Design,Synthesis, and Biological Evaluation of Simplified Side Chain Hybrids of the Potent Actin Binding Polyketides Rhizopodin and Bistramide

The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC₅₀ values in the low‐nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G‐actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure–activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin–inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin–bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin–bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.     

L-659,989: A useful probe in the detection of multiple conformational states of PAF receptors

L-659,989 is a potent, specific and competitive plateletactivating factor (PAF) receptor antagonist. The 2,5-tritium labeled L-659,989, similar to [³H]PAF, specifically binds to rabbit platelet membranes with an equilibrium dissociation constant (K_D) of 1.60 (±0.20) nM in 10 mM MgCl₂. However, guanosine 5′-triphosphate (GTP) and several cations affect the specific binding of [³H]PAF and of [³H]L-659,989 to rabbit platelet membranes in different ways. K⁺, Mg²⁺, Ca²⁺ and Mn²⁺ potentiate the specific binding of both ligands. Na⁺ and Li⁺ inhibit the specific [³H]PAF binding, but enhance the binding of [³H]L-659,989; GTP reduces the [³H]PAF binding but has no effect on the binding of [³H]-L-659,989. Ni²⁺ inhibits the [³H]L-659-989 binding, but has no effect on the binding of [³H]PAF. In the presence of 150 mM NaCl, [³H]L-659,989 exhibits identical K_D and detectable binding sites (B_max) values as those in the presence of 10 mM MgCl₂, while K _d And B_max values of [³H]PAF are dramatically reduced in the presence of 150 mM NaCl compared to those in 10 mM MgCl₂. These results suggest the existence of multiple conformational states of the PAF specific receptor and that PAF and L-659,989 bind differently to those states. In the presence of 150 mM NaCl and 1 mM GTP, receptors appear to exist in a single conformational state with an equilibrium dissociation constant (K_B) of 0.93 μM for PAF as derived from the Schild plot. In isolated rabbit platelets pretreated with 10 μM ETH 227, a Na⁺-specific ionophore, the detectable [³H]PAF binding sites drop from 260 to 100 binding sites per platelet, but the binding sites for [³H]L-659,989 remain roughly the same. The Na⁺ binding sites which modulate the conformation of PAF receptors are therefore protected from extracellular Na⁺ until ionophore is added, and are probably located on the cytoplasmic side of the plasma membrane. Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.     

Nanopore detection of DNA molecules in magnesium chloride solutions

High translocation speed of a DNA strand through a nanopore is a major bottleneck for nanopore detection of DNA molecules. Here, we choose MgCl₂ electrolyte as salt solution to control DNA mobility. Experimental results demonstrate that the duration time for straight state translocation events in 1 M MgCl₂ solution is about 1.3 ms which is about three times longer than that for the same DNA in 1 M KCl solution. This is because Mg²⁺ ions can effectively reduce the surface charge density of the negative DNA strands and then lead to the decrease of the DNA electrophoretic speed. It is also found that the Mg²⁺ ions can induce the DNA molecules binding together and reduce the probability of straight DNA translocation events. The nanopore with small diameter can break off the bound DNA strands and increase the occurrence probability of straight DNA translocation events.     

Simulation studies on metastable phase equilibria in the aqueous ternary systems (NaCl-MgCl2-H2O) and (KCl-MgCl2-H2O) at 308.15 K

The solubilities and densities of the aqueous metastable ternary systems (NaCl-MgCl₂-H₂O) and (KCl-MgCl₂-H₂O) at 308.15 K were determined by the isothermal evaporation method. On the basis of the experimental results, the phase diagrams for those systems were plotted. It was found that the former system belongs to the hydrate-I type with one invariant point of (NaCl + MgCl₂·6H₂O), two univariant curves, and two crystallization regions corresponding to halite (NaCl) and bischo.te (MgCl₂6H₂O); and the latter system belongs to the type of incongruent-double salts with two invariant points of (KCl + KCl·MgCl₂6H₂O) and (MgCl₂·6H₂O + KCl·MgCl₂·6H₂O), three univariant curves, and three crystallization regions corresponding to potassium chloride (KCl), carnallite (KCl·MgCl₂·6H₂O) and bischofite (MgCl₂·6H₂O). No solid solutions were found in both systems.     

Solid-State NMR characterization of a superactive supported ziegler–natta catalyst

The formation of CH-type catalysts has been investigated by high-resolution and solid-state NMR. These catalysts are prepared from a soluble MgCl₂ and 2-ethyl-1-hexanol adduct (MgCl₂·3EH) by reaction with phthalic anhydride (PA) to form dioctylphthalate (DOP) and then with TiCl₄ in the presence of di-i-butylphthalate (BP). In the model systems MgCl₂·3EH/PA, MgCl₂/BP, and MgCl₂/TiCl₄/BP, the ester is complexed with MgCl₂ and /or TiCl₄ in two or more states. Only single-ester C?O and OCH₂ resonances are seen in TiCl₄/BP, probably due to exchange of ester coordinations. CH-catalysts prepared by three different procedures exhibit a single mode of bonding for the ester. The chemical shift values are consistent for ester complexed with MgCl₂. The most active and stereoselective catalyst has the most shielded chemical shift values for the C?O and —OCH₂— carbons, shortest T^H₁ and T^H_1p, and longest T_CH relaxation times. These parameters change monotonically with the decrease of activity and stereoselectivity of the catalyst preparation. © 1993 John Wiley & Sons, Inc.     

Activities of Cobalt Chloride in Molten Magnesium Chloride — Potassium Chloride Eutectic

The activities of CoCl₂ in molten MgCl₂?KCl at 475° have been determined by measuring the EMF of the galvanic cell.     

Metastable equilibrium for the quaternary system containing with lithium+potassium+magnesium+chloride in aqueous solution at 323K

The metastable equilibrium of the system contained with lithium, potassium, magnesium, and chloride in aqueous system was investigated at 323 K using an isothermal evaporation method. The isothermal experimental data and physicochemical properties, such as density and refractive index of the equilibrated solution, were determined. With the experimental results, the stereo phase diagram, the projected phase diagram, the water content diagram and the physicochemical properties versus composition diagrams were constructed. The projected phase diagram consists of three invariant points, seven univariant curves and five crystallization fields corresponding to single salts potassium chloride (KCl), lithium chloride monohydrate (LiCl·H₂O), bischofite (MgCl₂·6H₂O) and two double salts lithium carnallite (LiCl·MgCl₂·7H₂O) and potassium carnallite (KCl·MgCl₂·6H₂O). Salt KCl has the largest crystallization region; it contains almost 95% of the general crystallization field.     

Retention of mineral salts by a polyamide nanofiltration membrane

Retention measurements with single salt solutions (KCl, K₂SO₄, MgSO₄ and MgCl₂) were carried out with an AFC 30 organic membrane. The membrane showed high retentions for K₂SO₄ and MgSO₄ solutions and moderate ones for MgCl₂ and KCl solutions. The effective pore radius and the effective thickness to the porosity ratio of the membrane were determined from the limiting retention of glucose and permeability measurements, respectively. The Donnan Steric Pore Model (DSPM), based on the extended Nernst-Planck equation and a modified Donnan equilibrium accounting for steric effects, was used to characterize the membrane in terms of effective membrane volume charge. It appears that the membrane is positively charged in presence of MgCl₂ and MgSO₄ solutions and negatively charged for KCl and K₂SO₄ solutions. This was attributed to ionic adsorption at the interface membrane/solution.     

The solubility of magnesium metal and the recombination reaction in the industrial magnesium electrolysis

The solubility and dispersion of Mg in the systems MgCl₂, MgCl₂-NaCl and MgCl₂-KCl has been studied. An extensive study of Mg solubility in MgCl₂ did not show any influence on the content of MgO or added NaOH or Na₂B₄O₇. At 750°C the solubility was found to be 0.16 mol%. The solubility increased with increasing temperature and decreased on the addition of NaCl or KCl. In 25 mol% NaCl-75 mol% MgCl₂ the solubility was as low as 0.02 mol% at 815°C. The amount of Mg dispersed was found to be negligible with the present experimental set-up. The results are discussed with reference to the back reaction between Mg and Cl₂ in the industrial electrolysis. It seems likely that the rate determining step in this reaction is the rate of formation of small metal particles in the melt.     

Hydration Shells of DNA from the Point of View of Terahertz Time-Domain Spectroscopy

Hydration plays a fundamental role in DNA structure and functioning. However, the hydration shell has been studied only up to the scale of 10–20 water molecules per nucleotide. In the current work, hydration shells of DNA were studied in a solution by terahertz time-domain spectroscopy. The THz spectra of three DNA solutions (in water, 40 mm MgCl₂ and 150 mM KCl) were transformed using an effective medium model to obtain dielectric permittivities of the water phase of solutions. Then, the parameters of two relaxation bands related to bound and free water molecules, as well as to intermolecular oscillations, were calculated. The hydration shells of DNA differ from undisturbed water by the presence of strongly bound water molecules, a higher number of free molecules and an increased number of hydrogen bonds. The presence of 40 mM MgCl₂ in the solution almost does not alter the hydration shell parameters. At the same time, 150 mM KCl significantly attenuates all the found effects of hydration. Different effects of salts on hydration cannot be explained by the difference in ionic strength of solutions, they should be attributed to the specific action of Mg²⁺ and K⁺ ions. The obtained results significantly expand the existing knowledge about DNA hydration and demonstrate a high potential for using the THz time-domain spectroscopy method.     

A Modified Actin (Gly65Val Substitution) Expressed in Cotton Disrupts Polymerization of Actin Filaments Leading to the Phenotype of Ligon Lintless-1 (Li1) Mutant

Dynamic remodeling of the actin cytoskeleton plays a central role in the elongation of cotton fibers, which are the most important natural fibers in the global textile industry. Here, a high-resolution mapping approach combined with comparative sequencing and a transgenic method revealed that a G65V substitution in the cotton actin Gh_D04G0865 (GhACT17D in the wild-type) is responsible for the Gossypium hirsutum Ligon lintless-1 (Li₁) mutant (GhACT17DM). In the mutant GhACT17DM from Li₁ plant, Gly65 is substituted with valine on the lip of the nucleotide-binding domain of GhACT17D, which probably affects the polymerization of F-actin. Over-expression of GhACT17DM, but not GhACT17D, driven by either a CaMV35 promoter or a fiber-specific promoter in cotton produced a Li₁-like phenotype. Compared with the wild-type control, actin filaments in Li₁ fibers showed higher growth and shrinkage rates, decreased filament skewness and parallelness, and increased filament density. Taken together, our results indicate that the incorporation of GhACT17DM during actin polymerization disrupts the establishment and dynamics of the actin cytoskeleton, resulting in defective fiber elongation and the overall dwarf and twisted phenotype of the Li₁ mutant.     

Electrochemical behavior of antimony and electrodeposition of Mg–Li–Sb alloys from chloride melts

The electrochemical behavior of Sb(III) ions was investigated in LiCl–KCl molten salt at 673 K. The reaction mechanism and transport parameters of electroactive species were determined by transient electrochemical techniques (such as cyclic voltammetry, square wave voltammetry, chronopotentiometry and chronoamperometry) at a molybdenum electrode. The results showed that electrochemical reduction of Sb(III) in LiCl–KCl melts occurred in a reaction step with an exchange of three electrons. A voltammogram with a different scan rate in LiCl–KCl containing 1.45 × 10⁻⁴ mol cm⁻³ SbCl₃ showed that the deposition/dissolution reaction of Sb(III) ions was not completely reversible. The diffusion coefficient of Sb(III) ions was 1.65(±0.01) × 10⁻⁵ cm⁻² s⁻¹ at 673 K. The electroreduction of Sb(III) ions at an Al electrode was also studied by cyclic voltammetry and open circuit chronopotentiometry in the temperature range of 668–742 K. The redox potential of Sb(III)/Sb at an Al electrode was observed at the more positive potentials values than those at an inert electrode. This potential shift due to the formation of intermetallic compound with Al electrode. AlSb alloys were prepared in LiCl–KCl–SbCl₃ melts at 742 K by potentiostatic electrolysis at an Al electrode. The activity of Sb and the Gibbs energy of AlSb formation were also calculated. Mg–Li–Sb alloys were obtained by galvanostatic electrolysis at 673 K and the electrochemical codeposition of Mg, Li and Sb was investigated on a molybdenum electrode in LiCl–KCl containing MgCl₂ and SbCl₃ melts at 673 K by cyclic voltammetry, chronopotentiometry and chronoamperometry. Cyclic voltammograms, chronopotentiometry and chronoamperometry measurements indicated that the electrochemical codeposition of Mg, Li and Sb metal occurred at current densities lower than −0.466 A cm⁻² or at an applied potential more negative than −2.350 V vs. Ag/AgCl. X-ray diffraction (XRD) suggested that Mg₃Sb₂ and Li₃Sb were formed in Mg–Li–Sb alloys. The distribution of Sb element in Mg–Li–Sb alloys from the analysis of scan electron micrograph (SEM) and energy dispersive spectrometry (EDS) indicated that Sb metal showed a distribution which resembled an interlaced network.     

Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

The actin filament‐binding and filament‐severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF‐01 and GC‐04) are shown to bind to G‐actin with dissociation constants of (285±33) and (132±13) nM , respectively. The crystal structures of actin complexes with GC‐04, SF‐01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop‐D from the lower protomer on the same half‐filament. With previous studies showing that the GC‐04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F‐actin would make them more effective at severing filaments compared with plasma gelsolin. Structure‐based analyses are used to suggest more reactive or targetable forms of GC‐04 and SF‐01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.     

Separation of Counterions during Pressure-Driven Transport of Electrolyte Mixtures across Charged Porous Membranes

Abstract

It has been previously predicted theoretically that a substantial separation of counterions will occur during the pressure-driven transport of electrolyte mixtures across charged porous membranes. This presumption has been supported experimentally using negatively charged sulfonated polysulfone and ternary electrolyte solutions with a simple coion like Cl^?. In dilute solutions the selectivity has approached values between 8 and 10 and sometimes even greater. The experimental findings of the relationship of selectivity to feed ionic strength and feed composition agree fairly well with the theory. Moreover, the theoretical prediction is also supported by the correlation of selectivity with mobilities of counterions and transmembrane volume flow. The less mobile counterions of symmetrical mixtures like KCl/LiCl have a rejection inferior to the more mobile ones when porous charged membranes are used. The reverse effect was observed when more dense membranes of the same polymer and degree of substitution were employed. However, some deviations from normality were noticed when the KCl/MgCl₂ mixture was used such as changes in the sign of the selectivity logarithm and the nonmonotonic dependences of the selectivity on the feed ionic strength and transmembrane volume flow. This leads to the assumption that the mobility of the Mg²⁺ ion in the membrane phase is lower than that of the K⁺ ion, which is just opposite of their bulks. This relative decrease in the Mg²⁺ ion's mobility has been interpreted in terms of stronger electrostatic interactions with membrane fixed charges. Moreover, the lack of anomalies when the LiCl/MgCl₂ solution is used leads to the assumption that the mobility of the Mg²⁺ ion in the membrane phase is between that of Li⁺ and K⁺ ions.     

Effect of different dopants on porous calcium silicate composite bone scaffolds by 3D gel-printing

Porous CaSiO₃ composite scaffolds with different dopants, such as MgSiO₃, MgCl₂ and CaSO₄, were successfully prepared by 3D gel-printing (3DGP). (m, n) is proposed to describe the filament geometry features. The results show that doping can improve the strength of porous composite scaffolds and MgCl₂-doped composite scaffolds had the highest modulus of elasticity of 1241 MPa. The shrinkage rate range of the composite scaffolds was 11.44–13.16%, and their porosity was all about 60%. When porous composite scaffolds were soaked in SBF for 28 days at 37°С, the degradation rate was 2.7% (pure), 0.3% (MgSiO₃), 0.2% (MgCl₂), 5.27% (CaSO₄), respectively. It explains that MgSiO₃ and MgCl₂ inhibited the in vitro degradation of CaSiO₃, while CaSO₄ promoted. It is obviously that doped MgCl₂ can improve the mechanical properties of porous scaffolds, and doped CaSO₄ can improve the degradation of scaffolds, which play an important role in bone repair engineering.     

A thermally regenerable composite sorbent of crosslinked poly(acrylic acid) and ethoxylated polyethyleneimine for water desalination by Sirotherm process

Crosslinked poly(acrylic acid) (XPAA) made by copolymerization of acrylic acid and ethylene glycol dimethacrylate in bulk was further reacted with 80% ethoxylated polyethyleneimine, and the latter insolubilized by treatment with glutaraldehyde. The resulting composite sorbent, XPAA(EPEI.XG), containing carboxylic acid groups and weakly basic tertiary amine groups in close proximity in the same resin bead exhibited thermally regenerable desalination property, simulating the well‐known Sirotherm? resins. For NaCl and MgCl₂, the sorbent has saturation capacities of 0.796 and 0.839 meq/g (dry) sorbent, respectively, at 30°C but less than 0.1 meq/g (dry) sorbent at 80–90°C. The equilibrium sorption data at 30°C fit well to both Langmuir and Freundlich isotherms for single‐component sorption and to Butler‐Ockrent and Jain‐Snoeyink models for bicomponent sorption. Although the sorption of NaCl exhibits a plateau in the pH range of 4–5, that of MgCl₂ increases sharply above pH 4 because of additional sorption by cation exchange at the ionic sites formed at higher pH. The sorption rate data show characteristics of particle‐diffusion controlled ion‐exchange process, yielding diffusivity values of 1.0–1.3 × 10^?6 cm²/s for NaCl and 3.0–3.5 × 10^?7 cm²/s for MgCl₂, in the initial period at 30°C, with the diffusivity falling abruptly in both cases at higher conversions. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

烷基吗啉在氯化钠和氯化钾表面的吸附

采用密度泛函理论(DFT)的PW91方法,研究了十二烷基吗啉(DMP)分子在带缺陷的NaCl(100)和KCl(100)上的吸附情况.缺陷引入后晶体表面离子电荷发生较大变化,使得NaCl(100)表现出正电性,而KCl(100)则表现出负电性.DMP在NaCl(100)的Na顶位发生吸附,吸附能约为-157.00 kJ...     

Fusibility study of the magnesium cell electrolyte containing MgCl2, CaCl2, NaCl and KCl

The four-component magnesium cell electrolyte containing MgCl₂, CaCl₂, NaCl and KCl has been converted to a quasi-ternary system by keeping the proportion of NaCl and KCl in the mixture equimolecular. The triangular phase diagram has been drawn depicting the fusibility isotherms of the system. It has been possible to obtain complete liquid mixtures at temperatures as low as 400° C by suitably adjusting the proportions of the four components of the molten salt mixture.     

Carnallite decomposition into magnesia,hydrochloric acid and potassium chloride: A thermal analysis study; formation of pure periclase

A thermal analysis study of the one-stage decomposition of small (mg) quantities of carnallite, KCl. MgCl₂, 6H₂O → KCl + MgO + 5H₂O ↑ + 2HCl ↓, showed that dehydration and hydrolysis require temperatures above 300 °C. Decomposition of greater amounts, and analysis of the products, showed that at 450 °C, 88 to 90% of the magnesium occurs as chloride-free high-purity periclase. At higher temperatures increasing amounts of chlorides remain in the periclase and are difficult to separate. Unglazed porcelain is a suitable material for the decomposition vessel.     

Plugging behavior of gellan in porous saline media

In this article, the hydrodynamic behavior of dilute aqueous solutions of a natural polysaccharide—gellan in the porous media under the modeled oilfield conditions is described. The hydrodynamic properties of gellan and poly(acrylamide) solutions in saline porous media are compared. The influence of inorganic salts NaCl, KCl, CaCl₂, MgCl₂, and BaСl₂ on sol–gel and gel–sol transitions of dilute gellan solutions was evaluated. The mechanism of sol–gel transition in the presence of individual alkaline and alkaline‐earth metal salts is described on the basis of literature data. The viscometric measurements revealed that the effectiveness of salts to enhance gelation of gellan changes in the following order: BaСl₂ > CaCl₂ ≈ MgCl₂ > KCl > NaCl. The sol–gel and gel–sol phase transitions of gellan solution were also observed upon addition of oil field water containing 73 g L^?1 of alkaline and alkaline earth metal ions. During the injection of gellan solutions into the porous media saturated by saline water an oscillation of the injection pressure was observed. Such behavior of gellan is explained by either the sol‐to‐gel and the gel‐to‐sol transitions of the polymer taking place in saline water or the step‐by‐step plugging of high permeable channels until all high permeable channels of sand packs are plugged due to gellan invasion. The application of brine‐initiated gelation of gellan for water shutoff operations (WSO) in field conditions was demonstrated. Higher technological effectiveness of gellan injection in comparison with existing gelation systems was shown. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41256.