How the stereochemistry of a central cyclopentyl ring influences the self-assembling properties of archaeal lipid analogues: synthesis and cryoTEM observations

The relative stereochemistry (cis or trans) of a 1,3-disubstituted cyclopentane unit placed in the middle of tetraether archaeal bipolar lipid analogues was found to have a dramatic influence on their supramolecular self-assembling properties. The synthesis of two diastereomers varying only by the stereochemistry of the cyclopentyl unit was achieved following a multistep diastereoselective route. The corresponding lipid films were hydrated and were observed by cryoTEM. The micrographs showed several types of unilamellar nano-objects such as lamellas or irregular vesicles for the cis-isomer, whereas the trans-isomer exhibited exclusively multilamellar vesicles with a regular spherical shape. Even if the cyclopentyl ring takes part of a long alkyl chain (32 carbon atoms), the pseudorotation of the carbocycle would influence the global conformation of the bipolar lipid and consequently would modify the orientation of the lactosyl polar headgroups.     

Synthesis of archaeal bipolar lipid analogues: a way to versatile drug/gene delivery systems

A synthetic route for the preparation of symmetrical and unsymmetrical archaeal tetraether-like analogues has been described. The syntheses are based upon the elaboration of hemimacrocyclic tetraether lipid cores from versatile building blocks followed by simultaneous or sequential introduction of polar head groups. Functionalizations of the tetraether lipids with neutral lactose or phosphatidylcholine polar heads and cationic glycine betaine moieties were envisaged both to increase membrane stability and to exhibit interactions with charged nucleic acids. Additionally, mannose and lactose triantennary clusters designed as multivalent ligands for selective interaction with lectin-type receptors were also efficiently synthesized for active cell/tissue targeting.     

Time-resolved SAXS study of the effect of a double hydrophilic block-copolymer on the formation of CaCO3 from a supersaturated salt solution

The effect of a double hydrophilic block-copolymer additive (made of polyaspartic acid and polyethyleneglycol, pAsp(10)-b-PEG(110)) on the initial formation of calcium carbonate from a supersaturated salt solution has been studied in situ by means of time-resolved synchrotron small-angle X-ray scattering (SAXS). A stopped-flow cell was used for rapidly mixing the 20 mM aqueous reactant solutions of calcium chloride and sodium carbonate. In reference measurements without polymer additive the very rapid formation of primary, overall spherical CaCO(3) particles with a radius of ca. 19 nm and a size polydispersity of ca. 26% was observed within the first 10 ms after mixing. A subsequent, very rapid aggregation of these primary particles was evidenced by a distinct upturn of the SAXS intensity at smallest angles. During the aggregation process the size of the primary particles remained unchanged. From an analysis of the absolute scattering intensity the mass density of these particles was determined to 1.9 g/cm(3). From this rather low density it is concluded that those precursor particles are amorphous, which has been confirmed by simultaneous wide-angle X-ray diffraction measurements. Upon adding 200 pm of the block-copolymer no influence on the size, the size polydispersity and morphology of the primary particles, nor on the kinetics of their formation and growth, was found. On the other hand, the subsequent aggregation and precipitation process is considerably slowed down by the additive and smaller aggregates result. The crystalline morphology of the sediment was studied in situ by WAXS ca. 50 min after mixing the reactants. Several diffraction rings could be detected, which indicate that a transformation of the metastable, amorphous precursor particles to randomly oriented vaterite nanocrystallites has taken place. In addition, a few isolated Bragg spots of high intensity were detected, which are attributed to individual, oriented calcite microcrystals that nucleated at the wall of the capillary.     

Spectral diffusion at the water/lipid interface revealed by two-dimensional fourth-order optical spectroscopy: a classical simulation study

Using a classical simulation protocol for nonlinear optical signals, we predict the two-dimensional (2D) spectra of water near a monolayer of [1,2-dimytristoyl-sn-glycero-3-phosphatidylcholine] (DMPC) generated by three IR probe pulses followed by one visible probe pulse. Sum-frequency-generation 1D spectra show two peaks of the OH stretch representing two environments: near-bulk water nonadjacent to DMPC and top-layer water adjacent to DMPC. These peaks create a 2D pattern in the fourth-order signal. The asymmetric cross-peak pattern with respect to the diagonal line is a signature of coherence transfer from the higher- to the lower-frequency modes. The nodal lines in the imaginary part of the 2D spectrum show that the near-bulk water has fast spectral diffusion resembling that of bulk water despite the orientation by the strong electrostatic field of DMPC. The top-layer water has slower spectral diffusion.     

Design of original bioactive formulations based on sugar-surfactant/non-steroidal anti-inflammatory catanionic self-assemblies: a new way of dermal drug delivery

A new kind of catanionic assembly was developed that associates a sugar-based surfactant with a non-steroidal anti-inflammatory drug (NSAID). Three different assemblies using indomethacin, ibuprofen and ketoprofen as NSAIDs were easily obtained in water by an acid-base reaction. These assemblies formed new amphiphilic entities because of electrostatic and hydrophobic effects in water and led to the spontaneous formation of vesicles. These catanionic vesicles were then tested as potential NSAID delivery systems for dermatological application. The anti-inflammatory activity was evaluated in vivo, and this study clearly showed an improved therapeutic effect for NSAIDs that were formulated as catanionic vesicles. These vesicles ensured a slower diffusion of the NSAID through the skin. This release probably increased the time of retention of the NSAID in the targeted strata of the skin. Thus, the present study suggests that this catanionic bioactive formulation could be a promising dermal delivery system for NSAIDs in the course of skin inflammation treatment.     

Biocompatible water-in-oil emulsion as a model to study ascorbic acid effect on lipid oxidation

A biocompatible water-in-oil (W/O) emulsion has been used as a model to study the effect of ascorbic acid (AA) on the oxidation of the oil (glycerol trioleate, GTO) continuous phase. The model system consisted of 3 wt % water dispersed in GTO containing 0.5 wt % sodium oleate (NaO)/oleic acid (OA) mixture (NaO/OA = 20/80 mol/mol %) as a stabilizer. To study the ascorbic acid effect on GTO light-promoted oxidation, we added aqueous solutions of ascorbic acid to GTO in place of distilled water. Results obtained as peroxide values show that ascorbic acid activity depends on its concentration and it is affected by the characteristics of the W/O interface. In the presence of ascorbyl palmitate (AP) or sorbitan trioleate (Span 85) in the continuous phase, ascorbic acid activity increases in the first few hours of oxidation. The effect of ascorbic acid has been related to emulsion structure by calculating characteristic parameters of the droplet size distributions by means of optical microscopy.     

Structures and spectroscopic properties of meso-tetrasubstituted porphyrin complexes: Meso-substitutional and central metallic effect study based on density functional theory calculations

Effects of the meso-substituents and central metals on the molecular structures, atomic charges, molecular orbital energy gaps, electronic absorption spectra, and infrared (IR) spectra of 12 meso-tetrasubstituted porphyrin complexes including metal-free porphyrins H₂P or (Por = TPP, TFPP, TClPP, TPyP) (1–4) and their metal complexes MPor (M = Mg, Zn; Por = TPP, TFPP, TClPP, TPyP) (5–12) [TPP = meso-tetrakis(phenyl)porphyrinate; TFPP = meso-tetrakis(4-fluorophenyl)porphyrinate; TClPP = meso-tetrakis(4-chlorophenyl)porphyrinate; TPyP = meso-tetrakis(4-pyridyl) porphyrinate] are systematically studied by density functional theory calculations at the B3LYP/6-31G(d) level. Good consistency was found between the calculated molecular structures and the experimental X-ray crystallography ones for 1, 3, and 4, and between the simulated electronic absorption and IR spectra and the experimental ones for 1 and 4. The calculation results reveal that introducing substituents at the meso positions of porphyrin induces increasing change in the molecular structures, atomic charges distribution, HOMO and LUMO energy, electronic absorption spectra, and IR spectra along with the increase in the electron-withdrawing ability of substituents in the order of phenyl, 4-fluorophenyl, 4-chlorophenyl, and pyridyl group. Furthermore, the central metal in porphyrins displays much significant influence on the structure and spectroscopic properties of meso-substituted porphyrin complexes. The electronic absorption and IR spectra of 1–12 are compared and assigned in detail. The present work should be not only helpful towards understanding the meso-substitutional and central metallic effects on the structure and spectroscopic properties of meso-substituted porphyrin complexes, but also useful in correctly assigning electronic absorption and IR spectra for porphyrin complexes.     

Sum frequency generation spectroscopic study of the condensation effect of cholesterol on a lipid monolayer

Sum frequency generation (SFG) spectra and surface pressure–molecular area (π–A) isotherms have been obtained for mixed cholesterol–DPPC monolayers with cholesterol mole fractions, x(chol.), from 0 to 1.0, at the air–water interface, under same conditions, at 22 °C. Analysis of the spectra indicated that incorporation of cholesterol into the monolayers at 3 mN m⁻¹ greatly increases the conformational and orientational order of the alkyl chains of DPPC, maximizing these properties at x(chol.)=0.4. Analysis also indicated that order in the mixed monolayers at 15 and 35 mN m⁻¹ is not affected by incorporation of cholesterol. The π–A isotherms measured at 3 mN m⁻¹ for the mixed monolayer with x(chol.)=0.4 have the largest negative deviation of the molecular area relative to those of ideal mixtures (the so-called “condensation effect” of cholesterol), indicating the most thermodynamically stable state. Comparison of results from SFG spectra and π–A isotherms explicitly proved that the condensation effect can be interpreted in terms of conformational and orientational ordering of the alkyl chains of DPPC.     

Effect of the electrostatic charge on the mechanism inducing liposome solubilization: a kinetic study by synchrotron radiation SAXS

The anionic surfactant sodium dodecyl sulfate (SDS) was used to induce the initial steps of the solubilization of liposomes. The structural transformations as well as the kinetics associated with this initial period were studied by means of time-resolved small-angle X-ray scattering (SAXS) using a synchrotron radiation source. Neutral and electrically charged (anionic and cationic) liposomes were used to investigate the effect of the electrostatic charges on the kinetics of these initial steps. The mechanism that induces the solubilization process consisted of adsorption of surfactant on the bilayers and desorption of mixed micelles from the liposomes surface to the aqueous medium. In all cases the time needed for desorption of the first mixed micelles was shorter than that for complete adsorption of the surfactant on the liposomes surface. The present work demonstrates that adsorption of the SDS molecules on negatively charged liposomes was slower and release of mixed micelles from the surface of these liposomes was faster than for neutral liposomes. In contrast, in the case of positively charged liposomes, the adsorption and release processes were, respectively, faster and slower than those for neutral vesicles.     

In situ SAXS study on a new mechanism for mesostructure formation of ordered mesoporous carbons: thermally induced self-assembly

A new mechanism for mesostructure formation of ordered mesoporous carbons (OMCs) was investigated with in situ small-angle X-ray scattering (SAXS) measurements: thermally induced self-assembly. Unlike the well-established evaporation-induced self-assembly (EISA), the structure formation for organic-organic self-assembly of an oligomeric resol precursor and the block-copolymer templates Pluronic P123 and F127 does not occur during evaporation but only by following a thermopolymerization step at temperatures above 100 °C. The systems investigated here were cubic (Im3m), orthorhombic Fmmm) and 2D-hexagonal (plane group p6mm) mesoporous carbon phases in confined environments, as thin films and within the pores of anodic alumina membranes (AAMs), respectively. The thin films were prepared by spin-coating mixtures of the resol precursor and the surfactants in ethanol followed by thermopolymerization of the precursor oligomers. The carbon phases within the pores of AAMs were made by imbibition of the latter solutions followed by solvent evaporation and thermopolymerization within the solid template. This thermopolymerization step was investigated in detail with in situ grazing incidence small-angle X-ray scattering (GISAXS, for films) and in situ SAXS (for AAMs). It was found that the structural evolution strongly depends on the chosen temperature, which controls both the rate of the mesostructure formation and the spatial dimensions of the resulting mesophase. Therefore the process of structure formation differs significantly from the known EISA process and may rather be viewed as thermally induced self-assembly. The complete process of structure formation, template removal, and shrinkage during carbonization up to 1100 °C was monitored in this in situ SAXS study.     

Anesthetic molecules embedded in a lipid membrane: a computer simulation study

The effect of four general anesthetic molecules, i.e., chloroform, halothane, diethyl ether and enflurane, on the properties of a fully hydrated dipalmitoylphosphatidylcholine (DPPC) membrane is studied in detail by long molecular dynamics simulations. Furthermore, to address the problem of pressure reversal, the effect of pressure on the anesthetic containing membranes is also investigated. In order to ensure sufficient equilibration and adequate sampling, the simulations performed have been at least an order of magnitude longer than the studies reported previously in the literature on general anesthetics. The results obtained can help in resolving several long-standing contradictions concerning the effect of anesthetics, some of which were the consequence of too short simulation time used in several previous studies. More importantly, a number of seeming contradictions are found to originate from the fact that different anesthetic molecules affect the membrane structure differently in several respects. In particular, halothane, being able to weakly hydrogen bound to the ester group of the lipid tails, is found to behave in a markedly different way than the other three molecules considered. Besides, we also found that two changes, namely lateral expansion of the membrane and increasing local disorder in the lipid tails next to the anesthetic molecules, are clearly induced by all four anesthetic molecules tested here in the same way, and both of these effects are reverted by the increase in pressure.     

Effect of peptide lipidation on membrane perturbing activity: a comparative study on two trichogin analogues

The effect of lipidation on the membrane perturbing activity of peptaibol antibiotics was investigated by performing a comparative study on two synthetic analogues of the natural peptide trichogin GA IV. Both analogues were labeled with a hydrophobic fluorescent probe, but one of them lacked the N-terminal n-octanoyl chain, present in the natural peptide. Spectroscopic studies show that the fatty acyl chain produces two opposite effects: it increases the affinity of the monomeric peptide for the membrane phase, but, at the same time, it favors peptide aggregation in water, thus inhibiting membrane binding by reducing the effective monomer concentration. In the membrane phase the two analogues exhibit the same aggregation and orientation behavior, indicating that the n-octanoyl chain plays no specific role in determining their orientation or membrane perturbing activity. Indeed, the dependence of peptide-induced membrane leakage on total peptide concentration is basically the same for the two analogues, because the aforementioned opposite effects, caused by peptide lipidation, tend to balance. These findings make questionable the use of lipidation as a general method for increasing the peptide membrane-perturbing activity, as its validity seems to be restricted to parent compounds of limited overall hydrophobicity.     

Protein inclusion in lipid membranes: a theory based on the hypernetted chain integral equation

A theory for describing the structure of the hydrocarbon chains around a protein inclusion embedded in a lipid bilayer is developed on the basis of the hypernetted chain integral equation formalism for liquids. The exact lateral density-density response function of the hydrocarbon core, which is extracted from a molecular dynamics simulation of a pure lipid bilayer, is used as input to the theory. Numerical calculations show that the average lipid order is perturbed over a distance of 25 to 30 A around a hard repulsive cylinder of 5 A radius representing an alpha-helical polyleucine protein inclusion. The lipid-mediated protein-protein interaction is calculated and is shown to be non-monotonic, being repulsive at an intermediate range but attractive at short range. It is found that the lipid matrix contributes a free energy well of 8 kBT to the association of two cylindrical inclusions.     

Characterization of bupivacaine-loaded formulations based on liquid crystalline phases and microemulsions: the effect of lipid composition

This report details the structural characterization and the in vitro drug-release properties of different local anesthetic bupivacaine (BUP)-loaded inverted-type liquid crystalline phases and microemulsions. The effects of variations in the lipid composition and/or BUP concentration on the self-assembled nanostructures were investigated in the presence of the commercial distilled glycerol monooleate Myverol 18-99K (GMO) and medium-chain triglycerides (MCT). Synchrotron small-angle X-ray scattering (SAXS) and rotating dialysis cell model were used to characterize the BUP formulations and to investigate the in vitro BUP release profiles, respectively. The evaluation of SAXS data for the BUP-loaded GMO/MCT formulations indicates the structural transition of inverted-type bicontinuous cubic phase of the symmetry Pn3m → inverted-type hexagonal (H(2)) phase → inverted-type microemulsion (L(2)) with increasing MCT content (0-40 wt %). In the absence of MCT, the solubilization of BUP induces the transition of Pn3m → H(2) at pH 7.4; whereas a transition of Pn3m → (Pn3m + H(2)) is detected as the hydration is achieved at pH 6.0. To mimic the drug release and transport from in situ formed self-assembled systems after subcutaneous administration, the release experiments were performed by injecting low viscous stimulus-responsive precursors to a buffer in the dialysis cell leaving the surface area between the self-assembled system and the release medium variable. Our results suggest that the pH-dependent variations in the lipidic partition coefficient, K(l/w), between the liquid crystalline nanostructures and the surrounding buffer solution are significantly affecting BUP release rates. Thus, a first step toward understanding of the drug-release mechanism of this drug-delivery class has been undertaken tackling the influence of drug ionization as well as the type of the self-assembled nanostructure and its release kinetics under pharmaceutically relevant conditions.     

Block polymethacrylonitrile copolymers based on a central polyether or polyacetal block: A study of the salt/copolymer complexes

Some block copolymers based on polymethacrylonitrile (PMAN) and polyethers or polyacetals were synthesized in an anionic way. To appreciate the salt/polymer interactions, polymer electrolytes were prepared by the dissolution of lithium imide or lithium perchlorate in PMAN homopolymer and copolymers. The investigation of the triblock copolymer complexes allowed the solvating competition between nitrile‐ and ether‐ or acetal‐functional groups to be highlighted. The polydioxolane solvating ability was equivalent to that of PMAN but lower than that of polyoxyethylene or polyoxypropylene. Moreover, we were interested in the salt effect as block compatibilization was concerned. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 3665–3673, 2005     

The effect of phenyl group on the electronic and phosphorescent properties of cyclometalated analogues of platinum(II) terpyridine complexes: a theoretical study

In this work, we theoretically investigate the effect of phenyl group on the electronic and phosphorescent properties of cyclometalated platinum(II) complexes, thereby designing an efficient blue emitting material. Three platinum(II) complexes Pt(N^N^N)Cl (N^N^N = terpyridine), Pt(N^C^N)Cl (N^C^N = 1,3-di(2-pyridyl)-benzene) and Pt(N^N^C)Cl (N^N^C = 6-phenyl-2,2′-bipyridines) are chosen as the models. Their electronic and phosphorescent properties are investigated utilizing quantum theoretical calculations. The results reveal that the phenyl group significantly affects the molecular and electronic structures, charge distribution and phosphorescent properties. The coordination bond length trans to phenyl group is the longest among the same type of bonds owing to the trans influence of phenyl group. Moreover, the phenyl group largely restricts the geometry relaxation of cyclometalated ligand. The strong σ-donor ability of Pt–C bond makes more electrons center at Pt atom and the fragments trans to phenyl group. In comparison with Pt(N^N^N)Cl and Pt(N^N^C)Cl, the complex Pt(N^C^N)Cl has the smallest excited-state geometry relaxation and the biggest emission energy and spatial overlap between the transition orbitals in the emission process. As a result, Pt(N^C^N)Cl has the largest emission efficiency, which well agrees with the experimental observation. Based on these calculation results, a potentially efficient blue-emitting material is designed via replacing pyridine groups in Pt(N^C^N)Cl by 3-methylimidazolin-2-ylidene.     

13C-13C spin-spin coupling constants in structural studies: XLIII. Stereochemical study on functionalized 3-iminopyrrolizines

Three 1-ethylsulfanyl-3-imino-3H-pyrrolizine-2-carboxamides were synthesized by intramolecular cyclization of substituted (2Z)-2-cyano-3-ethylsulfanyl-3-(1H-pyrrol-2-yl)prop-2-enamides. The products were assigned syn configuration at the C=N bond and preferential s-cis orientation of the carbamoyl group on the basis of the experimental ¹³C-¹³C coupling constants and high-level nonempirical quantum-chemical calculations.     

Substituent effect on diastereoselectivity in Type-II ene cyclisation: a theoretical study

Methyl and methoxy substituted transition states (TS) of Type-II ene cyclisation have been optimized by ab-initio method and relative stability of the diastereomeric TSs have been calculated. In all TSs, equatorial substituent positions have been found to be preferred over the axial positions except for the 4′-substituted methoxy derivative, in which the methoxy group prefers to retain axial position. It has also been noted that the presence of the methoxy group(s) in other position(s) may affect the stability of axially oriented TS and thus alters the overall stereoselectivity of the reaction.