Influence of the polydispersity of polymeric surfactants on the enantioselectivity of chiral compounds in micellar electrokinetic chromatography

Poly(sodium undecenoyl-L-leucinate) (poly-L-SUL) was fractionated by the use of different molecular weight cutoff (MWCO) filters to narrow the polydispersity of the macromolecular sizes of the polymeric surfactant. The resulting polymeric surfactant fractions were characterized by the use of three techniques: (1) pulsed field gradient nuclear magnetic resonance (PFG-NMR) was used to determine the hydrodynamic radii, (2) analytical ultracentrifugation (AUC) was used to determine the molecular weights, and (3) steady-state fluorescence was used to determine the polarity of the nonfractionated and fractionated polymeric surfactants. From the data acquired from PFG-NMR, AUC, and fluorescence, it was noted that the hydrodynamic radii and molecular weight of the fractionated poly-L-SUL increased, while the polarity decreased with the increase in the size of the MWCO filter. However, a similarity in physical properties was observed between the nonfractionated and 10-30K fractionated poly-L-SUL except for the hydrodynamic radius and diffusion coefficients. The influence of different macromolecular sizes of poly-L-SUL on the chiral separation of phenylthiohydantion (PTH)-amino acids and coumarinic derivatives, as test analytes, was elucidated by the use of micellar electrokinetic chromatography (MEKC). The size of polymeric surfactants as a prerequisite for chiral separation was demonstrated by comparing the separation properties of fractionated versus nonfractionated polymeric surfactants. Fractionated poly-L-SUL resulted in enhanced resolution and separation efficiency of the test analytes as compared to the case of the nonfractionated poly-L-SUL. This observation indicates that minimizing polydispersity of polymeric surfactants may be important for some chiral separation applications.     

A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization

Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(35)-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD.     

Thermal behavior of some aromatic copolyethers containing a propylenic spacer

The main objective of this paper is to study the thermal stability of some aromatic copolyethers containing a propylenic spacer. Some of the investigated copolyethers displayed a liquid crystalline (LC) behavior, with the presence of the mesogenic groups in the main chain, inducing high values of the thermal transition temperatures. As a consequence, a thermal stability study was necessary to establish the maximum temperature value for the LC behavior characterization. A thermal degradation mechanism is proposed, taking into consideration the azobenzenic unit as the weakest link in the polymer chain and thus, the starting point of the thermal degradation process. The degradation mechanisms were correlated with the chemical structure and the polarity and conformation of the chains. Conformational analysis was performed using molecular simulations. Freeman-Caroll and Coats-Redfern methods were used to calculate some kinetic characteristics.     

Enantioselectivity of structurally modified poly(sodium undecenoyl-L-leucinate) by insertion of Triton X-102 surfactant molecules

The effectiveness of Triton X-102 (TX-102), as a structural modifier of the polymeric surfactant sodium undecanoyl-L-leucinate (L-SUL) was investigated for enhanced enantiomeric recognition of various chiral compounds in micellar electrokinetic chromatography (MEKC). Increasing concentrations of TX-102 were separately added into the micellar solutions of L-SUL and then polymerized to form poly-L-SUL. The resulting polymers were purified by use of 3500 molecular-weight-cutoff (MWCO) dialysis membranes. Fluorescence and pulsed field gradient-nuclear magnetic resonance (PFG-NMR) techniques were used to elucidate the structural effects of TX-102 on poly-L-SUL. Evaluation of data from fluorescence measurements suggested an increase in polarity with increasing concentration of TX-102. However, the polarity decreased at higher concentrations of TX-102. Evaluation of data from PFG-NMR suggested an increase in hydrodynamic radius upon increasing the concentration of TX-102. The racemates of coumarinic and phenythiohydantoin amino acid derivatives, and pindolol were used as test analytes in MEKC. A notable increase in resolution and capacity factors of the test analytes was observed when the modified poly-L-SUL was used in MEKC measurements. Examination of the data obtained from fluorescence, PFG-NMR, and MEKC suggests a strong correlation between the polarity and the hydrodynamic radii of TX-102 modified micelles and the enantiomeric resolution of the test analytes.     

Combined Experimental and Simulation Studies Suggest a Revised Mode of Action of the Anti‐Alzheimer Disease Drug NQ‐Trp

Inhibition of the aggregation of the monomeric peptide β‐amyloid (Aβ) into oligomers is a widely studied therapeutic approach in Alzheimer’s disease (AD). Many small molecules have been reported to work in this way, including 1,4‐naphthoquinon‐2‐yl‐L ‐tryptophan (NQ‐Trp). NQ‐Trp has been reported to inhibit aggregation, to rescue cells from Aβ toxicity, and showed complete phenotypic recovery in an in vivo AD model. In this work we investigated its molecular mechanism by using a combined approach of experimental and theoretical studies, and obtained converging results. NQ‐Trp is a relatively weak inhibitor and the fluorescence data obtained by employing the fluorophore widely used to monitor aggregation into fibrils can be misinterpreted due to the inner filter effect. Simulations and NMR experiments showed that NQ‐Trp has no specific “binding site“‐type interaction with mono‐ and dimeric Aβ, which could explain its low inhibitory efficiency. This suggests that the reported anti‐AD activity of NQ‐Trp‐type molecules in in vivo models has to involve another mechanism. This study has revealed the potential pitfalls in the development of aggregation inhibitors for amyloidogenic peptides, which are of general interest for all the molecules studied in the context of inhibiting the formation of toxic aggregates.     

Dynamics of Asp23-Lys28 salt-bridge formation in Abeta10-35 monomers

In the amyloid fibrils formed from long fragments of the amyloid beta-protein (Abeta-protein), the monomers are arranged in parallel and lie perpendicular to the fibril axis. The structure of the monomers satisfies the amyloid self-organization principle; namely, the low free energy state of the monomer maximizes the number of intra- and interpeptide contacts and salt bridges. The formation of the intramolecular salt bridge between Asp(D)23 and Lys(K)28 ensures that unpaired charges are not buried in the low-dielectric interior. We have investigated, using all-atom molecular dynamics simulations in explicit water, whether the D23-K28 interaction forms spontaneously in the isolated Abeta10-35 monomer. To validate the simulation protocol, we show, using five independent trajectories spanning a total of 100 ns, that the pKa values of the titratable groups are in good agreement with experimental measurements. The computed free energy disconnectvity graph shows that broadly the ensemble of compact random coil conformations can be clustered into four basins that are separated by free energy barriers ranging from 0.3 to 2.7 kcal/mol. There is significant residual structure in the conformation of the peptide in each of the basins. Due to the desolvation penalty, the structural motif with a stable turn involving the residues VGSN and a preformed D23-K28 contact is a minor component of the simulated structures. The extent of solvation of the peptides in the four basins varies greatly, which underscores the dynamical fluctuations in the monomer. Our results suggest that the early event in the oligomerization process must be the expulsion of discrete water molecules that facilitates the formation of interpeptide-interaction-driven stable structures with an intramolecular D23-K28 salt bridge and an intact VGSN turn.     

Hemilabile imino-phosphine palladium(II) complexes: synthesis,molecular structure,and evaluation in Heck reactions

The ligands 2-(diphenylphosphino)benzyl-(2-thiophene)methylimine (V) and 2-(diphenylphosphino) benzyl-(2-thiophene)ethylimine (VI) were prepared from 2-(diphenylphosphino)benzaldehyde and thiophene amines with very good yields. An equimolar reaction of V and VI with either PdCl₂(cod) (cod = cyclooctadiene) or PdClMe(cod) afforded palladium(II) complexes I–IV. The molecular structure of II was confirmed by X-ray crystallography. The coordination geometry around the palladium atom exhibited distorted square planar geometry at the palladium centre. Complexes I, II, and IV were evaluated as catalysts for Heck coupling reactions of iodobenzene with methyl acrylate under mild reaction conditions; 0.1 mole % catalyst, Et₃N base, MeCN reflux for 8 h, 80°C; isolated yield on a 10 mmol scale with catalyst I (64 %), II (68 %), and IV (58 %). They all exhibited significant activities.     

Novel anionic copolymerized surfactants of mixed achiral and chiral surfactants as pseudostationary phases for micellar electrokinetic chromatography

One disadvantage of amino acid-based chiral selectors for micellar electrokinetic chromatography (MEKC) is that either they have very low solubility or are insoluble at acidic pHs. In order to increase solubilities at lower pHs, we have synthesized a highly water-soluble achiral surfactant and copolymerized it with an amino acid-based chiral surfactant. These two surfactants were polymerized either separately or at various molar rations of binary solutions, yielding pure molecular or copolymerized surfactant (CoPS), respectively. All surfactants were characterized by use of several analytical techniques prior to using them as novel pseudostationary phases in MEKC. The chromatographic performance of the CoPS in MEKC was tested with chiral and achiral analytes. The highly soluble sulfate head group significantly increased the solubility of amino acid-based CoPS over a wide range of pH. Three chiral binaphthyl derivatives were tested and each surfactant system was found to have different selectivity.     

Enantioselectivity of alcohol-modified polymeric surfactants in micellar electrokinetic chromatography

A novel method of modifying sodium undecanoyl-L-leucinate (SUL) micelles employed in chiral separation of analytes in micellar electrokinetic chromatography (MEKC) to enhance selectivity toward specific analytes is discussed. The current study aimed at modifying the SUL micelles by introducing different alcohols into the mono-SUL micelles. The micellar solutions were then polymerized in the presence of alcohols followed by postpolymerization extraction of the alcohols to yield alcohol-free polymeric surfactants (poly-L-SUL). The effects of hexanol (C(6)OH) and undecylenyl alcohol (C(11)OH) on micellar properties of this surfactant were investigated by use of surface tensiometry, fluorescence spectroscopy, pulsed field gradient-nuclear magnetic resonance (PFG-NMR), and MEKC. The surface tension and PFG-NMR studies indicated an increase in the critical micelle concentration (cmc) and micellar size upon increasing the alcohol concentration. Fluorescence measurements suggested that alcohols induce closely packed micellar structures. Coumarinic and benzoin derivatives, as well as (+/-)-1, 1'-binaphthyl-2,2'-dihydrogen phosphate (BNP) were used as test analytes for MEKC experiments. Examination of MEKC data showed remarkable resolutions and capacity factors of coumarinic derivatives obtained with modified poly-L-SUL as compared to the unmodified poly-L-SUL. Evaluation of fluorescence, PFG-NMR, and MEKC data suggest a strong correlation between the polarity and hydrodynamic radii of alcohol-modified micelles and the resolution of the test analytes.