Aromatic Head Group Research Articles

Synthesis and Biological Evaluation of FTY720 (Fingolimod) Derivatives with Aromatic Head Group as Anticancer Agents.

FTY720 is employed for the treatment of multiple sclerosis and exerts apoptotic effects on various cancers through protein phosphatase 2A (PP2A) activation. In compound 4, the dihydroxy head group of FTY720 was modified into dihydroxy phenyl group. The cell survival in compound 4 treated colorectal and gastric cancer cells was significantly reduced as compared with control, 34.6 and 25.1%, respectively. The docking study of compound 4 showed that the aromatic head group effectively binds to PP2A.

The Aromatic Head Group of Spider Toxin Polyamines Influences Toxicity to Cancer Cells.

Spider venoms constitute incredibly diverse libraries of compounds, many of which are involved in prey capture and defence. Polyamines are often prevalent in the venom and target ionotropic glutamate receptors. Here we show that a novel spider polyamine, PA366, containing a hydroxyphenyl-based structure is present in the venom of several species of tarantula, and has selective toxicity against MCF-7 breast cancer cells. By contrast, a polyamine from an Australian funnel-web spider venom, which contains an identical polyamine tail to PA366 but an indole-based head-group, is only cytotoxic at high concentrations. Our results suggest that the ring structure plays a role in the cytotoxicity and that modification to the polyamine head group might lead to more potent and selective compounds with potential as novel cancer treatments.

Self-Assembly and Drug Release Capacities of Organogels via Some Amide Compounds with Aromatic Substituent Headgroups.

In this work, some amide compounds with different aromatic substituent headgroups were synthesized and their gelation self-assembly behaviors in 22 solvents were characterized as new gelators. The obtained results indicated that the size of aromatic substituent headgroups in molecular skeletons in gelators showed crucial effect in the gel formation and self-assembly behavior of all compounds in the solvents used. Larger aromatic headgroups in molecular structures in the synthesized gelator molecules are helpful to form various gel nanostructures. Morphological investigations showed that the gelator molecules can self-assembly and stack into various organized aggregates with solvent change, such as wrinkle, belt, rod, and lamella-like structures. Spectral characterizations suggested that there existed various weak interactions including π-π stacking, hydrogen bonding, and hydrophobic forces due to aromatic substituent headgroups and alkyl substituent chains in molecular structures. In addition, the drug release capacities experiments demonstrated that the drug release rate in present obtained gels can be tuned by adjusting the concentrations of dye. The present work would open up enormous insight to design and investigate new kind of soft materials with designed molecular structures and tunable drug release performance.

Down-regulation of tomato PHYTOL KINASE strongly impairs tocopherol biosynthesis and affects prenyllipid metabolism in an organ-specific manner.

Tocopherol, a compound with vitamin E (VTE) activity, is a conserved constituent of the plastidial antioxidant network in photosynthetic organisms. The synthesis of tocopherol involves the condensation of an aromatic head group with an isoprenoid prenyl side chain. The latter, phytyl diphosphate, can be derived from chlorophyll phytol tail recycling, which depends on phytol kinase (VTE5) activity. How plants co-ordinate isoprenoid precursor distribution for supplying biosynthesis of tocopherol and other prenyllipids in different organs is poorly understood. Here, Solanum lycopersicum plants impaired in the expression of two VTE5-like genes identified by phylogenetic analyses, named SlVTE5 and SlFOLK, were characterized. Our data show that while SlFOLK does not affect tocopherol content, the production of this metabolite is >80% dependent on SlVTE5 in tomato, in both leaves and fruits. VTE5 deficiency greatly impacted lipid metabolism, including prenylquinones, carotenoids, and fatty acid phytyl esters. However, the prenyllipid profile greatly differed between source and sink organs, revealing organ-specific metabolic adjustments in tomato. Additionally, VTE5-deficient plants displayed starch accumulation and lower CO2 assimilation in leaves associated with mild yield penalty. Taken together, our results provide valuable insights into the distinct regulation of isoprenoid metabolism in leaves and fruits and also expose the interaction between lipid and carbon metabolism, which results in carbohydrate export blockage in the VTE5-deficient plants, affecting tomato fruit quality.

Rubbery wound closure adhesives. II. initiators for and initiation of 2-octyl cyanoacrylate polymerization

The polymerization of 2-octyl cyanoacrylate (OctCA) initiated by five N-bases [N,N-dimethyl-p-toluidine (DMT), pyridine (Pyr), triethyl amine (Et3N), azobicyclo[2.2.2]octane (ABCO), and diazobicylo[2.2.2]octane (DABCO)] was investigated. Our main objective was to assess the suitability and relative reactivity of these initiators for neat OctCA polymerization as wound closure adhesives. Methodologies were developed to determine stir-stop and set times of OctCA polymerization and to use these quantities to assess initiation reactivity. According to these studies Et3N, ABCO, DABCO, and Pyr are most reactive initiators, while DMT is much less reactive. Polymerizations were much faster in the presence of small amounts of tetrahydrofuran than toluene, indicating solvent polarity effects. Initiator reactivity is discussed in terms of structural parameters. NMR and MALDI-TOF analyses of low molecular weight P(OctCA) prepared with DMT did not show evidence for the expected aromatic head group proposed by earlier investigators, which suggests complex initiation mechanism. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1652–1659

Comprehensive study on the impact of the cation alkyl side chain length on the solubility of water in ionic liquids

A comprehensive study on the phase behaviour of two sets of ionic liquids (ILs) and their interactions with water is here presented through combining experimental and theoretical approaches. The impact of the alkyl side chain length and the cation symmetry on the water solubility in the asymmetric [CN−1C1im][NTf2] and symmetric [CN−1CN−1im][NTf2] series of ILs (N up to 22), from 288.15K to 318.15K and at atmospheric pressure, was studied. The experimental data reveal that the solubility of water in ILs with an asymmetric cation is higher than in those with the symmetric isomer. Several trend shifts on the water solubility as a function of the alkyl side chain length were identified, namely at [C6C1im][NTf2] for asymmetric ILs and at [C4C4im][NTf2] and [C7C7im][NTf2] for the symmetric ILs. To complement the experimental data and to further investigate the molecular-level mechanisms behind the dissolution process, density functional theory calculations, using the Conductor-like Screening Model for Real Solvents (COSMO-RS) and the electrostatic potential-derived CHelpG, were performed. The COSMO-RS model is able to qualitatively predict water solubility as a function of temperature and alkyl chain lengths of both symmetric and asymmetric cations. Furthermore, the model is also capable to predict the somewhat higher water solubility in the asymmetric cation, as well as the trend shift as a function of alkyl chain lengths experimentally observed. Both COSMO-RS and the electrostatic potential-derived CHelpG show that the interactions of water and the IL cation take place on the IL polar region, namely on the aromatic head and adjacent methylene groups that explains the differences in water solubility observed for cations with different chain lengths. Furthermore, the CHelpG calculations for the isolated cations in the gas phase indicates that the trend shift of water solubility as a function of alkyl chain lengths and the difference of water solubility in symmetric may also result from the partial positive charge distribution/contribution of the cation.

Interactions between quaternary ammonium surfactants and polyethylenimine at high pH in film forming systems

HypothesisFilm formation and film structure in films formed on solutions of cationic surfactants with polyethylenimine is influenced by the surfactant structure, including both the tail length and the nature of the headgroup, which alter the micelle properties. ExperimentsA series of cationic surfactants were synthesized and conductivity measurements were used to compare the critical micelle concentrations for these surfactants and their behaviour with and without polyethylenimine at high pH. Small angle neutron scattering measurements were used to characterise the size and shape of the micelles in the presence and absence of the polymer. Film formation between polyethylenimine and the various surfactants was trialled, and the interfacial film structures measured using neutron reflectivity. FindingsFilm formation is shown to depend on surfactant tail length, with thicker films forming for surfactants with longer hydrophobic tails. The surfactant headgroup structure affects counterion binding to the micelles, and in the case of the aromatic headgroups, the headgroup affects the extent of micellar growth when polymer is added. Films with the greatest mesostructural ordering were grown using hexadecylpyridinium bromide surfactants.

Structure–Activity Relationship Study of Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors

The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.

Genome-Wide Association Study and Pathway-Level Analysis of Tocochromanol Levels in Maize Grain

Tocopherols and tocotrienols, collectively known as tocochromanols, are the major lipid-soluble antioxidants in maize (Zea mays L.) grain. Given that individual tocochromanols differ in their degree of vitamin E activity, variation for tocochromanol composition and content in grain from among diverse maize inbred lines has important nutritional and health implications for enhancing the vitamin E and antioxidant contents of maize-derived foods through plant breeding. Toward this end, we conducted a genome-wide association study of six tocochromanol compounds and 14 of their sums, ratios, and proportions with a 281 maize inbred association panel that was genotyped for 591,822 SNP markers. In addition to providing further insight into the association between ZmVTE4 (γ-tocopherol methyltransferase) haplotypes and α-tocopherol content, we also detected a novel association between ZmVTE1 (tocopherol cyclase) and tocotrienol composition. In a pathway-level analysis, we assessed the genetic contribution of 60 a priori candidate genes encoding the core tocochromanol pathway (VTE genes) and reactions for pathways supplying the isoprenoid tail and aromatic head group of tocochromanols. This analysis identified two additional genes, ZmHGGT1 (homogentisate geranylgeranyltransferase) and one prephenate dehydratase parolog (of four in the genome) that also modestly contribute to tocotrienol variation in the panel. Collectively, our results provide the most favorable ZmVTE4 haplotype and suggest three new gene targets for increasing vitamin E and antioxidant levels through marker-assisted selection.

Structure–Activity Relationship Studies of Argiotoxins: Selective and Potent Inhibitors of Ionotropic Glutamate Receptors

Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors.

Functional characterization of long-chain prenyl diphosphate synthases from tomato

The electron transfer molecules plastoquinone and ubiquinone are formed by the condensation of aromatic head groups with long-chain prenyl diphosphates. In the present paper we report the cloning and characterization of two genes from tomato (Solanum lycopersicum) responsible for the production of solanesyl and decaprenyl diphosphates. SlSPS (S. lycopersicum solanesyl diphosphate synthase) is targeted to the plastid and both solanesol and plastoquinone are associated with thylakoid membranes. A second gene [SlDPS (S. lycopersicum solanesyl decaprenyl diphosphate synthase)], encodes a long-chain prenyl diphosphate synthase with a different subcellular localization from SlSPS and can utilize geranyl, farnesyl or geranylgeranyl diphosphates in the synthesis of C45 and C50 prenyl diphosphates. When expressed in Escherichia coli, SlSPS and SlDPS extend the prenyl chain length of the endogenous ubiquinone to nine and ten isoprene units respectively. In planta, constitutive overexpression of SlSPS elevated the plastoquinone content of immature tobacco leaves. Virus-induced gene silencing showed that SlSPS is necessary for normal chloroplast structure and function. Plants silenced for SlSPS were photobleached and accumulated phytoene, whereas silencing SlDPS did not affect leaf appearance, but impacted on primary metabolism. The two genes were not able to complement silencing of each other. These findings indicate a requirement for two long-chain prenyl diphosphate synthases in the tomato.

Illuminating Ionotropic Glutamate Receptors: Characterization of Fluorescent Antagonists Based on Polyamine Toxins

Ionotropic glutamate (iGlu) receptors, including the NMDA and AMPA subfamilies, mediate fast excitatory synaptic transmission in the mammalian central nervous system. NMDA and AMPA receptors play critical roles in learning and memory and are implicated in multiple neurological and psychiatric diseases. Argiotoxins (exemplified by the prototypical ArgTX-636) are so-called polyamine toxins isolated from the venom of the orb weaver spider Argiope lobata. Argiotoxins consists of an aromatic head group coupled via an amino acid linker to a polyamine moiety and act as open-channel blockers of the iGlu receptor ion channel with nanomolar affinity. Structure-activity studies of synthetic argiotoxin analogs have shown that modification of the polyamine tail can tweak NMDA versus AMPA selectivity (REF NELSON ET AL). Furthermore, the aromatic head group can tolerate substantial modification without loss of affinity.The aim of the present study is to develop NMDA- and AMPA selective argiotoxin analogs containing fluorescent moieties to enable imaging studies of native iGlu receptors and to serve as potential FRET donor or acceptor ligands. Specifically, a series ArgTX-636 analogs with fluorescein, coumarin and boron-dipyrromethene (BODIPY) derived fluorophores incoporated at or replacing the headgroup moiety were synthesized and characterized at recombinant AMPA and NMDA receptors expressed in Xenopus Laevis oocytes (GluA1 and GluN1/2A, respectively). Several analogs were found to posses high-affinity NMDA and/or AMPA receptor binding while maintaining desirable fluorescent properties.

Synthesis and photocatalytic property of gold nanoparticles by using a series of bolaform Schiff base amphiphiles

Gold nanoparticles were synthesized via a series of bolaform amphiphiles with hydrophilic ethyleneamine spacers and aromatic headgroups at a liquid–liquid interface. By stirring the aqueous solution containing AuCl4− ions with the chloroform solution of bolaform amphiphile, AuCl4− ions were transferred into the organic phase and reduced to gold nanoparticles. Spectral and morphological measurements indicated that these bolaform amphiphiles could serve as both capping and reducing agents. Different gold nanostructures could be obtained depending on the different spacers, headgroups of bolaform amphiphiles and the molar ratios of amphiphile to AuCl4− ions. The photocatalytic properties of as-made gold nanoparticles on the degradation of methyl orange indicated that the substituted groups and molecular structures in the amphiphiles indeed played an important role in changing the sizes of as-made gold nanoparticles and subsequently regulating their catalytic behaviors. The present work gave an original investigation of synthesis and regulation of gold nanostructures by utilizing bolaform amphiphiles with different substituted headgroups and spacers.

Supramolecular Assembly and Headgroup Effect in Interfacial Organized Films (II): A Study of Some Single Chain Amphiphiles

Some single chain Schiff bases amphiphiles with different substituted headgroups have been designed and their interfacial phase behaviors and coordination with Cu(II) ions were investigated. It has been found that depending on the size of aromatic headgroups, the formed nanostrucures showed obvious differences, indicating different aggregation behaviors in the Langmuir-Blodgett films. The spreading Cu(II)-coordinated films could be transferred and subsequently characterized by spectral methods and morphological measurement. In addition, during the coordination process of ligand with Cu(II) ions in organized molecular films, some conformational change of long alkyl chains was observed. The present work showed clearly the headgroup effect of amphiphiles on regulating the aggregation behaviors in Langmuir-Blodgett films.

Successive coordination of palladium(II)-ions and terpyridine-ligands to a pyridyl-terminated self-assembled monolayer on gold

The deposition of palladium on a novel, reversibly protonatable, pyridyl-terminated self-assembled monolayer on gold substrates has been studied by X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure spectroscopy (NEXAFS spectroscopy) and time of flight-secondary ion mass spectrometry (ToF-SIMS). For this purpose, 12-(pyridin-4-yl)dodecane-1-thiol, consisting of a surface-active head group, an unfunctionalized hydrocarbon backbone and a terminal pyridyl group, has been synthesized and deposited on gold surfaces. Coordination of Pd(II) ions to the pyridyl group was examined. Furthermore, a reversible protonation/deprotonation cycle has been applied, and the relation between protonation and the amount of complexed palladium was studied. Investigation of the SAM by angle-resolved NEXAFS spectroscopy revealed the aliphatic backbone to be preferentially upright oriented with the aromatic head group being not preferentially oriented. The palladium layer was further coordinated with a CF3-labeled terpyridine ligand in order to prove the accessibility of the Pd(II) ions to further complexation and the platform useful for deposition of further layers toward a multi-layered system.

Enthalpy measurements for the formation of salt-induced wormlike micelles using isothermal titration microcalorimetry

A simple yet novel method, isothermal titration microcalorimetry (ITC), was employed to determine the enthalpy change of salt-induced wormlike micelle formation. The observed changes in molar enthalpy of 1-hexadecyl-3-methylimidazolium bromide (C 16mimBr), sodium tosylate (NaTos) and sodium salicylate (NaSal) in aqueous solutions have been measured. The transformation enthalpy change from spherical micelle to wormlike micelle (Δ H tra) has been obtained from the simulation method based on the microcalorimetric data. Then the enthalpy change of wormlike micelle formation (Δ H w) was obtained using a suitable cycle which was closed by the enthalpy change of micelle formation (Δ H m) and the transformation enthalpy change (Δ H tra). The value of Δ H w indicated that the wormlike micelle formation in C 16mimBr/NaTos system was exothermic while it was endothermic in C 16mimBr/NaSal system. The planar structure of the salicylate anion and the π–π interaction between the salicylate anion and the aromatic headgroup of C 16mimBr may attribute to this difference. Moreover, the technique presented here to obtain Δ H w could be extended to other salt-induced wormlike micelle systems.

Voltage‐dependent and ‐independent block of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor channels

Polyamine-containing toxins and synthetic dicationic derivatives of adamantane and phenylcyclohexyl selectively antagonize Ca(2+)-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor channels. These compounds demonstrate voltage-dependent open-channel block and are trapped by closed channels. In this study, we describe an alternative mechanism of non-competitive AMPA receptor inhibition caused by 9-aminoacridine and some of its derivatives. These compounds exhibit similar potency against Ca(2+)-permeable and Ca(2+)-impermeable AMPA receptors. The inhibition is largely voltage-independent, binding and unbinding do not require presence of agonist. We conclude that 9-aminoacridine binds to a shallow site in the AMPA receptor, which is located above the activation gate. A comparison of three-dimensional structures of the antagonists suggests that the 'V-like' shape of the hydrophobic headgroup favors voltage-dependent binding to the deep site in the channel pore, whereas the compounds possessing flat aromatic headgroups preferably bind to the shallow site. The characterization of the novel mechanism of AMPA receptor channel antagonism opens a way to develop a new family of pharmacological agents, which can be of scientific and practical importance.

Catalytic Reactions of the Homogentisate Prenyl Transferase Involved in Plastoquinone-9 Biosynthesis

Homogentisate solanesyl transferase (HST) catalyzes the prenylation and decarboxylation of homogentisate to form 2-methyl-6-solanesyl-1,4-benzoquinol, the first intermediate in plastoquinone-9 biosynthesis. In vitro, HST from Spinacia oleracea L., Arabidopsis thaliana, and Chlamydomonas reinhardtii were all found to use not only solanesyl diphosphate but also short chain prenyl diphosphates of 10-20 carbon atoms as prenyl donors. Surprisingly, with these donors, prenyl transfer was largely decoupled from decarboxylation, and thus the major products were 6-prenyl-1,4-benzoquinol-2-methylcarboxylates rather than the expected 2-methyl-6-prenyl-1,4-benzoquinols. The 6-prenyl-1,4-benzoquinol-2-methylcarboxylates were not substrates for HST-catalyzed decarboxylation, and the enzyme kinetics associated with forming these products appeared quite distinct from those for 2-methyl-6-prenyl-1,4-benzoquinol formation in respect of catalytic rate, substrate K(m) value, and the pattern of inhibition by haloxydine, a molecule that appeared to act as a dead end mimic of homogentisate. These observations were reconciled into a simple model for the HST mechanism. Here, prenyl diphosphate binds to HST to form at least two alternative complexes that go on to react differently with homogentisate and prenylate it either with or without it first being decarboxylated. It is supposed that solanesyl diphosphate binds tightly and preferentially in the mode that compels prenylation with decarboxylation.

Simulation of Structure, Orientation, and Energy Transfer between AlexaFluor Molecules Attached to MscL

Measurements of time-resolved fluorescence anisotropy and fluorescence resonance energy transfer are finding many applications in the study of biological macromolecules as they enable structural properties of the host molecules to be determined in their natural environment. A difficulty in interpreting these experiments is that they both require knowledge of the relative orientation of the fluorophores, a property that is almost impossible to measure. Here we conduct simulations of AlexaFluor488 and AlexaFluor568 attached to two sites on the membrane channel MscL to provide an alternative mechanism for determining the likely configurations and orientational freedom of the fluorophores, as well as the most likely value of the orientation factor κ2 for energy transfer between them. The fluorophores are relatively mobile, and are found to be more so when immersed in bulk water than when they interact with the lipid membrane. The fluorophores never insert deeply into the lipid, despite their hydrophobic linkers and aromatic headgroup structures. Properties such as the fluorescence anisotropy decay can be predicted from simulations of the fluorophores in bulk water that closely match experimental data. In contrast, when the fluorophores were attached to the large MscL protein it was difficult to sample all the possible configurations of the fluorophores due to the computational time required. While this approach is likely to provide useful data on solvent-accessible fluorophores attached to small proteins, simulations lasting >50ns or the use of biasing forces are required to accurately predict orientation factors for use in energy transfer experiments on larger membrane-bound proteins.

Molecular recognition and physicochemical properties in the discovery of selective antibacterial minor groove binders

AbstractThe polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pKa of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs. Copyright © 2008 John Wiley & Sons, Ltd.