Bolaamphiphiles promote phospholipid translocation across vesicle membranes

A series of membrane-spanning bolaamphiphiles (molecules with two hydrophilic end groups connected by a hydrophobic linker) were prepared by a modular synthetic method and evaluated for their abilities to affect the dynamics of a surrounding bilayer membrane. The goal was to determine if the bolaamphiphiles promote the translocation of phospholipids across vesicle membranes. The bolaamphiphiles were incorporated at low levels (up to 5 mol %) in vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Inward translocation assays were performed using fluorescent, NBD-labeled phospholipid probes with phosphocholine (PC) or phosphoglycerol (PG) headgroups. The membrane-spanning bolaamphiphiles promote the translocation of both phospholipid probes in the order PG > PC, whereas shorter bolaamphiphiles (structures that must adopt a U-shape and keep both end groups in the same leaflet of the membrane), and regular amphiphiles with one hydrophilic end group, are inactive. These results are an exception to the rule-of-thumb that membrane-spanning bolaamphiphiles are inherently membrane-stabilizing molecules that inhibit all types of membrane transport.     

Temperature-dependent self-assembly and mixing behavior of symmetrical single-chain bolaamphiphiles

The temperature-dependent self-assembly and the mixing behavior of symmetrical single-chain bolaamphiphiles with different polymethylene chain lengths and different headgroup structures were investigated in water by differential scanning calorimetry (DSC), cryo transmission electron microscopy (cryo-TEM), and small angle neutron scattering (SANS). The even-numbered polymethylene-1,omega-bis(phosphocholines) (PC-C n-PC) are known to form nanofibers composed of stretched molecules with an all- trans alkyl chain conformation (Drescher, S.; Meister, A.; Blume, A.; Karlsson, G.; Almgren, M.; Dobner, B. Chem.Eur. J. 2007, 13, 5300-5307). The odd-numbered analogues were synthesized to study a possible even-odd effect of these bolaamphiphiles during their aggregation in water. In addition to these bolaamphiphiles with phosphocholine headgroups, a new series of polymethylene-1,omega-bis(phosphodimethylethanolamines) (Me2PE-Cn-Me2PE) with smaller headgroup sizes was synthesized. These bolaamphiphiles show an additional fiber-fiber transition when the alkyl chain length exceeds 26 carbon atoms. The mixing behavior of both types of bolaamphiphiles indicates that differences in the alkyl chain length up to six carbon atoms are tolerated within the fiber structure. The mixing of two Me2PE-Cn-Me2PE or PC-Cn-PC type bolaamphiphiles with different alkyl chain lengths offers the possibility to adjust the temperature, where the cross-linking of the fibers is disrupted and where the fibers break apart. As a consequence, temperature switchable hydrogels are obtained that can be fine-tuned for drug delivery applications. The comparison with dotriacontane-1,32-diyl-bis[2-(methylammonio)-ethylphosphate] (MePE-C32-MePE), a new bolaamphiphile with even smaller phosphomonomethylammonio headgroups, illustrates the importance of the headgroup size for the aggregation behavior. This bolaamphiphile self-assembles exclusively into lamellar structures, and this aggregate type persists in mixtures with the fiber forming Me2PE-C32-Me2PE.     

Membrane-mimetic films of asymmetric phosphatidylcholine lipid bolaamphiphiles

Membrane-spanning phospholipid bolaamphiphiles either alone or as a constituent of a multicomponent lipid membrane may prove to be facile building blocks for generating robust bioactive membrane-mimetic assemblies. We have previously reported the synthesis of asymmetric dialkyl phospholipid bolaamphiphiles that contain ester linked phosphatidylcholine and amine functionalities at opposite chain ends. In this report, we describe the synthesis of phospholipid bolaamphiphiles that are conjugated to biotin via the terminal amine with or without a poly(ethylene oxide) spacer arm of varying chain length. The behavior of biotinylated bolaamphiphiles as a self-assembled monolayer at an air-water interface was characterized by epi-fluorescence microscopy and revealed that domain structure and pi-A isotherms were substantially influenced by linker type and size. Substrate bound assemblies were produced by Langmuir-Blodgett deposition onto planar substrates coated with an avidin derivatized polyelectrolyte multilayer. Significantly, external reflectance infrared spectroscopy confirmed the fabrication of bolaamphiphile thin films that display extended stability in vitro.     

双头基两亲分子研究进展

本文介绍了双头基两亲分子的结构特征与性质, 概述了由双头基两亲分子在气液界面形成的单分子膜以及在体相中形成的囊泡的特征, 并介绍了这类两亲分子在催化、生物矿化、药物缓释、膜破解以及纳米材料等方面的应用研究。对其研究前景进行了展望。     

Organized assemblies in bolaamphiphile/oppositely charged conventional surfactant mixed systems

Five ionic bolaamphiphiles were synthesized and the aggregation behavior of bola single systems and bola/oppositely charged conventional surfactant mixed systems was studied. Small spherical vesicles were formed in all these mixed systems revealed by transmission electron microscopy (TEM). Variation of the structure of the hydrophobic chain of bolaamphiphiles has great influences on the vesicle formation ability. Vesicles were also found in the single system of a carboxylate bolaamphiphile, which was attributed to the hydrolysis of the bolaamphiphile. The results of FT-IR and X-ray diffraction (XRD) showed that bolaamphiphiles spanned through the vesicle membranes in these mixed systems. Super thermostability of the vesicles in this kind of mixed system was also investigated.     

Self-assembly of bipolar amphiphiles

Over the past 2 years, various symmetrical and unsymmetrical bipolar amphiphiles (bolaamphiphiles) have been synthesized to study their self-organizing and packing properties alone as well as in mixtures with conventional amphiphiles. This review focuses on the lyotropic properties of these bolaamphiphiles and describes their in some cases quite unusual supramolecular self-assembling properties in aqueous media and at the air–water and liquid–solid interface.     

Metal-complexed nanofiber formation in water from dicarboxylic valylvaline bolaamphiphiles

Nanofiber formation of dipeptide-based bolaamphiphiles, bis (N-alpha-amide--valyl--valine) 1,n-alkane dicarboxylate (n=6, 8, 10, and 12) in water was analyzed by TEM, SEM, IR, and XRD. The bolaamphiphiles proved to be coordinated to divalent transition-metal cations, such as Co2+, Ni2+, Cu2+, and Zn2+, giving precipitates, colloidal dispersions (loose hydrogels), and hydrogels upon self-assembly at 23 or 70 degrees C. Longer oligomethylene chains and strong interaction between the metal cations and the carboxylate anions are responsible for the hydrogel formation. Energy-filtering transmission electron microscopy (EF-TEM) and field-emission scanning electron microscopy (EF-SEM) images revealed that the colloidal dispersions and the hydrogels consist of a large number of nanofibers with widths of 15-20 nm and lengths of several micrometers. FT-IR and powder XRD measurement supported the existence of a beta-sheet structure-based nanofibers complexing with metal cations.     

Design and synthesis of asymmetric acyclic phospholipid bolaamphiphiles

[structure: see text] A synthetic route was devised for the generation of asymmetric lipid bolaamphiphiles through the sequential esterification of an alkyldioic acid, bearing distinct terminal protecting groups, with propanylamine and lyso-phosphatidylcholine headgroups. Bolaamphiphile self-assembly was investigated in solvent mixes of varying polarity by nuclear magnetic resonance (NMR) and Fourier transform-infrared (FT-IR) spectroscopy, as well as in water by cryo-high-resolution scanning electron microscopy (cryo-HRSEM). We anticipate that asymmetric lipid bolaamphiphiles will provide facile building blocks for engineering a variety of unique membrane-mimetic structures.     

Formation of columnar mesophases by calamitic molecules: a modulated SmA phase in mixtures of amphiphilic and bolaamphiphilic biphenyl derivatives

Binary mixtures of bolaamphiphilic biphenyl derivatives with each other and with amphiphilic biphenyl derivatives were investigated by means of optical microscopy. The miscibility of the bolaamphiphiles is very sensitive to the molecular length of the components. The SmA phases of bolaamphiphiles with the same length are completely miscible. If the length difference between the two components of the binary system increases, a miscibility gap occurs. Due to their different phase structures (bilayer versus monolayer) no miscibility in the SmA phases was found for amphiphilic and bolaamphiphilic compounds with comparable molecular lengths. However, in some cases a novel mesophase was induced in the contact region. This mesophase was investigated by X-ray diffraction. It represents a two-dimensionally modulated (columnar) phase with a rectangular lattice (Col r), but the local order is similar to that of disordered smectics. Its formation is explained in terms of ribbon structures resulting from the collapse of smectic bilayers, in strong analogy to the antiphases (SmA) of terminally polar calamitic mesogens.     

Construction of a DNA-Based Supramolecular Nanosheet That Emits Bluish-White Light from Charge-Transfer Excited States of the Nucleobases

1,ω-Inosinic acid-bearing bolaamphiphiles dI(18), dI(19), and dI(20) with a 3′-phosphorylated inosine as a universal base connected to each end of an oligomethylene chain were synthesized for the first time. Single-component self-assemblies of these bolaamphiphiles and their binary self-assemblies with salmon sperm DNA were studied by AFM; temperature-dependent UV absorption, fluorescence, and circular dichroism spectroscopy; and gel electrophoresis. The binary self-assembly of dI(20) and salmon sperm DNA (dI(20)-DNA) had a nanosheet structure with a homogeneous thickness of about 6 nm and widths of several micrometers. Interestingly, an aqueous solution of the nanosheets showed a broad absorption band originating from the charge-transfer (CT) states of the nucleobase in the long-wavelength region (>300 nm), and the molar absorptivity per nucleobase was calculated to be approximately 150 times that of single-stranded (dT20 and dA20) and double-stranded (dT20-dA20) oligonucleotides. In addition, a continuous and broad emission band originating from CT excited states of the nucleobases was observed in the visible region. These observations indicate that CT states of the nucleobases were formed and stabilized in the supramolecular nanosheet and that bluish white light was emitted from CT excited states of the nucleobases.     

Interfacial self-organization of bolaamphiphiles bearing mesogenic groups: relationships between the molecular structures and their self-organized morphologies

This article discusses the relationship between the molecular structure of bolaamphiphiles bearing mesogenic groups and their interfacial self-organized morphology. On the basis of the molecular structures of bolaamphiphiles, we designed and synthesized a series of molecules with different hydrophobic alkyl chain lengths, hydrophilic headgroups, mesogenic groups, and connectors between the alkyl chains and the mesogenic group. Through investigating their interfacial self-organization behavior, some experiential rules are summarized: (1) An appropriate alkyl chain length is necessary to form stable surface micelles; (2) different categories of headgroups have a great effect on the interfacial self-organized morphology; (3) different types of mesogenic groups have little effect on the structure of the interfacial assembly when it is changed from biphenyl to azobenzene or stilbene; (4) the orientation of the ester linker between the mesogenic group and alkyl chain can greatly influence the interfacial self-organization behavior. It is anticipated that this line of research may be helpful for the molecular engineering of bolaamphiphiles to form tailor-made morphologies.     

General synthesis and aggregation behaviour of a series of single-chain 1,omega-bis(phosphocholines)

The synthesis and physicochemical characterisation of a series of polymethylene-1,omega-bis(phosphocholines) with even-numbered chain lengths between 22 and 32 carbon atoms is described. Two new synthetic strategies for the preparation of long-chain 1,omega-diols as hydrocarbon building blocks are presented. The temperature-dependent self-assembly of the single-chain bolaamphiphiles was investigated by cryo transmission electron microscopy (cryo-TEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR).     

Controlling Aqueous Self‐Assembly Mechanisms by Hydrophobic Interactions

We report an innovative template‐assisted synthetic protocol for the selective functionalization of terminal triple bonds in oligophenyleneethynylenes (OPE) by pre‐organization in aqueous solution. By this approach, three new OPE‐based bolaamphiphiles substituted with hydrophilic poly(2‐ethyl‐2‐oxazoline) (PEtOx) chains of different length have been synthesized. The chain length was observed to strongly influence the aqueous supramolecular polymerization: bolaamphiphiles with longer hydrophilic chains aggregate into spherical nanoparticles in a stepwise fashion, whereas 2D anisotropic platelets are formed cooperatively if shorter PEtOx chains are used. Our results demonstrate that hydrophobic interactions can be strong enough to trigger cooperative effects in aqueous self‐assembly processes.     

Switchable Solubility of Azobenzene-Based Bolaamphiphiles

The ability to design amphiphiles with predictable solubility properties is of everlasting interest in supramolecular chemistry. Relevant structural parameters include the hydrophobic–hydrophilic balance and structural flexibility. In this work, we investigate the water solubility of azobenzene-based triglycerol bolaamphiphiles (TGBAs). In particular, we analyzed the structural effects of backbone hydrophobicity, flexibility, and cis/trans isomerization on the water solubility of a subset of five TGBAs. This leads to the first example of a non-ionic bolaamphiphile whose water solubility can be changed by irradiation with light. The underlying kinetics were monitored using liquid chromatography and a closer analysis of the underlying aggregation processes provides a mechanistic understanding of the light-driven dissolution process. We anticipate that the results obtained will help to engineer bolaamphiphiles with predictable solution properties in the future.     

Aggregation and layering transitions in thin films of X-, T-, and anchor-shaped bolaamphiphiles at the air-water interface

Aggregation in Langmuir films is usually understood as being a disorderly grouping of molecules turning into chaotic three-dimensional aggregates and is considered an unwanted phenomenon causing irreversible changes. In this work we present the studies of 11 compounds from the group of specific surfactants, known as bolaamphiphiles, that exhibit reversible aggregation and, in many cases, transition to well-defined multilayers, which can be considered as a layering transition. These bolaamphiphiles incorporate rigid π-conjugated aromatics as hydrophobic cores, glycerol-based polar groups and hydrophobic lateral chains. Molecules of different shapes (X-, T-, and anchor) were studied and compared. The key property of these compounds is the partial fluorination of the lateral chains linked to the rigid cores of the molecules. The most interesting feature of the compounds is that, depending on their shape and degree of fluorination, they are able to resist aggregation and preserve a monolayer structure up to relatively high surface pressures (T-shaped and some X-shaped molecules), or create well-defined trilayers (X- and anchor-shaped molecules). Experimental studies were performed using Langmuir balance, surface potential and X-ray reflectivity measurements.     

A family of hydrogels based on ureido-linked aminopolyol-derived amphiphiles and bolaamphiphiles: synthesis, gelation under thermal and sonochemical stimuli, and mesomorphic characterization

This article describes the systematic preparation of a novel family of carbohydrate amphiphiles and bolaamphiphiles in which hydrophilic and hydrophobic units are connected via a ureido or bis(ureido) moiety. The sugar core is derived from aminopolyols such as D-glucamine (1), N-methyl-D-glucamine (2), or the sugar-like species tris(hydroxymethyl)aminomethane (3). The O-unprotected derivatives behave as self-organizing nonionic surfactants with good water gelation ability, which can be induced under thermal or ultrasound-driven stimuli. In addition, some derivatives of 1 and 2, and rarely 3 also formed lyotropic liquid crystals with lamellar or hexagonal structures that exhibit low-temperature transitions.     

Syntheses of d-Glucosaminyl Bolaamphiphiles1

Abstract

Twelve N-acetyl or NH2-free D-glucosaminyl bolaamphiphiles have been synthesized by the intermediate of N-allyloxycarbonyl-d-glucosaminyl precursors. Thus, glycosylation of α,ω-diols with 1,3,4,6-tetra-O-acetyl-2-allyloxycarbonylamino-2-deoxy-β-d-glucopyranose (1) gave the bis(glycosides) 2a-h in good yields and without column chromatography. Alkaline treatment of these derivatives followed by acetylation gave the peracetylated N-acetyl compounds 3a-h which were further deprotected by the Zemplén deacetylation procedure to the N-acetyl-d-glucosaminyl bolaamphiphiles 4a-h. The bis(glycosides) 2c,d,g were also transformed into the O-acetylated amino-free derivatives 5c,d,g by chemospecific deprotection of the N-allyloxycarbonyl groups with palladium (0). Further deprotection of the ester functions led to the completely deprotected bolaamphiphiles 7c,d,g with high yields. Fully deprotected compounds 7a,d,g,h were also obtained from 2a,d,g,h by alkaline treatment and purification by column chromatography. Surface tension measurements were realized for aqueous solutions containing the soluble bolaamphiphiles.     

Evidence for a reverse U-shaped conformation of single-chain bolaamphiphiles at the air-water interface

Infrared reflection absorption spectroscopy and X-ray reflectivity have been used to elucidate the molecular orientation and hydrocarbon chain conformation and packing of the symmetric long-chain bolaamphiphiles dotriacontane-1,1'-diyl-bis-[2-(trimethylammonio)ethylphosphate] (PC-C32-PC) and dotriacontane-1,1'-diyl-bis-[2-(dimethylammonio)ethylphosphate] (Me2PE-C32-Me2PE) at the air-water interface. At low surface pressures, these bipolar amphiphiles are found to lie flat on the water surface with a disordered chain. With increasing surface pressure, the alkyl chain becomes more ordered. Concomitantly, the chain is bent pointing into the air, whereas both polar headgroups keep contact with the water subphase. At an area of 0.9-1.1 nm2 per molecule, a surface pressure plateau is reached for both bolaamphiphiles, where the molecules adopt a reverse U-shaped conformation with a strongly tilted alkyl chain. Further compression leads to the formation of 3-D aggregates.     

De novo design of a bolaamphiphilic peptide with only natural amino acids

A new self-assembling bolaamphiphilic peptide has been designed and synthesized using only natural amino acids. This simple peptide is composed of two lysines connected by 4-8 alanines to maintain the characteristics of the traditional bolaamphiphiles. Based on an irregular secondary structure, it can self-assemble into nanospheres, nanorods, or nanofibers with lengths up to micrometers. The long nanofibers can be broken into smaller fragments by sonication, however, they could reassemble into nanofibers after incubation. Furthermore, the nanostructures were shown to have considerable thermostability. This new bolaamphiphilic peptide differs from any other self-assembling peptides or bolaamphiphiles, and possibly provides a new approach to fabricate nanomaterials.     

Synthesis and Self‐Assembly of Bolaamphiphiles Based on β‐Amino Acids or an Alcohol

The synthesis of bolaamphiphiles from unusual β‐amino acids or an alcohol and C₁₂ or C₂₀ spacers is described. Unusual β‐amino acids such as a sugar amino acid, an AZT‐derived amino acid, a norbornene amino acid, and an AZT‐derived amino alcohol were coupled with spacers under standard conditions to get the novel bolaamphiphiles 5 – 8 (Scheme 1), 12 and 13 (Scheme 2), and 17 and 20 (Scheme 3). Some of these compounds, on precipitation from MeOH/H₂O, self‐assembled into organized molecular structures.