Mycosamine orientation of amphotericin B controlling interaction with ergosterol: sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge

Amphotericin B (AmB 1) is known to assemble together and form an ion channel across biomembranes. The antibiotic consists of mycosamine and macrolactone moieties, whose relative geometry is speculated to be determinant for the drug's channel activity and sterol selectivity. To better understand the relationship between the amino-sugar orientation and drug's activity, we prepared conformation-restricted derivatives 2-4, in which the amino and carboxyl groups were bridged together with various lengths of alkyl chains. K+ influx assays across the lipid-bilayer membrane revealed that ergosterol selectivity was markedly different among derivatives; short-bridged derivative 2 almost lost the selectivity, while 3 showed higher ergosterol preference than AmB itself. Monte Carlo conformational analysis of 2-4 based on NOE-derived distances indicated that the amino-sugar moiety of 2 comes close to C41 because of the short bridge, whereas those of 3 and 4 are pointing outward. The mutual orientation of the amino-sugar moiety and macrolide ring is so rigid in derivatives 2 and 3 that these conformations should be unchanged upon complex formation in lipid membranes. These results strongly suggest that the large difference in sterol preference between derivatives 2 and 3 is ascribed to the different orientation of amino-sugar moieties. These findings allowed us to propose a simple model accounting for AmB-sterol interactions, in which hydrogen bonding between 2'-OH of AmB and 3beta-OH of ergosterol plays an important role.     

Ab initio and analytic intermolecular potentials for Ar-CH(3)OH

Ab initio calculations at the CCSD(T)/aug-cc-pVTZ level of theory were used to characterize the Ar-CH(3)OH intermolecular potential energy surface (PES). Potential energy curves were calculated for four different Ar + CH(3)OH orientations and used to derive an analytic function for the intermolecular PES. A sum of Ar-C, Ar-O, Ar-H(C), and Ar-H(O) two-body potentials gives an excellent fit to these potential energy curves up to 100 kcal mol(-1), and adding an additional r(-n) term to the Buckingham two-body potential results in only a minor improvement in the fit. Three Ar-CH(3)OH van der Waals minima were found from the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ calculations. The structure of the global minimum is in overall good agreement with experiment (X.-C. Tan, L. Sun and R. L. Kuczkowski, J. Mol. Spectrosc., 1995, 171, 248). It is T-shaped with the hydroxyl H-atom syn with respect to Ar. Extrapolated to the complete basis set (CBS) limit, the global minimum has a well depth of 0.72 kcal mol(-1) with basis set superposition error (BSSE) correction. The aug-cc-pVTZ basis set gives a well depth only 0.10 kcal mol(-1) smaller than this value. The well depths of the other two minima are within 0.16 kcal mol(-1) of the global minimum. The analytic Ar-CH(3)OH intermolecular potential also identifies these three minima as the only van der Waals minima and the structures predicted by the analytic potential are similar to the ab initio structures. The analytic potential identifies the same global minimum and the predicted well depths for the minima are within 0.05 kcal mol(-1) of the ab initio values. Combining this Ar-CH(3)OH intermolecular potential with a potential for a OH-terminated alkylthiolate self-assembled monolayer surface (i.e., HO-SAM) provides a potential to model Ar + HO-SAM collisions.     

Generalized van Vleck perturbation theory (GVVPT2) study of the excited states of benzene and the azabenzenes

Generalized van Vleck perturbation theory (GVVPT2) for molecular electronic structures is applied to examine the azabenzene series: benzene, pyridine, pyrazine, symmetric triazine and symmetric tetrazine. The spectra of azabenzenes are complex with large numbers of excited states at low energies comprising n --> pi* and pi --> pi* excited states and also doubly excited states of the n,n --> pi*,pi* type. The calculations are complicated due to strong correlation effects in the nitrogen lone-pair orbitals and the pi electrons. This study is the first to use GVVPT2 on conjugated systems. Comparison is made with experimental data and complete active space second-order perturbation theory, equation of motion coupled cluster and similarity transformed equation of motion coupled cluster theory data. Using polarized valence double split basis sets for benzene and pyrazine (cc-pVDZ) and pyridine (ANO-S) and polarized triple split basis sets (ANO-L) for triazine and tetrazine, the n --> pi* and pi --> pi* states are computed with an average error of 0.28 eV in comparison with available experimental data.     

Pi-envelopes of Lie superalgebras

In this paper we find necessary and sufficient conditions on a finite-dimensional Lie superalgebra under which any associative PI-envelope of is finite-dimensional. We also extend M. Scheunert's result which enables one to pass from color Lie superalgebras to the ordinary ones, to the case of gradings by an arbitrary abelian group.

     

Atomic interactions in the p-type clathrate I Ba8Au5.3Ge40.7

Single crystals of Ba(8)Au(5.3)Ge(40.7) [space group Pm(3)n (No. 223), a = 10.79891(8) ?] were prepared by a Bridgman technique. The crystal structure refinement based on single-crystal X-ray diffraction data does not reveal any vacancies in the Au/Ge framework or in the cages. In addition to the ionic bonding between Ba and the anionic framework, a direct interaction between Ba and Au atoms was identified in Ba(8)Au(5.3)Ge(40.7) by applying the electron localizability indicator. As expected by the chemical-bonding picture, Ba(8)Au(5.3)Ge(40.7) is a diamagnet and shows p-type electrical conductivity with a hole carrier concentration of 7.14 × 10(19) cm(-3) at 300 K and very low lattice thermal conductivity of ≈0.6 W m(-1) K(-1) at 500 K. The thermoelectric figure of merit ZT of single crystals of Ba(8)Au(5.3)Ge(40.7) attains 0.3 at 511 K and reaches 0.9 at 680 K in a polycrystalline sample of closely similar composition. This opens up an opportunity for tuning of the thermoelectric properties of materials in the Ba-Au-Ge clathrate system by changing the chemical composition.     

Nonwettable thin films from hybrid polymer brushes can be hydrophilic

Hybrid brushes composed of two liquid polymers, poly(dimethylsiloxane) (PDMS) and a highly branched ethoxylated polyethylenimine (EPEI), were synthesized on Si wafers by the "grafting to" method and by applying a combinatorial approach (fabrication of gradient brushes). The combinatorial approach revealed a strong effect of "layer assisted tethering", which allowed us to synthesize hybrid brushes twice as thick as the reference homopolymer brushes. The hybrid brushes are stable thin films that can rapidly and reversibly switch between hydrophilic and hydrophobic states in water and air, respectively. The switching in water affects a rapid release of amino functional groups which can be used to regulate adhesion and reactivity of the material. The switching in air rapidly returns the brush to a hydrophobic state. The hybrid brush is hydrophilic because of two mechanisms: (1) exposure of EPEI chains to the brush-water interface under water, and (2) retention of some fraction of water via swollen EPEI chains (the EPEI chains swell by 2-3 times), which are conserved by a PDMS cap in air. The hybrid brush is wettable under water, and at the same time, the brush is nonwettable in air because water droplets are trapped in a metastable state when the water contact angle is above 90 degrees .     

Fluorescent sensors for Hg(2+) in micelles: a new approach that transforms an ON-OFF into an OFF-ON response as a function of the lipophilicity of the receptor

A new approach to the use of micelles in the fluorescent sensing of metal cations is proposed and applied to the case of Hg(2+). We demonstrate how it is possible to transform a system from an ON-OFF to an OFF-ON sensor by changing the length of the chain used to lipophilise a ligand that resides inside TritonX-100 micelles together with pyrene as the fluorophore. Three tetrathia-monoaza macrocyclic ligands have been synthesised with the same ring but functionalised on the nitrogen atom with a methyl (C1-NS4), an n-butyl (C4-NS4) or an n-dodecyl (C12-NS4) chain. The three ligands have been fully characterised in water containing TritonX-100 micelles by means of potentiometric titrations and their apparent protonation and complexation constants with Hg(2+) were determined. On the basis of the distribution diagrams obtained, the more lipophilic C12-NS4 has been developed as an ON-OFF fluorescent sensor for mercury: working at pH<4, in the absence of Hg(2+) the ligand is inside the micelles, protonated and non-quenching, while on addition of mercury the [C12-NS4Hg](2+) complex forms which remains inside the micelles and is quenching. On the other hand, the ligand of intermediate chain length, C4-NS4, can be used to obtain an OFF-ON sensor at 7.07.0 the ligand is unprotonated, it stays inside the micelles and is quenching, while addition of Hg(2+) in the 7.0-9.5 pH range results in the formation of [C4-NS4Hg](2+), which is hydrophilic enough to leave the micelles and to be released into the bulk solution where it is no longer capable of quenching pyrene fluorescence. Additional studies on C1-NS4, C3-NS4 and C8-NS4 indicate that the optimal chain length to observe this OFF-ON behaviour is C(3)-C(4).     

Converting poorly soluble materials into stable aqueous nanocolloids

Aqueous nanocolloids of poorly soluble materials were produced via sonicated layer-by-layer (LbL) encapsulation with polycation / polyanion shells. Synergy of simultaneous breaking powder particles with ultrasonication and coating them with polycations allowed for the production of 150-200 nm diameter polyelectrolyte coated nanoparticles with sufficient surface electrical potential for colloidal stability. This technique increases water dispersibility of low soluble materials ranging from anticancer drugs to anticorrosion agents, dyes and inorganic salts.     

Specific features of the reactions of quinazoline and its 4-hydroxy and 4-chloro substituted derivatives with C-nucleophiles

Reactions of quinazoline 1 with indole, pyrogallol and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to C-4 adducts 2, 3 and 5. Adduct 4 is formed by heating 1 with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with 1 without acid catalysis to form dipyrazolylmethane 6. 4-Chloroquinazoline 8 reacts with 1-phenyl-3-methylpyrazol-5-one to form 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl) quinazoline 9 and dipyrazolylmethane 6. Heating 8 with 2-methylindole leads to the formation of 4-(2-methylindol-3-yl) quinazoline 10 and tris(2-methylindol-3-yl)methane 11.     

Effect of particle geometry on phase transitions in two-dimensional liquid crystals

Using a version of density-functional theory which combines Onsager approximation and fundamental-measure theory for spatially nonuniform phases, we have studied the phase diagram of freely rotating hard rectangles and hard discorectangles. We find profound differences in the phase behavior of these models, which can be attributed to their different packing properties. Interestingly, bimodal orientational distribution functions are found in the nematic phase of hard rectangles, which cause a certain degree of biaxial order, albeit metastable with respect to spatially ordered phases. This feature is absent in discorectangles, which always show unimodal behavior. This result may be relevant in the light of recent experimental results which have confirmed the existence of biaxial phases. We expect that some perturbation of the particle shapes (either a certain degree of polydispersity or even bimodal dispersity in the aspect ratios) may actually destabilize spatially ordered phases thereby stabilizing the biaxial phase.