Novel biotinylated bile acid amphiphiles: micellar aggregates formation and interaction with hepatocytes

Amphiphilic bile acids linked through an oligoethylene glycol to a biotin moiety were synthesized and shown to create micellar structures in aqueous environment, interact with avidin and be efficiently incorporated into hepatocyte cells, suggesting their potential as a drug delivery system against liver diseases.     

A new type of boronic acid fluorescent reporter compound for sugar recognition

Fluorescent boronic acids that change fluorescent properties upon carbohydrate binding are very useful for the preparation of fluorescent sensors for sugars. Herein we report 5-quinolineboronic acid (5-QBA) that shows significant fluorescent property changes through a unique pK_a-switching mechanism upon binding a diol in aqueous solution.     

Novel self-assembled molecular aggregates formed by fluoroalkyl end-capped oligomers and their application

A variety of fluoroalkyl end-capped oligomers were prepared under mild conditions by the use of fluoroalkanoyl peroxide as a key intermediate. These oligomers can form the self-assembled molecular aggregates with the aggregations of end-capped fluoroalkyl groups in aqueous and organic media. Fluorinated self-assembled molecular aggregates containing carboxyl and sulfo groups were suggested to interact with positively charged HIV-1 to exhibit a potent anti-HIV-1 activity in vitro. In contrast, fluoroalkyl end-capped oligomers containing cationic segments exhibited not only the unique surface active properties imparted by fluorine as well as the usual low-molecular fluorinated surfactants, but also high surface antibacterial activity. Fluoroalkyl end-capped oligomers containing betaine-type segments were found to cause a gelation where the strong aggregation of the end-capped fluoroalkyl groups is involved in establishing the physical gel network in water and polar organic solvents under non-crosslinked conditions. Similarly, fluoroalkyl end-capped oligomers containing hydroxyl groups could cause a gelation, where the aggregation of fluoroalkyl groups and hydrogen-bonding interaction is involved in establishing a physical gel network in water and polar organic solvents under non-crosslinked conditions. Fluoroalkanoyl peroxide is also a convenient tool for the preparation of new fluoroalkyl end-capped oligomers containing recognition moieties such as diacetone segments. These fluorinated oligomers containing recognition moieties could form the self-assembled molecular aggregates to recognize selectively the hydrophilic amino and N,N-dimethylamino compounds as guest molecules.     

Glucose recognition by a supramolecular complex of boronic acid fluorophore with boronic acid-modified cyclodextrin in water

A boronic acid fluorophore (C1-APB)/boronic acid-modified γ-cyclodextrin (3-PB-γ-CyD) complex as a supramolecular sensor has been designed for selective glucose recognition in water. The fluorescent response behavior of the C1-APB/3-PB-γ-CyD complex under various pH conditions revealed that a C1-APB/3-PB-γ-CyD complex solution containing glucose showed a large increase in the fluorescence intensity under alkaline pH conditions. In contrast, only small increases in the fluorescence intensity were noted for fructose and without sugar solutions. The observed response selectivity for the C1-APB/3-PB-γ-CyD complex was on the order of glucose > galactose, mannose > fructose. The evidence on a large value of the inclusion constant (K(L·CyD) = 6.5 × 10(3) M(-1)), a marked broadening of the (1)H NMR spectra, and an enhancement of induced circular dichloism (ICD) intensity for the C1-APB/3-PB-γ-CyD complex by glucose binding supported the multi-point interaction of the C1-APB/3-PB-γ-CyD complex with glucose. These results demonstrated that the C1-APB/3-PB-γ-CyD complex functioned as an efficient supramolecular sensor for selective glucose recognition in water.     

Reversible conformational transitions of a polymer brush containing boronic acid and its interaction with mucin glycoprotein

Reversible changes of the height of a polymer brush containing phenylboronic acid were studied. The polymer brush thickness underwent reversible changes of 0.5–1 nm, in response to the changes in composition of the contacting aqueous phase from deionized water to bicarbonate buffer and vice versa, apparently due to the conformational transition of the weak polyelectrolyte to the more extended electrically charged state. Adsorption of mucin glycoprotein to the polymer brush took place due to boronate/sugar interactions between the glycoprotein and the graft copolymer and resulted in further increase of the brush height by ca. 1.5 nm, as observed by means of spectral correlation spectroscopy and ellipsometry.

     

A comparative Langmuir-Blodgett study on a set of covalently linked porphyrin-based amphiphiles: a detailed atomic force microscopic study

A set of covalently linked phenyl-amidophenyl-substituted porphyrin amphiphiles with n-C15H31 tails have been synthesized and completely characterized. These amphiphiles form good Langmuir-Blodgett (LB) films at the air/water interface. Mean molecular areas for the series were measured from the isotherms and found to increase as the number of aliphatic chains increased from one to four. No influence of the subphase pH was observed on the isotherms. LB films can be transferred successfully onto different solid surfaces. The LB films were characterized using tapping mode atomic force microscopy (AFM). Bis-, tris-, and tetra-substituted porphyrins were found to be fairly good film-forming amphiphiles, whereas irregular aggregates were seen in the case of the monosubstituted porphyrin amphiphile. Multilayers were also formed with tetra-substituted amphiphiles on mica. Detailed AFM studies of tetra-substituted amphiphiles have been carried out to investigate the effect of preparation procedure and solid substrates on film formation and transfer. The absorption and fluorescence spectra for the amphiphiles in solution and LB films deposited onto mica and glass were recorded, which demonstrated the successful transfer of LB films onto the substrates and provided more information about the arrangement of porphyrin molecules within the LB films. For comparison, self-assembled monolayers (SAMs) and the cast thin films of the amphiphiles were prepared and characterized.     

Use of the interaction of a boronic acid with a merocyanine to develop an anionic colorimetric assay

A displacement assay based on the interaction of Brooker’s merocyanine (BM), a merocyanine dye, with an excess of phenylboronic acid (BA) was studied in acetonitrile. BM is colored in solution, but its reaction with BA yields a colorless covalently linked BA-BM species. This strategy was studied in the presence of different anions (F⁻, Cl⁻, Br⁻, I⁻, , , CH₃COO⁻, and ), but only fluoride, a strongly nucleophilic anion, and to a much lesser extent acetate, reacted with BA-BM, displacing BM through a bimolecular nucleophilic substitution mechanism, and coloring the solution. Experimental data were collected and are shown here in order to gain a better understanding of this chromogenic sensor.     

Straightforward synthesis and crystal structures of the 3-piperazine-bisbenzoxaboroles and their boronic acid analogs

The straightforward synthesis of a highly biologically active 3-piperazine-bisbenzoxaborole and its fluorine analog has been described. The obtained bisbenzoxaboroles have been used in the synthesis of their phenylboronic acids analogs. One diboronic acid has been also isolated as hydrochloride salt as well as its methyl monoester. All the described compounds display unique molecular architectures, which have been determined by X-ray measurements.     

Effect of stereogenic centers on the self-sorting, depolymerization, and atropisomerization kinetics of porphyrin-based aggregates

We present our results on the mixing of different porphyrin molecules in supramolecular assemblies. Herein, chiral amplification experiments reveal the subtle role of the structural (mis)match between these monomers. We show that according to the "sergeant-and-soldiers" principle, a chiral porphyrin "sergeant" efficiently mixes with achiral "soldiers" in the same helical aggregate and strongly biases its handedness. However, when we mix two porphyrin enantiomers in a majority-rules experiment, no chiral amplification is observed at all, which is due to their narcissistic self-sorting into conglomerate-like aggregates. The mixing between two enantiomers in the same stack only occurs in a diluted-majority-rules experiment, in which enantiomeric mixtures of sergeants are diluted with achiral soldiers. The different outcomes of these chiral amplification phenomena are verified by modeling studies that reveal high mismatch penalties, which are ascribed to the high stereocenter loading of 12 methyl groups onto the monomers. Mixed-metal chiral amplification experiments between copper- and zinc-porphyrins show the same distinction in their mixing behavior, which is further supported by fluorescence measurements. The selective removal of chiral Zn-porphyrins from these mixed-metal systems is performed with the Lewis base quinuclidine that depolymerizes the Zn-porphyrins upon axial ligation. This extraction process proceeds at different time scales, depending on the mixed state: slow extraction kinetics for the mixed sergeant-and-soldiers and diluted-majority-rules systems and an instant extraction for the phase-separated majority-rules system. By simultaneously monitoring the supramolecular chirality during extraction, a chiral memory effect is observed for both mixed systems that show slow extraction kinetics. For the sergeant-and-soldiers system, the remaining supramolecular backbone contains achiral monomers only, which give rise to a long lasting chiral memory with slow, entropy-driven atropisomerization. Yet in case of the diluted-majority-rules system, the remaining backbone contains a mixture of achiral and chiral monomers in its unpreferred helicity; giving rise to a short chiral memory, in which the fast atropisomerization is enthalpy-driven due to the high mismatch penalty.     

Porphyrin-based organogels: control of the aggregation mode by a pyridine-carboxylic acid interaction

To find a new strategy for designing porphyrin-based organogelators, hydrogen-bond-donating (carboxylic acid)/accepting (pyridine) substituents or electron-donating (dialkylamino)/withdrawing (pyridine) substituents were introduced into peripheral positions of a porphyrin (1cp or 1ep, respectively), and the gelation properties were compared with those of symmetrical reference compounds bearing two pyridyl substituents or two ester groups (1pp or 1ee, respectively). It was found that the symmetrical molecules show a solubility that is quite inferior to that of 1cp and 1ep having a dipole moment and precipitate from most organic solvents. 1cp, 1ep, and 1ee formed gels with cyclohexane, methylcyclohexane, and several alcoholic solvents, but scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed that their superstructures constructed in the organogels are very different. In cyclohexane, 1cp resulted in a sheetlike structure, whereas 1ep and 1ee resulted in a fiberlike structure. The difference is attributed to the two-dimensional interactive forces in 1cp consisting of the porphyrin-porphyrin pi-pi stacking and the carboxylic acid-pyridine hydrogen bonding. In fact, when the hydrogen-bonding interaction was weakened by alcoholic solvents or by adding pyridine or N,N-(dimethylamino)pyridine, the sheetlike structure was transfigured to the fiberlike structure. Further detailed analyses of their aggregation modes were conducted by spectroscopic methods such as ultraviolet-visible (UV-vis) absorption, Fourier transform infrared (FT-IR), and X-ray diffraction (XRD). On the basis of these findings, the influence of these peripheral substituents on the gel formation and the aggregation mode was discussed.     

Synthesis of non-proteinogenic phenylalanine analogues by Suzuki cross-coupling of a serine-derived alkyl boronic acid

Protected serine-derived boronic acids have been prepared as β-anionic alanine equivalents, and undergo efficient Suzuki cross-coupling with a variety of aryl halides to give, after elaboration, non-proteinogenic phenylalanine analogues.     

Stability of two-dimensional crystalline aggregates of a protein studied by molecular dynamics

Two-dimensional protein (ferritin) aggregates with a square lattice symmetry, which were formed within a thin liquid layer on a mercury surface, were studied by molecular dynamics (MD) simulation. For the simulation, the ferritin molecule was modeled by an assembly of 49 spheres, and the intermolecular interactions were given by simple formulae. During the simulation, molecules were confined within a layer, which corresponds to the thin liquid layer. An annealing MD simulation was done starting from a random molecular configuration within the layer, and aggregates with the square lattice symmetry were also obtained. To study the stability of aggregates, dissociation processes of the aggregates were analyzed using MD simulations at room temperature. Interactions between the nearest-neighbor molecules were regarded as bonds. Mean bond energies and correlation coefficients between the bond energies were calculated from the MD trajectories. A decay profile according to the dissociation was obtained, yielding a dissociation rate constant. Buried bonds were stronger than peripheral bonds. The larger the aggregate size, the stronger the bond for each of the buried and peripheral bonds. A simple theoretical account, which is applicable to a general bonded network, was introduced to analyze the dynamics of the aggregates. © 1994 by John Wiley & Sons, Inc.     

Conformational control of flexible molecular tweezers by intramolecular CH/π interaction

The synthesis of new flexible molecular tweezers based on 3,4,8,10,11,13-hexahydro-1H,6H-2,5,9,12-tetraoxa-benzo[1,2:4,5]dicyclooctene bearing two naphthalenes is presented. Intramolecular CH/π interaction between the alkyl ring and the two terminal naphthalenes controls the conformation to give a self-quenched cleft form.     

Study on the interaction between oxolinic acid aggregates and protein and its analytical application

It was found that oxolinic acid (OA) at high concentration can self-assemble into nano- to micro- meter scale OA aggregates in Tris-HCl (pH 7.48) buffer solution. The nanoparticles of OA were adopted as fluorescence probes in the quantitative analysis of proteins. Under optimum conditions, the fluorescence quenching extent of nanometer scale OA aggregates was in proportion to the concentration of albumins in the range of 3.0 × 10⁻⁸ to 3.0 × 10⁻⁵ g mL⁻¹ for bovine serum albumin (BSA) and 8.0 × 10⁻⁸ to 8.0 × 10⁻⁶ g mL⁻¹ for human serum albumin (HSA). The detection limits (S/N = 3) were 3.4 × 10⁻⁹ g mL⁻¹ for BSA, and 2.6 × 10⁻⁸ g mL⁻¹ for HSA, respectively. Samples were satisfactorily determined. The interaction mechanism of the system was studied using fluorescence, UV-vis, resonance light scattering (RLS) and transmission electron microscope (TEM) technology, etc., indicating that the nonluminescent complex was formed between serum albumin molecular and OA, to disaggregate the self-association of OA, which resulted in the dominated static fluorescence quenching in the system.     

A self-assembled porphyrin-based dimeric capsule constructed by a Pd(II)-pyridine interaction which shows efficient guest inclusion

Novel self-assembled molecular capsules were constructed from two moles of pyridine-containing porphyrin derivatives and four moles of Pd(II) complexes utilizing a pyridine-Pd(II) interaction. The (1)H NMR spectral studies established that these self-assembled molecular capsules 5 and 6 have a highly symmetrical D(4)(h)() structure as well as a large inside cavity. It was shown that molecular capsule 6 can include a large bipyridine guest by a two-point simultaneous pyridine-Zn(II) interaction.     

Investigation in monolayers of double-chain fluorocarbon amphiphiles Effect of headgroups on molecular packing and interaction between hydrocarbon and fluorocarbon monolayers

The surface pressure-area diagrams of double-chain fluorocarbon amphiphiles with different headgroup compositions show that the amphiphiles arrange almost perpendicularly to the water subphase and the structure of headgroups exerts significant influence on the amphiphile packing. Strong hydrogen bonding and weak electrostatic interaction favor the formation of stable monolayers. Perfluorooctanoic acid (FOA) cannot form monolayer at water/air interface and can only form liquid monolayer in subphase of calcium nitrate solution. Complete phase separation of palmitic acid and a fluorocarbon amphiphile with shorter hydrocarbon spacer group, 1, could be demonstrated in monolayers by using the phase rule of Crisp. The creation of phase-separated monolayers is possible when the monolayer is composed of a mixture of palmitic acid and a fluorocarbon amphiphile with longer hydrocarbon spacer group, 2. It can be suggested that the miscibility of hydrocarbon amphiphiles with fluorocarbon amphiphiles is determined by the hydrocarbon fraction of fluorocarbon amphiphiles.     

The effect of boronic acid acidity on performance of viologen-based boronic acids in a two-component optical glucose-sensing system

A two-component saccharide sensing system using the fluorescent dye, hydroxypyrene trisulfonic acid, combined with a boronic acid functional viologen as a receptor/quencher in pH 7.4 buffer solution has been further investigated. The effect of substituents on the acidity of the boronic acid was measured. The boronic acid pK_a changed in the expected manner when electron donating or withdrawing groups were present. The glucose binding constants were dependent on pK_a, but no simple correlation was observed for the Stern-Volmer quenching constants and the fluorescence signal modulation.     

Synthesis and crystal morphology control of AlPO4-5 molecular sieves by microwave irradiation

AlPO₄-5 molecular sieves have been synthesized by the hydrothermal and solvothermal reactions using triethylamine as a template, aluminum isopropoxide and orthophosphate as the aluminum and phosphorus resource under microwave irradiation. The influences of various experimental parameters, such as reaction time, reaction temperature and reaction power, have been systematically investigated. The morphology control of AlPO₄-5 molecular sieves was achieved by changing the dosage of solvent and HF to control the solvent polarity and control the nucleation respectively. The products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and so on. The results show that the aspect ratio of the AlPO₄-5 molecular sieves increases with the increase of the solvent polarity and with the increasing concentration of HF, the morphology of AlPO₄-5 molecular sieves changes from hexagonal plate to hexagonal rod.     

Structure-based discovery of a boronic acid bioisostere of combretastatin A-4

Targeting the microtubule system represents an attractive strategy for the development of anticancer agents. In this study, we report a class of combretastatin A-4 (CA-4) analogs derivatized with a boronic acid moiety replacing the hydroxyl group on the C-ring of CA-4. Docking studies of the X-ray structures of our aryl-boronic analogs onto an X-ray structure of the alpha,beta-tubulin heterodimer suggested that cis-6 was a potent inhibitor of the colchicine binding. The model indicated that there would be strong hydrogen bonding between the boronic acid moiety and Thr-179 and Val-181 of alpha-tubulin. We demonstrate that the cis-6 boronic acid bioisostere of CA-4: (1) inhibits tubulin assembly, (2) competitively displaces colchicine, and (3) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4.     

Biological activity of selected boronic acids and their derivatives

A series of substituted phenylboronic acids and benzoxaboroles were evaluated for their antimicrobial activity. Antibacterial and antifungal action activity of several compounds was tested against Escherichia coli 67, Staphylococcus aureus 209‐p, Mycobacterium luteum VCM B‐868, Aspergillus niger VCM F‐1119 and Candida tenuis VCM Y‐70. Substituted phenylboronic acids have low biological activity against all the investigated species. Benzoxaboroles reveal higher biological activity in comparison with the corresponding acids. The highest activity was observed for small benzoxaborole molecules, and the unsubstituted benzoxaborole has only slightly lower biological activity as compared with the 5‐fluoro‐substituted one (AN2690). The compound possessing two oxaborole fragments has very high biological activity towards Mycobacterium luteum and both investigated fungi. Copyright © 2012 John Wiley & Sons, Ltd.