Function Of Hydrophobicity Research Articles

Abstract 2803: Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity

Abstract Auristatins are a class of clinically validated antimitotic agents utilized as payloads in antibody-drug conjugates (ADCs). Auristatins display many of the desirable properties necessary for ADC cytotoxins, such as low nanomolar potency, cell permeability, and activity across multidrug-resistant (MDR+) cell lines. Herein, we report the development of novel auristatins, which have a unique combination of these favorable properties. The hydrophilic monomethyl auristatin F (MMAF) was chosen as the parent structure, and a medicinal chemistry campaign was undertaken to functionalize various sites of the auristatin with hydrophobic moieties in an effort to improve membrane permeability. The structure-activity relationships (SAR) of the new auristatins demonstrated clear trends correlating hydrophobicity, structure, and polarity with permeability and in vitro cytotoxicity. The highest-performing molecules showed a preference for hydrophobic functionalization at the N-terminal dolavaline. The payloads were linked to the C-terminal position of the auristatin with a lysosomally cleavable maleimido-dipeptide linker. Examination of the ADCs revealed low ng/mL activity in CD30+ and CD19+ cell lines in vitro. Anti-CD70 ADCs demonstrated high in vivo efficacy in a 786-O xenograft and complete remissions (CRs) in the efflux-positive renal cell carcinoma model. Anti-CD30 ADCs were dosed in a CD30+ and CD30- admixed Karpas/Karpas-35R xenograft model to demonstrate proof-of-concept in vivo bystander activity. In summary, these novel auristatins showed potential across multiple indications as ADC payloads. Citation Format: Philip N. Moquist, Tim D. Bovee, Andrew B. Waight, Sarah Owen, Jamie A. Mitchell, Margo Zaval, Marsha Quick, Sharsti Sandall, Kim K. Emmerton, Nicole Blesie, Robert P. Lyon, Peter Senter, Svetlana Doronina. Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2803.

Preparation of Cationic Mixed-Mode Acrylamide-Based Monolithic Stationary Phases for Capillary Electrochromatography

A series of amphiphilic macroporous mixed-mode acrylamide-based continuous beds bearing positively charged quaternary ammonium groups is synthesized for capillary electrochromatography (CEC) under variation of the concentration of the cationic monomer in the polymerization mixture. Positively charged mixed-mode monolithic stationary phases are synthesized in pre-treated fused silica capillaries of 100 µm I.D via single step free radical copolymerization of cyclodextrin-solubilized N-tert-butylacrylamide, a hydrophilic crosslinker (piperazine diacrylamide), a hydrophilic neutral monomer (methacrylamide), and a positively charged monomer ([2-(methacryloyloxy)ethyl]trimethyl ammonium methyl sulfate) in aqueous solution containing the lyotropic salt ammonium sulfate as a pore-forming agent. The synthesized monolithic stationary phases contain hydrophobic, hydrophilic, and charged functionalities. They can be employed for the CEC separations of different classes of neutral and charged solutes (with varied polarity) in the reversed-phase mode, in the normal-phase mode, in the ion-exchange mode, in a mixed-mode, or in the hydrophilic interaction liquid chromatography (HILIC) mode. The influence of the concentration of the cationic monomer in the polymerization mixture on retention factor, electroosmotic mobility, and methylene selectivity (αmeth) is studied under isocratic conditions for alkylphenones in the reversed-phase mode by capillary electrochromatography (CEC). Scanning electron microscopy (SEM) micrographs demonstrate that the morphology of the synthesized monoliths (i.e., the domain size) is strongly influenced by the variation of the concentration of the cationic monomer in the polymerization mixture.

Diverse classes of HDAC8 inhibitors: in search of molecular fingerprints that regulate activity.

HDAC8 is one of the crucial enzymes involved in malignancy. Structural explorations of HDAC8 inhibitory activity and selectivity are required. A mathematical framework was constructed to explore important molecular fragments responsible for HDAC8 inhibition. Bayesian classification models were developed on a large set of structurally diverse HDAC8 inhibitors. This study helps to understand the structural importance of HDAC8 inhibitors. The hydrophobic aryl cap function is important for HDAC8 inhibition whereas benzamide moiety shows a negative impact on HDAC8 inhibition. This work validates our previously proposed structural features for better HDAC8 inhibition. The comparative learning between the statistical and intelligent methods will surely enrich future drug design aspects of HDAC8 inhibitors.

PEA/V-SiO2 core-shell structure for superhydrophobic surface with high abrasion performance

Organic/inorganic core-shell nanostructure of PEA/V-SiO2 emulsion has been firstly synthesized along with comparison of conventional SiO2 and pure PEA materials . Their chemical bondings and morphology properties have been observed though characterization methods such as transmission electron microscopy, X-ray photon spectrum and infrared spectrum, etc. The nanoparticle of mean diameter within 200 nm has been obtained that was well dispersed into the pure solvent. After that, the water repelling textile has been prepared to measure the surface contact angle which reached above 151.5°. The super hydrophobic function abrasion resistance is also characterized and such improvement is attributed to the highly entanglements and nanostructure established by PEA/V-SiO2 above the textile surface.

Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines.

Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5‐diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 μg/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

Dynamics of a Water Nanodrop through a Holey Graphene Matrix: Role of Surface Functionalization, Capillarity, and Applied Forcing

Nanoporous graphene has emerged as an excellent material for desalination and water purification. Holey graphene (HG) is a special form of nanoporous graphene, where multilayers of nanoporous graphene get arranged in spatially separated stacks. In this paper, we employ molecular dynamics simulations to unravel the dynamics of a water drop in presence of an applied force F in such holey graphene architecture, which is characterized by the presence of either hydrophilic functionalization (HIF) or hydrophobic functionalization (HOF) of the edges of the holes. For realistic values of F, the consideration of water drop makes the capillary effects important, which in turn interplays with the wettability of the surface functionalization to ensure that the HG with the HOF causes both an enhanced flux and an enhanced permeated water volume. We relate these phenomena to the augmented water-hydrophilic-edge attraction that arrests the dewetting of water from the graphene stacks and slows the speed of water flowing p...

Rice Starch Particle Interactions at Air/Aqueous Interfaces-Effect of Particle Hydrophobicity and Solution Ionic Strength.

Starch particles modified by esterification with dicarboxylic acids to give octenyl succinic anhydride (OSA) starch is an approved food additive that can be used to stabilize oil in water emulsions used in foods and drinks. However, the effects of the OSA modification of the starch particle on the interfacial interactions are not fully understood. Here, we directly measured the packing of films of rice starch granules, i.e., the natural particle found inside the plant, at air/aqueous interfaces, and the interaction forces in that system as a function of the particle hydrophobicity and ionic strength, in order to gain insight on how starch particles can stabilize emulsions. This was achieved by using a combined Langmuir trough and optical microscope system, and the Monolayer Interaction Particle Apparatus. Native rice starch particles were seen to form large aggregates at air/water interfaces, causing films with large voids to be formed at the interface. The OSA modification of the rice starches particles decreased this aggregation. Increasing the degree of modification improved the particle packing within the film of particles at the air/water interface, due to the introduction of inter-particle electrostatic interactions within the film. The introduction of salt to the water phase caused the particles to aggregate and form holes within the film, due to the screening of the charged groups on the starch particles by the salt. The presence of these holes in the film decreased the stiffness of the films. The effect of the OSA modification was concluded to decrease the aggregation of the particles at an air/water interface. The presence of salts, however, caused the particles to aggregate, thereby reducing the strength of the interfacial film.

Template-Free Self-Assembly of Fluorine-Free Hydrophobic Polyimide Aerogels with Lotus or Petal Effect

Aerogels have been widely used in the fields like thermal insulation, energy storage, environmental remediation, catalysis, drug release, sensor, and cosmic dust collection, etc. Hydrophobic functionalization not only determines the surface energy and basic physical properties of the target aerogels but also be critical for their long-term stability due to their highly open-porous structures. However, there is still lack of facial and versatile methodologies for the hydrophobic functionalization of aerogels, especially for the nonsilica ones. Herein, two efficient fluorine-free strategies were developed to synthesize various hydrophobic and even superhydrophobic polyimide (PI) aerogels. First, superhydrophobic PI aerogels with contact angle higher than 150° were fabricated by the segregation self-assembly process between poly[4,4'-(4,4'-isopropylidenediphenoxy)bis(phthalic anhydride)- co- p-phenylene diamine] and poly[biphenyl-3,3',3,4'-tetracarboxylic dianhydride- co-2,2'-dimethylbenzidine] (poly(BPDA-DMBZ)). These PI aerogels exhibited a lotus effect that water droplets could not wet the surface but could easily roll off. Second, various hydrophobic PI aerogels, including the well-documented superhydrophilic PI aerogels derived from DMBZ-BPDA and 4,4'-oxydianiline-BPDA, were synthesized by the density-induced hydrophilicity-hydrophobicity transition approach. These PI aerogels exhibited a petal effect that water droplets on the aerogel surface appeared spherical in shape, which could not roll off even when the aerogel was turned upside down. These two reported strategies might open new and straightforward ways to hydrophobic functionalization of other polymeric aerogel systems.

Reduction of bacterial attachment on hydroxyapatite surfaces: Using hydrophobicity and chemical functionality to enhance surface retention and prevent attachment.

Water-soluble, linear polymers with high-acid functionality are commonly used in oral care formulations to provide benefits such as bioactive complexation and delivery, as well as inhibition of the bacteria deposition and colonization, commonly referred to as 'anti-attachment'. Unfortunately, structure-activity relationship (SAR) studies of these polymers are scarce, thus, a systematic approach to design polymers with a desired property (e.g. anti-attachment) is limited. Multifunctional anti-attachment amphiphilic molecules (AMs) featuring a sugar backbone, hydrophobic arms, a poly(ethylene glycol) tail, and a chemical anchor effectively deposited on soft ceramic surfaces and reduced bacterial adhesion. The chemical compositions of the AMs were fine-tuned to better coordinate with dental enamel surfaces and prevent bacterial colonization. A graft-to approach was used to investigate the effect of the chemical anchor on AM deposition and retention. The chemical composition, absorption/desorption, and wettability properties of the bioactives and bioactive-coated surfaces were investigated using nuclear magnetic resonance, X-ray photon spectroscopy, quartz crystal microbalance, and contact angle. In addition, the ability of the AMs to provide anti-bacterial attachment on a simulated enamel surface was evaluated in vitro using bacterial repulsion assays. The SAR between surface retention and anti-attachment properties of the AMs demonstrates the feasibility and tunability of using these polymers as bioactive agents that provide anti-attachment benefits on dental enamel surfaces.

Effect of proteins, glucose and NaCl on growth, biosynthesis and functionality of bacteriocins of Lactobacillus sakei subsp. sakei 2a in foods during storage at 4 °C: Tests in food models

Bacteriocins produced by lactic acid bacteria are used as food biopreservatives. In consequence of amphiphilic characteristics and high content of hydrophobic amino acids, biosynthesis and antimicrobial functionality of bacteriocins can be affected by components in the food matrix. This study evaluated the influence of proteins/peptides, glucose and NaCl on growth and bacteriocins production by Lactobacillus sakei subsp. sakei 2a, using simulated food models prepared with combinations of meat extract, yeast extract, proteose-peptone, starch, glucose and NaCl. A semi-purified extract of bacteriocins was used to investigate their functionality against Listeria monocytogenes added to the models, stored at 4 °C for 10 days. Results were compared to those obtained with a similar extract of a non-bacteriocinogenic strain of Lb. sakei, prepared according to the same purification protocol. Results indicated that growth and bacteriocin production in the tested conditions was minimal. Glucose had a small but positive affect on both measurements. However, the functionality of the bacteriocins against Listeria monocytogenes in the models during refrigerated storage was similar, indicating that none of the components at the tested concentrations had an evident influence on the activity. These results subsidize the correct application of bacteriocins of lactic acid bacteria in protein-based foods for biopreservation.

Design of Aminopeptidase N Inhibitors as Anti-cancer Agents

Aminopeptidase N (APN) is an important metalloenzyme. It regulates multivariate cellular functions by different mechanisms such as enzymatic cleavage of peptides. This may play a role in endocytosis and regulate signal transduction. APN, a member of the M1 zinc metallopeptidase family, plays crucial roles in a variety of functions such as migration and invasion, and angiogenesis and metastasis of tumor cells. Therefore, APN inhibitors may be useful for the treatment of cancer. In this Perspective, structure-activity relationships of APN inhibitors are discussed to get an idea of possible lead candidates. APN inhibitors should possess an aryl hydrophobic function along with a zinc binding group attached to the hydrophobic group(s) to achieve high potency. This and other design aspects of APN inhibitors are discussed in this Perspective.

Inkjet Printing Enabled Controllable Paper Superhydrophobization and Its Applications.

Papers' intrinsic interconnected porous structures and hydrophilic properties usually results in difficulty and complexity in partial functionalization and regulation processes because the capillary effect may lead to the fast diffusion of modifiers from one side to the other. Here, we report a simple and innovative inkjet printing approach that led to precise hydrophobic functionalization controllable in both planar and steric dimensions. Fabrication of Janus superwetting papers and superwettable patterned papers with high precision was achieved by computer-controlled inkjet printing. Elaborate controls of ink quantity enabled superhydrophobic functionalization on one side of the paper substrate, with the opposite side superhydrophilic. Static water contact angles up to 154° were obtained on the inkjet-printed side of the paper, thanks to an appropriate combination of surface chemistry with dual-scale surface roughness. Furthermore, paper-based microfluidics were fabricated and the resolution of which were estimated to be ca. 600 μm. Meanwhile, a paper-based analytical device for colorimetric sensing of Ni(II) was designed and demonstrated based on superwettable patterned papers by inkjet printing. The inkjet printing approach reported here represents a key step forward in fabricating Janus materials and complicate patterns for practical applications.

Leucine-Based Polymer Architecture-Induced Antimicrobial Properties and Bacterial Cell Morphology Switching.

To evaluate the comparative antibacterial activity of leucine-based cationic polymers having linear, hyperbranched, and star architectures containing both hydrophilic and hydrophobic segments against Gram-negative bacterium, Escherichia coli (E. coli), herein we performed zone of inhibition study, minimum inhibitory concentration (MIC) calculation, and bacterial growth experiment. The highest antibacterial activity in terms of the MIC value was found in hyperbranched and star architectures because of the greater extent of cationic and hydrophobic functionality, enhancing cell wall penetration ability compared to that of the linear polymer. The absence of the bacterial regrowth stage in the growth curve exhibited the highest bactericidal capacity of star polymers, when untreated cells (control) already reached to the stationary phase, whereas the bacterial regrowth stage with a delayed lag phase was critically observed for linear and hyperbranched architectures displaying lower bactericidal efficacy. Coagulation of E. coli cells, switching of cell morphology from rod to sphere, and lengthening due to stacking in an antimicrobial polymer-treated environment at the bacterial regrowth stage in liquid media were visualized critically by field emission scanning electron microscopy and confocal fluorescence microscopy instruments in the presence of 4′,6-diamidino-2-phenylindole stain.

Determination of polymeric impurities in asunaprevir drug substance and product using size exclusion effect of reversed-phase columns

This paper describes the development of a simple reversed-phase HPLC method that can quantitate trace amounts of a polymeric degradants (BMT-041910) in asunaprevir drug substance and formulated drug product with quantitation limits of ∼0.05% w/w. The method has overcome several challenges of polymer quantitation such as band broadening, peak coeluting and low sensitivity. The hydrophobic function group (BOC) of BMT-041910 is removed to increase its aqueous solubility by a simple sample treatment procedure (des-BOC). The des-BOC polymer (BMT-052076) is excluded from stationary phase pores and eluted as a single peak before solvent front, and then its peak area response can be used to determine BMT-041910 amount. The HPLC conditions were optimized using a 250 × 4.6 mm Waters XSelect CSH column maintained at 30 °C with a mobile phase of water-acetonitrile-trifluoroacetic acid (20:80:0.1 v/v/v). The feasibility of other HPLC approaches including size exclusion chromatography and normal phase chromatography were also investigated and found to be less suitable for this particular application. Validation data for this method in terms of precision, linearity, accuracy and sensitivity are also presented.

The study of dynamic force acted on water strider leg departing from water surface

Water-walking insects such as water striders can skate on the water surface easily with the help of the hierarchical structure on legs. Numerous theoretical and experimental studies show that the hierarchical structure would help water strider in quasi-static case such as load-bearing capacity. However, the advantage of the hierarchical structure in the dynamic stage has not been reported yet. In this paper, the function of super hydrophobicity and the hierarchical structure was investigated by measuring the adhesion force of legs departing from the water surface at different lifting speed by a dynamic force sensor. The results show that the adhesion force decreased with the increase of lifting speed from 0.02 m/s to 0.4 m/s, whose mechanic is investigated by Energy analysis. In addition, it can be found that the needle shape setae on water strider leg can help them depart from water surface easily. Thus, it can serve as a starting point to understand how the hierarchical structure on the legs help water-walking insects to jump upward rapidly to avoid preying by other insects.

基于大理石石粉的超疏水涂层制备及性能

本文以固化后的有机硅聚合物为低表面能物质，大理石石粉纳米颗粒为无机填料，喷涂在不同基材的表面后，制备了具有超疏水性能的PTFMS-TEOS杂化涂层。考察了大理石石粉与有机硅聚合物复合的比例及温度对涂层疏水性的影响。用接触角测量仪和扫描电子显微镜分别对超疏水表面进行了结构分析和形貌表征。结果显示，当大理石石粉与PTFMS-TEOS质量比1:3时杂化涂层表面具有较好的超疏水功能，静态接触角可达153˚，这主要是涂层表面含有低表面能氟原子及具有纳米粗糙结构共同作用的结果。 A super hydrophobic PTFMS-TEOS hybrid coating was prepared after solidified silicone polymer as low surface energy material, marble powder and nano particle as inorganic filler and sprayed on different substrates. The effect of the proportion and temperature of marble stone powder and organosilicon polymer on the hydrophobicity of the coating was investigated. The surface of the superhydrophobic surface was analyzed and characterized by the contact angle measuring instrument and the scanning electron microscope respectively. The results show that when the marble powder and PTFMS-TEOS mass ratio is 1:3, the surface of the hybrid coating has super hydrophobic function, and the static contact angle can reach 153 degrees, which is mainly due to the joint action of low surface energy fluorine atoms and nano rough structure on the coating surface.

Transparent and double sided hydrophobic functionalization of cotton fabric by surfactant-assisted admicellar polymerization of fluoromonomers

We report a simple procedure to prepare hydrophobic cotton textiles by admicellar polymerization.

Hydrophobically-modified Chitosan Microspheres for Release of Diosgenin

Chitosan microspheres (CS) prepared by water-in-oil emulsion/glutaraldehyde cross-linking-evaporation and simple coacervation/cross-linking with sodium tripolyphosphate were covalently linked to diosgenin hemiesters. The diosgenin content found using elemental analysis was ca. 6 to 42 wt-% and it showed dependence on the type of diosgenin hemiesters and on the method of preparation of the CS microspheres. Fourier transform infrared spectroscopy confirmed the hydrophobic functionalization of CS with the diosgenin hemiesters by amide bond formation. The effect of CS modification with diosgenin on the thermal properties was also studied using differential scanning calorimetry. Microsphere sizes determined using optical microscopy ranged from 60 to 700 um, while scanning electron microscopy depicted morphology dependent on the selected method to obtain CS microspheres. In vitro release studies performed in aqueous medium indicated a drug release dependence on the diosgenin hemiester linkers, the steroid content and the acidity of the solution. Sustained diosgenin release in acidic aqueous solution (pH 6.0) reached from 34 to 81% after 48 h.

Immobilization of Gold and Silver on a Biocompatible Porous Silicone Matrix to Obtain Hybrid Nanostructures

During the last decade an enormous research effort has been deployed with respect to porous materials. Design, pore size, shape, morphology and density are crucial features for increasing the surface area of silicone materials, aiming for a better biological response so cells can adhere and grow. Many medical applications utilize polydimethylsiloxane (PDMS) in medical implants, despite its hydrophobic surface that does not stimulate cellular adhesion. Porosity and morphology are important factors in the wettability of PDMS, but modifying the hydrophobic surface functionalization is required. To achieve this goal, the use of coatings with gold and silver nanoparticles or nanofilms can be used as a strategy to improve biocompatibility. This is due to the effect on mammalian cell adhesion and proliferation related to gold nanoparticles, as well as the prevention of infections related to silver nanoparticles. In this study, the pores in the silicone matrix were formed using sugar crystals as a template agent, and later passed through a lixiviation process to form a porous silicon matrix. Next, the matrix was placed inside a colloidal suspension; a process that allowed the immobilization of these particles on the surface matrix. A hybrid stable material was synthetized through this process. The water absorption level of the porous silicone matrix with and without the nanoparticles was determined. The water uptake of the matrix was higher when the nanoparticles were immobilized on the surface. Van der Waals and hydrogen bonding interactions account for this, promoting the retention of a higher concentration of water molecules. Higher water uptake has been identified as being a key factor for improving biological response, cellular adhesion and growth, which accelerates implant integration in the body.

Synthesis of hydrophilic and hydrophobic carbon quantum dots from waste of wine fermentation.

Wine lees are one of the main residues formed in vast quantities during the fermentation of wine. While toxic when applied to plants and wetlands, it is a biodegradable material, and several alternatives have been proposed for its valorization as: dietary supplement in animal feed, source for various yeast extracts and bioconversion feedstock. The implementation of stricter environment protection regulations resulted in increasing costs for wineries as their treatment process constitutes an unavoidable and expensive step in wine production. We propose here an alternative method to reduce waste and add value to wine production by exploiting this rich carbon source and use it as a raw material for producing carbon quantum dots (CQDs). A complete synthetic pathway is discussed, comprising the carbonization of the starting material, the screening of the most suitable solvent for the extraction of CQDs from the carbonized mass and their hydrophobic or hydrophilic functionalization. CQDs synthesized with the reported procedure show a bright blue emission (λmax = 433 ± 13 nm) when irradiated at 366 nm, which is strongly shifted when the wavelength is increased (e.g. emission at around 515 nm when excited at 460 nm). Yields and luminescent properties of CQDs, obtained with two different methods, namely microwave and ultrasound-based extraction, are discussed and compared. This study shows how easy a residue can be converted into an added-value material, thus not only reducing waste and saving costs for the wine-manufacturing industry but also providing a reliable, affordable and sustainable source for valuable materials.