Optimal Chain Length Research Articles

Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core

Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM; reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.

Oligo(l-glutamic acids) in Calcium Phosphate Precipitation: Chain Length Effect.

The understanding of calcium phosphate precipitation is of major interest in different fields of science, including medicine, biomaterials, and physical chemistry. The presence of additive biomacromolecules has been known to influence various stages of the precipitation process from nucleation to crystal growth. In the current work, well-defined sequences of short, negatively charged peptides, oligo(l-glutamic acids), were utilized as a model, inspired by contiguous sequences of acidic amino acids in natural biomineralization proteins. The precipitate morphology and phases, the element time profile in solution and in the precipitates, as well as the kinetics during the precipitation process were analyzed to explain the effect of these short peptides on calcium phosphate precipitation. The results show that peptides can delay the phase transformation of an amorphous precursor phase to hydroxyapatite and that there is an optimal chain length for this effect at a given concentration of peptide. This study is the first part of a two-part series and is followed by a subsequent work to reveal the mechanism by which these short peptides influence the calcium phosphate precipitation.

Harnessing the immunogenicity of peptide-based glycoconjugate vaccines

Abstract Glycoconjugate vaccines provide enormous health benefits globally, although they have been less successful in some populations at high risk for developing disease. In most cases, conjugation of the sugar antigen to the carrier protein has been done empirically with little attention on variables critical for the immune response. Recent findings offer new insights on their mechanism of actionsuggesting that carbohydrate presentation to T cells by antigen-presenting cells may enhance the efficacy of antibody responses and suggesting the use of a peptide instead a whole protein as carrier. Herein, we have developed a platform to optimize glycopeptide vaccine design by determining optimal polysaccharide chain length, peptide composition and conjugation site. We first determined that the use of a full-length polysaccharide induce optimal immunogenicity. We have further demonstrated the role of the peptide linker and the conjugation site in enhancing both the conjugation efficiency and the immune response to vaccines. When immunizing mice, we found—using GBSIII CPS as a model—that these glycoconjugates induced full protection in the challenge model. We extended the platform to develop a prototype vaccine for Francisella tularensis, coupling the O polysaccharide to an optimized peptide and observing significant protection. Remarkably, protection with a glycoconjugate vaccine against F. tularensis has been only recently obtained by using a genetically enlarged polysaccharide. The results show that peptide glycoconjugate vaccines provide a strong protection against bacterial challenges. We are currently applying the acquired knowledge to create more efficacious and longer lasting immunity to glycoconjugate vaccines.

Synthesis and Herbicidal Activity of Trifluoromethyl‐Substituted Phenyl Alkyl Ketoxime Esters of Bispyribac

AbstractA series of new trifluoromethyl‐substituted phenyl alkyl ketoxime esters of Bispyribac were synthesized as potential herbicides. All synthesized compounds were characterized by nuclear magnetic resonance (NMR) spectroscopy and high‐resolution mass spectrometry (HRMS). Sprout method and foliar spray method were used to study the herbicidal activity of the synthesized compounds. Among all synthesized compounds, compound 3 (4‐trifluoromethylphenyl n‐butyl ketoxime ester of Bispyribac) exhibits the highest herbicidal activity against Echinochloa crusgalli (L.) Beauv with median effect dose (ED50) of 1.7 μg/mL in pre‐emergence herbicidal activity study. The structure‐activity relationship analysis indicates that trifluoromethyl substitution on the phenyl group exhibits better activity than methoxy and methyl substitution on the phenyl group. The alkyl chain length also affects the activity significantly and the optimal alkyl chain length is four among the tested compounds. However, the substitution position of trifluoromethyl exhibits very limited influence on the activity. In post‐emergence herbicidal activity study, compound 3 (ED90 69.1056 g/hm2) exhibits better herbicidal activity against Echinochloa crusgalli (L.) Beauv than Pyribenzoxim (ED90 99.0810 g/hm2). Moreover, compound 3 exhibits better safety to hybrid rice variety II you 084 and rice variety Nanjing 44 than Pyribenzoxim in crop safety study. Compound 3 may serve as a lead compound for future herbicide discovery.

Eicosapentaenoic acid (EPA) has optimal chain length and degree of unsaturation to inhibit oxidation of small dense LDL and membrane cholesterol domains as compared to related fatty acids in vitro

BackgroundOxidation of small dense low-density lipoprotein (sdLDL) and membranes is causally related to atherosclerosis. The omega-3 fatty acid (FA) eicosapentaenoic acid (EPA, 20:5, ω-3) significantly reduced oxidized LDL in patients with hypertriglyceridemia by unknown mechanisms. We compared EPA effects to related FAs of varying chain length and unsaturation on oxidation of sdLDL and model membranes, and on cholesterol crystal domains. We compared EPA to the FAs: stearic (SA, 18:0), oleic (OA, 18:1, ω-9), linoleic (LA, 18:2, ω-6), alpha-linolenic (ALA, 18:3, ω-3), eicosanoic (EA, 20:0), eicosatrienoic (ETE, 20:3, ω-3), arachidonic (AA, 20:4, ω-6), docosapentaenoic (DPA, 22:5, ω-3), and docosahexaenoic (DHA, 22:6, ω-3). MethodsHuman sdLDL or model membranes of cholesterol and 1,2-Dilinoleoyl-sn-glycero-3-phosphocholine [18:2(cis)PC or DLPC] were preincubated with FAs followed by copper-induced oxidation. Malondialdehyde (MDA) or lipid hydroperoxides (LOOH) levels measured oxidation; small-angle X-ray diffraction assessed cholesterol domain formation. ResultsAfter 40 min, EPA reduced MDA levels 70% compared to vehicle (p < 0.001). Lesser inhibition was observed with DHA, DPA, ETE, and ALA (33%, 34%, 32%, and 16%, respectively; all p < 0.001 versus vehicle). Similar relative FA effects were observed in model membranes where EPA more substantially inhibited cholesterol crystal domain formation. ConclusionWe observed relationships between hydrocarbon length and unsaturation with antioxidant activity and membrane cholesterol domain formation. EPA had the most favorable molecular structure, likely contributing to membrane stability, improved lipoprotein clearance, and reduced inflammation. General significanceInsight is provided into FA hydrocarbon length and unsaturation relationships with antioxidant activity in lipoproteins and membranes, and cholesterol crystal domains formation.

Exploiting σ-hole interaction to design small uncharged ligand molecules to stabilize G-quadruplex-DNA: a computational study.

Small neutral seleno molecules were designed to stabilize G-quadruplex-DNA to accelerate the death of cancer cells. A new approach was considered in this study to design new ligands to stabilize G-quadruplex-DNA using the non-covalent σ-hole interaction. The systematic study has been performed with ligands in the absence and presence of σ-hole interaction to stabilize G-tetrad. Fluorine-substituted seleno ligands interact with the bases of G-quadruplex strongly with the σ-holes present in the ligands. The binding of the fluorinated ligands FSeCF2SeCF2 SeF2(4) (~75.0kcal/mol) is stronger than that of BRACO-19 (~70.0kcal/mol) calculated at the same level of theory with G-tetrad. It is reported that BRACO-19 is employed to inhibit the enzymatic activity of telomerase. The calculated results also reveal the importance of optimum chain length of ligands to achieve a better binding ability with G-tetrad. The MESP calculations and AIM analysis corroborate the trends of binding of these ligand molecules with G-quadruplexes. The small neutral molecules possess considerable advantage to pass through the lipid bilayer of the cell membrane by passive transport and are of choice in biological research and for clinical trials. Graphical AbtractSmall neutral ligands with σ-holes can stabilize G-quadruplex to inhibit enzymatic activity of telomerase.

Adopting Mixed Sulfur and Selenium Chalcogenides As High Energy Density Copolymer Cathodes in Rechargeable Sodium Metal Systems

The ever increasing demand for energy storage has encouraged exploration of battery systems with higher energy density and lower cost than Li-ion batteries.1 This work reveals the very first demonstration of a room temperature, sodium/polymeric mixed-chalcogenide battery. The chemistry is enabled by crosslinking of sulfur and selenium, which maintains the elemental mixture in long chains instead of crystalline rings, for a mechanistically different conversion cathode. Room temperature Li-S batteries, which boast ultra-high energy density (~2600 Wh/kg) and low cost/highly abundant sulfur, are expected to succeed the intercalation Li-ion battery (<400 Wh/kg), but to-date deliver impractical cycle life due to active material dissolution. The novel chain assembly provided by crosslinking prevents this behavior, enabling extensive cycle life.2 Herein the crosslinker type and molecular ratio are modulated for optimal chain length and performance. Furthermore, selenium delivers 20 orders of magnitude greater electrical conductivity than sulfur.3 The atomic ratio of sulfur to selenium is modulated for a balance of electrical conductivity and energy density. Notably, these cathodes are simplistically processed at temperatures below 200 ˚C. The crosslinked, mixed chalcogenide cathodes are paired with metallic sodium anodes, that are 3 orders of magnitude more abundant than lithium metal,1 and exhibit favorable plating behavior in the system-prescribed, ether-based electrolytes.4 This full cell touts a theoretical energy density of ~1000 Wh/kg and effective incorporation of highly abundant raw materials. Hong, X.; Mei, J.; Wen, L.; Tong, Y.; Vasileff, A. J.; Wang, L.; Liang, J.; Sun, Z.; Dou, S. X., Nonlithium Metal–Sulfur Batteries: Steps Toward a Leap. Advanced Materials 0 (0), 1802822.Simmonds, A. G.; Griebel, J. J.; Park, J.; Kim, K. R.; Chung, W. J.; Oleshko, V. P.; Kim, J.; Kim, E. T.; Glass, R. S.; Soles, C. L.; Sung, Y.-E.; Char, K.; Pyun, J., Inverse Vulcanization of Elemental Sulfur to Prepare Polymeric Electrode Materials for Li–S Batteries. ACS Macro Letters 2014, 3 (3), 229-232.Abouimrane, A.; Dambournet, D.; Chapman, K. W.; Chupas, P. J.; Weng, W.; Amine, K., A New Class of Lithium and Sodium Rechargeable Batteries Based on Selenium and Selenium–Sulfur as a Positive Electrode. Journal of the American Chemical Society 2012, 134 (10), 4505-4508.Seh, Z. W.; Sun, J.; Sun, Y.; Cui, Y., A Highly Reversible Room-Temperature Sodium Metal Anode. ACS Central Science 2015, 1 (8), 449-455.

Potential of long-chain oxymethylene ether and oxymethylene ether-diesel blends for ultra-low emission engines

Oxymethylene ether (OMEn) has recently drawn high attention due to its high pollutant emission reduction potential and the sustainable synthesis pathways involving carbon capture and renewable hydrogen. In this work, five blends of OMEn in diesel fuel in addition to pure OME3-5 and diesel fuel as reference were investigated in a single cylinder engine. Each OMEn-Diesel blend was prepared with a different chain length, ranging from OME1 to OME5. The blending ratio of OMEn in fossil diesel fuel was set to 35 vol%, corresponding to a ∼23.5% diesel fuel substitution on a heating value basis. We find that OMEn contributes to improved oxidation conditions, resulting in a more complete combustion compared to conventional diesel fuel operation. This is reflected by reduced emissions of unburned hydrocarbons and carbon monoxide (up to 90%), higher burned mass fractions after the main combustion phase, higher indicated efficiencies (up to +3%) and lower exhaust gas temperatures (up to −70 °C). Furthermore, while pure OMEn burns soot-free, a significant soot reduction was measured for the OMEn-Diesel blends.Based on the findings of this work, it is concluded that from a combustion and emission point of view, the OMEn chain length is of minor importance for applications where OMEn is blended with diesel fuel up to a ratio of 35 vol%. Thus, the main considerations for an optimal OMEn chain length range should focus on aspects like fuel properties and OMEn synthesis. In this regard, a simple and efficient synthesis process (e.g. synthesis of OME1) must be weighed up against favorable fuel properties of the synthesis product (e.g. OME3-5). Hence, bearing in mind that OMEn is not a drop-in fuel and will always demand a dedicated engine, the preference of long chain OMEn over OME1 is not straight forward and strongly depends on the application.

Dissipative Particle Dynamics Simulation on Bonding Reaction Between Surface Modified Nanoparticles

A simulation study was carried out by using dissipative particle dynamics (DPD) method to explore the effects of properties of coating chains, such as length, density, rigidity of polymer chains, as well as the distance between nanoparticles on bonding reaction of coating chains grafted onto nanoparticles. The results show that bonding ratios of coated chains strongly depend on the length and density of coating chains. For nanoparticles with different coating densities, the optimum chain length for bonding reaction are varied. The rigidity of coating chains exhibits vigorous effects on bonding reaction that highly depends on chain lengths. DPD simulation can be used to study the bonding reaction between coated nanoparticles, which may help experimental synthesis of nanocomposites with excellent properties.

Carbohydrate-Based Polymeric Surfactants for Chiral Micellar Electrokinetic Chromatography (CMEKC) Coupled to Mass Spectrometry.

Polymeric surfactants (molecular micelles, MoMs) with a variety of chiral head groups and chain lengths may be the most promising chiral selectors when used for sensitive detection of chiral compounds in micellar electrokinetic chromatography-mass spectrometry (MEKC-MS). Various carbohydrate-based MS compatible surfactants with phosphate and sulfate head groups have been recently synthesized in our laboratory for its application in CMEKC-MS. In this chapter, we illustrate that the synthesized glucopyranoside-based MoMs are fully compatible with electrospray ionization MS and can be successfully used as a chiral selector for high-throughput screening of multiple chiral compounds using MRM mode in CMEKC-MS/MS experiments. This chapter describes in detail synthesis and utility of α- and β-glucopyranoside-based polymeric surfactant with two different chain lengths and head groups. The presented examples optimize the effect of appropriate millimolar concentration of monomer sugar surfactants required for polymerization as it affects the separations of acidic and basic compounds. Under the optimized concentration of the monomer needed for polymerization (i.e., an equivalent monomer concentration of MoMs), the superiority of MEKC-MS over MEKC-UV is evident. Structurally similar basic drugs with the difference in hydrophobicity are first tested in MEKC-MS to find the optimum head group and optimum chain length with the aim for developing a widely applicable polymeric glucopyranoside-based surfactant. The partial enantioresolution of several structurally similar basic compounds is significantly improved when switching from one head group to another head group of the glucopyranoside MoMs. Thus, complementary separations using poly-N-β-D-SUGP versus poly-N-β-D-SUGS were seen. This phenomenon also exists when comparing the MoMs, which differ in an anomeric configuration such as poly-N-α-D-SUGP and poly-N-β-D-SUGP.

Designing nanoporosity in a swollen polymer for the controlled release of a highly volatile fragrance

AbstractControlling the fragrance release profile, especially the highly volatile top note, can prolong the desired scent of the fragrance. Here, the porosity of a swollen cross‐linked polyurethane acrylate (PUA) polymer, which is tuned by the length of a modulator, can influence the evaporation rate of the top note. In particular, the evaporation rate of benzyl acetate (BA), a common top note, is reduced by a factor of 6.5 (from 134 to 17 mg m–2 min–1) when BA is released from the best‐performing PUA against a reservoir of BA. The average diameter of an opening in the fragrance‐loaded PUA is ~6 nm, as determined by the thermoporosimetry approach. Such a pore size can effectively control the evaporation rate of BA, as predicted by the theoretical model, which reveals that a pore diameter of &lt;16 nm is required. Computational modelling reveals the optimal chain length for a modulator used for the sustained released of fragrance, confirming the experimental data. Finally, BA continues to be released from the PUA matrix for a prolonged period, even after 3 months, whereas the same quantity of BA would completely evaporate after 1 week in the absence of PUA matrix. Approximately 50wt% of BA remains after 60 days, making it one of the best techniques in sustaining the release of a top note.

Isoprenoid Amide Bisphosphonates As a Novel Class of Geranylgeranyl Diphosphate Synthase Inhibitors

Abstract Multiple myeloma is characterized by the production of monoclonal protein by clonal plasma cells and is a malignancy inherently susceptible to agents that disrupt protein homeostasis. We have previously demonstrated that targeting the geranylgeranylation of Rab GTPases is a novel mechanism by which to induce myeloma cell apoptosis via disruption of intracellular monoclonal protein trafficking and induction of the unfolded protein response pathway. Our previous efforts have focused on the development of novel triazole isoprenoid bisphosphonates as inhibitors of the enzyme geranylgeranyl diphosphate synthase (GGDPS). GGDPS is responsible for the synthesis of the 20-carbon isoprenoid (GGDP) that is utilized in protein geranylgeranylation reactions. Extensive structure-function analysis of the triazole-based inhibitors has revealed that both chain length and olefin stereochemistry have significant impact on inhibitor potency. Previous reports have utilized triazoles as bioisoteres of amides and we hypothesized that the converse might be true as well; namely that amides analogous to the triazoles would have efficacy as GGDPS inhibitors. To this end, we have prepared a number of novel isoprenoid amide bisphosphonates as potential GGDPS inhibitors. These new compounds were prepared from bisphosphonate 1 through a short reaction sequence including chain extension by conjugate addition of nitromethane, reduction to the amine 2, amide formation through reaction with a variety of carboxylic acids, and final hydrolysis of the phosphonate esters to obtain the salts 3. These analogues differed with respect to chain length (ranging from bishomoprenyl- to bishomogeranyl-length), olefin stereochemistry (E vs Z), absence of the proximal olefin (i.e., citronellyl) as well as the stereochemistry of the citronellyl derivatives (R vs S). All of the novel compounds were subjected to in vitro enzyme assays with GGDPS as well as for the related enzymes farnesyl diphosphate synthase, farnesyl transferase and geranylgeranyl transferase I, and IC50's were determined. Cellular activity in human myeloma cell lines (RPMI-8226, MM.1S) was assessed via immunoblot analysis of representative prenylated proteins. In addition, ELISA of intracellular levels of lambda light chain (a marker of disruption of Rab geranylgeranylation) was performed. These studies reveal that similar to the previously reported triazoles, both chain length and olefin stereochemistry have significant effects on GGDPS inhibitory activity. Extending the chain length from the bishomoprenyl length to the bishomogeranyl length increased cellular activity 50-fold: the lowest effective concentration (LEC) is 50 μM for the bishomoprenyl compound and 1 μM for the bishomogeranyl compound. Furthermore, changing the olefin stereochemistry to the bishomoneryl form (i.e., the Z-configuration), further enhanced the potency to an LEC of 0.5 μM. Interestingly, the stereochemistry of the citronellyl derivatives were found to have a significant impact on activity with the R-enantiomer being 10-fold more potent than the S-enantiomer (LEC of 5 μM vs 50 μM respectively). Enzyme assay studies confirmed the specificity of these agents as GGDPS inhibitors. In conclusion, these studies establish a novel family of amide isoprenoid bisphosphonates as GGDPS inhibitors with activity against myeloma cells. Further structure-function analysis will better define the optimal chain length and stereochemistry to maximize potency and enable future in vivo studies assessing efficacy as anti-myeloma therapy. Figure. Figure. Disclosures Wiemer: Terpenoid Therapeutics, Inc: Other: Founder. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Optimizing Spacer Length for Positioning Functional Groups in Bio-Waste

The goal of this study was to determine the optimal chain length needed for tethering functional groups on bio-wastes. The purpose of modifying the surface of bio-waste is to improve their affinity for phenols. To this end, four different aminated green tea leaves, with the amine group located at the end of 6, 8, 10, and 12 carbons were synthesized. Green approaches to functionalization lead to fewer reactive sites. Optimizing spacer length is one way to ameliorate this. The aminated tea leaves were prepared by a tosylation reaction followed by displacement with a diamine used in excess. The tea leaves with the amine at the end of six carbons proved to have the best ability to remove 2-chlorophenol (2-CP) from its aqueous solution. It was at least 3–4 times better than native spent tea leaves. The mechanism by which the phenol was removed proved to be primarily an acid–base reaction followed by H-bonding and dipole–dipole interactions. Because of the acid–base interactions, the relatively low-boiling 2-CP did not volatilize off the aminated tea leaves enabling recycling. On the other hand, with activated charcoal, the adsorbed 2-CP volatilized almost completely under ambient conditions.

Exploring side-chain length effect on β-phase of polyfluorene derivatives in electrospinning and their optical behavior

Unique coplanar β-conformation of polyfluorene, endowed with long effective conjugated length, is promising to form ordered and oriented structures that can result in improved carrier mobility, polarization emission and excellent spectral stability. Herein, a series of polydiarylfluorenes of different side-chains (PHDPF, PODPF or PNDPF) and poly (9-vinylcarbazole) composite nanofibers were prepared via electrospinning approach. It is observed that β-phase can be obtained in PODPF electrospun nanofibers whereas absent in those of PHDPF and PNDPF systems. It can be demonstrated that the optimal chain length for polydiarylfluorenes to β-conformation is an octyl side chain in electrospinning. In contrast with the electrospun nanofibers, there was no β-phase in the corresponding spin-coated film. For the β-phase electrospun nanofibers, the fluorescence quenching sensitivity on 2, 4-dinitrotoluene (DNT) vapor was obviously higher than that of amorphous electrospun nanofibers and spin-coated film, respectively. Synergistic molecular design and electrospun processing may offer a fascinating strategy for the control of polymer conformation to the adjustment of nano and micro optical devices such as organic fluorescence sensors, lasers and light-emitting diodes.

Understanding Specificity of Glycosaminoglycan Interactions with Proteins

Glycosaminoglycans (GAGs) play key roles in virtually all biologic responses through their interaction with proteins. Generally, GAGs are believed to interact non‐specifically with proteins. The primary reason for this belief is the highly electrostatic nature of their interactions and the fact that only one homogeneous GAG sequence has reached the clinic – the anticoagulant heparin pentasaccharide sequence. Are highly specific GAG–protein interactions so rare? Does nature rely primarily on non‐specificity to mediate the biological roles of GAGs? These questions are of major significance and insights into specificity of GAG–protein interactions may lead to many more GAG sequences reaching the clinic. Yet, a major challenge in understanding these interactions is the massive structural complexity of GAGs. Computational approaches are extremely useful in navigating this challenge and, in some cases, the only avenue to gain comprehensive insight. Computationally, most basic and many advanced questions on GAG–protein interactions can be answered including 1) does my protein bind to GAGs?, 2) where does the GAG bind?, 3) does the protein preferentially recognize a particular GAG type?, 4) what is the most optimal GAG chain length?, 5) what is the structure of the most favored GAG sequence?, 6) is the GAG–protein system ‘specific’, ‘non‐specific’, or a combination of both?, etc. Recent advances in the areas of thrombosis and cancer from our laboratories have led to discoveries of GAG sequences that are highly specific for their protein targets. The results raise the promise that many proteins may recognize GAGs with high specificity and clinically relevant GAG sequences are waiting to be identified.Support or Funding InformationP01 HL107152R01 HL090586R25 HL128639This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anisotropic reversed micelles with fluorocarbon-hydrocarbon hybrid surfactants in supercritical CO2.

Previous work (M. Sagisaka, et al. Langmuir 31 (2015) 7479-7487), showed the most effective fluorocarbon (FC) and hydrocarbon (HC) chain lengths in the hybrid surfactants FCm-HCn (sodium 1-oxo-1-[4-(perfluoroalkyl)phenyl]alkane-2-sulfonates, where m = FC length and n = HC length) were m and n = 6 and 4 for water solubilization, whereas m 6 and n 6, or m 6 and n 5, were optimal chain lengths for reversed micelle elongation in supercritical CO2. To clarify why this difference of only a few methylene chain units is so effective at tuning the solubilizing power and reversed micelle morphology, nanostructures of water-in-CO2 (W/CO2) microemulsions were investigated by high-pressure small-angle neutron scattering (SANS) measurements at different water-to-surfactant molar ratios (W0) and surfactant concentrations. By modelling SANS profiles with cylindrical and ellipsoidal form factors, the FC6-HCn/W/CO2 microemulsions were found to increase in size with increasing W0 and surfactant concentration. Ellipsoidal cross-sectional radii of the FC6-HC4/W/CO2 microemulsion droplets increased linearly with W0, and finally reached ∼39 Å and ∼78 Å at W0 = 85 (close to the upper limit of solubilizing power). These systems appear to be the largest W/CO2 microemulsion droplets ever reported. The aqueous domains of FC6-HC6 rod-like reversed micelles increased in size by 3.5 times on increasing surfactant concentration from 35 mM to 50 mM: at 35 mM, FC6-HC5 formed rod-like reversed micelles 5.3 times larger than FC6-HC6. Interestingly, these results suggest that hybrid HC-chains partition into the microemulsion aqueous cores with the sulfonate headgroups, or at the W/CO2 interfaces, and so play important roles for tuning the W/CO2 interfacial curvature. The super-efficient W/CO2-type solubilizer FC6-HC4, and the rod-like reversed micelle forming surfactant FC6-HC5, represent the most successful cases of low fluorine content additives. These surfactants facilitate VOC-free, effective and energy-saving CO2 solvent systems for applications such as extraction, dyeing, dry cleaning, metal-plating, enhanced oil recovery and organic/inorganic or nanomaterial synthesis.

Structure–Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents

Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.

Lysine Possesses the Optimal Chain Length for Histone Lysine Methyltransferase Catalysis

Histone lysine methyltransferases (KMTs) represent an important class of epigenetic enzymes that play essential roles in regulation of gene expression in humans. Members of the KMT family catalyze the transfer of the methyl group from S-adenosylmethionine (SAM) to lysine residues in histone tails and core histones. Here we report combined MALDI-TOF MS experiments, NMR analyses and quantum mechanical/molecular dynamics studies on human KMT-catalyzed methylation of the most related shorter and longer lysine analogues, namely ornithine and homolysine, in model histone peptides. Our experimental work demonstrates that while lysine is an excellent natural substrate for KMTs, ornithine and homolysine are not. This study reveals that ornithine does not undergo KMT-catalyzed methylation reactions, whereas homolysine can be methylated by representative examples of human KMTs. The results demonstrate that the specificity of KMTs is highly sensitive to the side chain length of the residue to be methylated. The origin for the degree of the observed activities of KMTs on ornithine and homolysine is discussed.

Synthesis of regioselectively acylated quercetin analogues with improved antiplatelet activity

The aim of the present study was to report on a complete synthetic approach, namely benzylation-hydrolysis-acylation‑hydrogenation, to the synthesis of regioselectively acylated quercetin analogues using low‑cost rutin as a starting material. Three quercetin analogues, quercetin‑3‑O‑propionate (Q‑pr), quercetin‑3‑O‑butyrate (Q‑bu) and quercetin‑3‑O‑valerate (Q‑va), containing 3‑, 4‑ and 5‑carbon aliphatic acyl chains, respectively, were synthesized and characterized with 1H nuclear magnetic resonance (NMR), 13C NMR and mass spectrometry. Compared with quercetin, all three analogues exhibited improved lipophilicity. The lipophilicity of the analogue increased with increasing acyl chain length. Q‑va exhibited the highest lipophilicity among the three analogues, but a lower water solubility compared with quercetin. By contrast, Q‑pr and Q‑bu exhibited 8.2‑ and 4.7‑fold higher water solubility compared with quercetin, respectively. The invitro and invivo studies demonstrated that Q‑pr and Q‑bu were more effective whereas Q‑va was less effective in inhibiting platelet aggregation compared with quercetin. These results indicated that the water solubility and the lipophilicity of the analogues must be improved in order to achieve higher antiplatelet activity, and an optimal acyl chain length is crucial for the synthesized quercetin analogues to be more effective.

Control of surfactant solution rheology using medium-chain cosurfactants

The rheological properties of surfactant solutions play an important role in their applications. Here we study systematically how different cosurfactants affect the rheological properties of mixed solutions of the anionic surfactant sodium laurylether sulfate (SLES) and the zwitterionic cocoamidopropyl betaine (CAPB). Mixed SLES+CAPB solutions are used in various formulations due to their excellent foaming and cleaning properties. These solutions possess nearly Newtonian behavior and low viscosity. However, the addition of cosurfactants in low concentrations may significantly increase the viscosity of these solutions and even transform them into viscoelastic gels. Here we study systematically a wide range of ionic and nonionic cosurfactants with different head-groups, chain-lengths and structures of the hydrophobic tails (linear, branched, double bonded). We reveal an optimal chain-length of 8–10 carbon atoms of the cosurfactant molecules which ensures the highest viscoelasticity of the triple SLES+CAPB+cosurfactant solutions. Cationic cosurfactants and nonionic ones with small head-group (e.g. fatty alcohols and fatty acids) are most efficient in increasing the solution viscoelasticity. There is a hierarchy in the parameters of the cosurfactant molecules which govern this behavior − most important is the head-group charge, then the chain-length and, finally, the presence of branching and double bonds in the hydrophobic tails. The observed trends are explained with the effect of the cosurfactant molecules on the properties of the entangled wormlike micelles formed in these solutions.