.4% ID/g versus 1.6% ID/g).

Biotin Derivatives Carrying Two Chelating DOTA Units. Synthesis, in Vitro Evaluation of Biotinidases Resistance, Avidin Binding, and Radiolabeling Tests

The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin-biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA. Two others were prepared starting from a on-resin lysine residue. The lysine alpha-NH2 was bonded to biotin, and then spacers were appended to the epsilon-NH2 and conjugated with two DOTA molecules. One compound contained a p-aminobenzoic acid spacer, which ensured higher head-to-tail distance and increased rigidity of the chain. These last two compounds had a very high ability to bond avidin and were labeled with 90Y at high specific activity. All the compounds were resistant to the action of serum biotinidases.

Effects of the nature of counterions in solution on interactions of phenoxazones, xanthones, and carbazoles containing benzo-crown groups with DNA

The interactions of DNA with phenoxazones, xanthones, and carbazoles containing the (benzo-18-crown-6)-4′-yl and (benzo-15-crown-5)-4′-yl radicals bonded to the chromophore via spacers of different lengths in the presence of Na+ and K+ ions were studied by spectrophotometry, circular dichroism, and dynamic birefringence. The thermodynamic parameters of the binding of the compounds with DNA and changes in the macromolecular parameters of the DNA molecule during complexation were determined. Based on the results of these studies, we suggested the models of bonding of these compounds to the double helix of DNA. It is shown that the mode of DNA binding with a phenoxazone derivative containing two (benzo-15-crown-5)-4′-yl radicals bonded via a fragment of glycine to chromophore depends on the type of the counterion in solution. In the presence of Na+, the chromophore is intercalated into the double helix of DNA; in the presence of K+, it is bound to DNA in the form of a dimer outside the double helix. The type of the counterion does not affect the mode of binding of other crown-containing compounds of actinocin with DNA. For compounds containing the (benzo-18-crown-6)-4′-yl radical, the mode of binding to DNA adepends only on the spacer length.

Organometallic [Re(CO)3]+and [Re(CO)2(NO)]2+Labeled Substrates for Human Thymidine Kinase 1

Thymidine was functionalized at position N3 with a tridentate iminodiacetic acid chelating system and a potentially tetradentate mercaptoethyliminodiacetic acid chelating system. Spacers of different lengths (ethyl and butyl) were introduced between the chelators and thymidine. The derivatives were labeled with the [Re(CO)(2)(NO)](2+) and [Re(CO)(3)](+) cores to give isostructural complexes with different overall charges. All complexes were analyzed by NMR, MS, and IR, and in addition, the X-ray structure of a [Re(CO)(2)(NO)](2+) labeled thymidine derivative functionalized at the N3 position was solved. The ligands incorporating the potentially tetradentate mercaptoethyliminodiacetic acid chelating system coordinated tridentately through iminodiacetic acid to both the [Re(CO)(2)(NO)](2+) core and the [Re(CO)(3)](+) core. This was surprising given that the reaction of [NEt(4)][Re(CO)(2)(NO)Br(3)] with the model ligand ethylmercaptoethyliminodiacetic acid led to dissociation of a carbonyl ligand and formation of a monocarbonyl-mononitrosyl complex, as confirmed by X-ray structure analysis. All of the organometallic thymidine derivatives were substrates for human thymidine kinase 1, a key enzyme in (cancer) cell proliferation. Neutral [Re(CO)(2)(NO)](2+) labeled thymidine derivatives revealed substrate activity ranging from 24 to 40%, and the structurally analogous anionic [Re(CO)(3)](+) labeled thymidine derivatives from 20 to 38% compared with the natural substrate thymidine.

Synthesis and biological testing of thioalkane- and thioarene-spaced bis-β- d-glucopyranosides

A three-step synthesis of bis-β- d-glucopyranosides containing thioalkane or thioarene spacers of different length and flexibility is described. The key-step reaction allows an easy modulation of final saccharidic products so that a library of molecules with different glycosidic residues and spacers can be obtained. Two of the new thioarene-spaced bis-β- d-glucopyranosides endow with a specific cytotoxic potential. A more detailed investigation of one of the two compounds ascertains that this effect is attributable to induction of cell death by apoptosis.

Synthesis and biological evaluation of multivalent carbohydrate ligands obtained by click assembly of pseudo-rotaxanes

Multivalent carbohydrate ligands have been prepared by assembling alpha-cyclodextrin-based pseudo-rotaxanes through "click chemistry". The inclusion complex formed by a lactosyl-alpha-CD conjugate and a decane axle carrying a lactosyl stopper at one extremity and an azido group at the other end was dimerized by bis-propargyl spacers of different lengths to provide oligorotaxanes having adjustable threading ratios. For the first time, saccharidic ligands have been introduced on rotaxanes both as a biological recognition element and as a capping group. The supramolecular species have been isolated and characterized by mass spectrometry as well as by 1D and DOSY NMR experiments. Their ability to inhibit the binding of Arachis hypogaea agglutinin to asialofetuin, assayed by enzyme linked lectin assays (ELLA), was shown to be valency-dependent.

New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape-specific ligands

Bridged cyclodextrin dimers and trimers, in which respectively two and three hydrophobic cavities lie in close proximity, display much higher binding affinities and molecular selectivities than do parent cyclodextrins (CDs). By joining betaCD units with links inserted at different positions (2-2', 3-2', 6-2' or 6-2'-6'') and interposing spacers of different lengths and shapes, multicavity structures can be synthesized that are precisely tailored to fit specific guest molecules. This enzyme-mimicking strategy can also be used to generate stable supramolecular adducts. A series of CD dimers and trimers was prepared in good yields by carrying out the critical synthetic steps under power ultrasound (US) or microwave (MW) irradiation. Starting from azide and acetylenic CD derivatives, we exploited an efficient MW-promoted Huisgen 1,3-dipolar cycloaddition in the presence of Cu(I) salts. The resulting bridged CD derivatives gave stable adducts with magnetic-resonance-imaging contrast agents (MRI CAs) containing gadolinium(III) chelates. These inclusion complexes were found to be 2 to 3 orders of magnitude more stable than those formed by betaCD and to be endowed with high relaxivity values.