Small-angle X-ray scattering study of self-assembling lipophilic guanines in organic solvents: G-quadruplex formation and cation effects in cyclohexane.

Lipophilic guanilic derivatives (lipoGs) dissolved in organic solvents can undergo different self-assembly pathways based on different H-bonded motifs, e.g., the cyclic discrete G-quartet, which forms in the presence of alkali-metal ions, and the "infinite" tape-like G-ribbon observed in the absence of ions. Using in-solution small-angle X-ray scattering, we analyzed a series of lipoGs dissolved in cyclohexane in the presence of different salts. The formation of G-quartet based supramolecular aggregates has been confirmed, evidencing the coexistence equilibrium of octamers and noncovalent molecular nanowires (the so-called G-quadruplexes). By global fitting the scattering data, the concentration of the two kinds of particles as well as the nanowire length have been derived as a function of temperature for the different compounds and salts. The thermodynamic parameters show that the self-assembly aggregation process is enthalpy driven, while the observed enthalpy-entropy compensation suggests that similar stacking interactions control the self-assembly of the different compounds. However, the strength of the stacking interactions, and then the nanowire stability, depends on the nature of templating cations and on their capacity to fill the central cavity of quadruplexes, with the order Sr(+) < Na(+) ≲ K(+).

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats.

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

Doped nematic phases: a tool for amplifying and detecting chirality.

Doping nematic liquid crystals with non-racemic chiral compounds induces twisted nematics (cholesteric phases). This phenomenon allows the detection via spectroscopic or non-spectroscopic methods of chiral compounds through the detection (and eventually quantification) of the macroscopic induced cholesteric twist.

Novel chiral macrocycles containing two electronically interacting arylene chromophores.

Novel chiral macrocycles consisting of two rigid oligoarylene rods and two chiral spiroindane clips have been synthesized by condensation of spiroindane diols and CF3-activated alpha-omega-difluorooligoaryls. Since a broad variety of planar aromatic macrocycles is known, our non-planar, chiral rings represent a new class of macrocyclic compounds. The first two examples, which contain quaterphenylene and diphenylbithiophene rods, are presented in this communication; for one of them a crystal structure is given. The chiroptical properties of the macrocycles can be interpreted as an interplay of the "intra-rod" helicity of individual oligoarylene rods and the "inter-rod" helicity between both chromophores of the macrocycle. The macrocycles can act as chiral dopands of commercially available, and novel, polymeric nematic liquid crystals (emissive polyfluorenes). The "intra-rod" helicity of individual oligoarylene rods is the main feature in determining the resulting helical twisting power (HTP). The cholestric induction in mesogenic, emissive polyfluorenes is of special interest for a realization of electronic devices that have a circularly polarized electroluminescence. The results are also important for an understanding of larger ensembles of chiral rodlike molecules, especially their pi-pi interactions.

Correlation between molecular structure and helicity of induced chiral nematics in terms of short-range and electrostatic-induction interactions. The case of chiral biphenyls.

The helical structure of the chiral nematic phases induced by chiral dopants in nematic solvents provides a macroscopic image of the molecular chirality of the dopant promoted by the orientational order. Chiral biphenyls are challenging systems because their twisting ability shows a strong dependence on the molecular structure, which does not conform to empirical correlation rules. This points out the need for adequate interpretative tools, able to establish a link between molecular properties and macroscopic response. In this paper the twisting ability of chiral biphenyls is reviewed, by reporting examples taken from the literature together with some new experimental results. The microscopic origin of the observed behavior is explained in terms of chirality and anisotropy of short-range and electrostatic-induction interactions. These are described, respectively, by a shape model and a reaction field method, having the common characteristics of a realistic representation of the structure and properties of the chiral dopants in terms of molecular surface, atom charges, and distributed polarizabilities.

The self-assembly of a lipophilic guanosine nucleoside into polymeric columnar aggregates: the nucleoside strucutre contains sufficient information to drive the process towards a strikingly regular polymer.

Lipophilic guanosine derivatives act as self-assembled ionophores. In the presence of alkali metal ions in organic solvents, these G derivatives can form tubular polymeric structures. The molecular aggregates formed by 3',5'-didecanoyl-2'-deoxyguanosine (1) have been characterised by SANS and NMR spectroscopy. The polymer is structured as a pile of stacked G quartets held together by the alkali metal ions that occupy the column's central channel. The deoxyribose moieties, with their alkyl substituents, surround the stacked G quartets, and the nucleoside's long-chain alkyl tails are in intimate contact with the organic solvent. In this polymeric structure, there is an amazing regularity in the rotamers around the glycosidic bond within each G quartet and in the repeat sequence of the G quartets along the columns. In hydrocarbon solvents, these columnar aggregates form lyomesophases of the cholesteric and hexagonal types.

Supramolecular detection of metal ion binding: ligand conformational control of cholesteric induction in nematic liquid crystalline phases.

Tripodal tetradentate ligands may act as chemosensor molecules. Their ability to torque a nematic into a cholesteric phase increases upon complexation with copper ion. Moreover, changes in overall shape of the complexes induced by different metals and counter ions were transferred sensitively to the supramolecular level, observed by proportionate changes in the degree of twisting. Modification of the oxidation state of the metal center also gave large changes in twisting power; this suggests potential application in electrochemical molecular switches. The handedness of the induced cholesteric phase is related to the stereochemistry of the ligand: The small amount of chiral dopant needed for the LC technique (less than 2 nmol) suggests the possible determination of the absolute configuration of the parent primary amines of the ligands.

The chirality of the cholesteric phases of DNA and G-wires: its connection to their molecular structures.

While the handedness of the cholesteric phases formed by assembled guanosine derivatives (G-wires) follow the correlation right-handed helices-->right-handed cholesterics (left-handed -->left-handed), the cholesteric phase formed by B-DNA (right-handed helix) is left-handed. This apparent discrepancy is overcome by considering pitch (p) variations with temperature. Plots of p(-1) versus T(-1) have, in fact, the same trend (positive intercept and negative slope) in the case of right-handed G-wires and B-DNA, while for the left-handed G-wire of deoxyguanosine monophosphate (dGMP), the opposite behavior is observed (negative intercept and positive slope). Therefore, the relation between molecular handedness and cholesteric helicity cannot, in general, be assessed by using measurements based on a single temperature; hence the temperature variation of the cholesteric parameters should be investigated. In all cases there is no remarkable salt effect on the cholesteric parameters.

The effect of ethidium bromide on the liquid crystalline phases of aqueous DNA.

The influence of the intercalation of ethidium bromide (EB) on the characteristics of the DNA cholesteric and hexagonal mesophases is studied by optical microscopy, circular dichroism, and X-ray diffraction. The distance between DNA rods in the hexagonal phase is not modified by the presence of EB whereas the pitch of the cholesteric mesophase is considerably shortened by the dye. This seems to be related to the stereochemical effect of the intercalation rather than to the presence of a random distribution of the positive charge of the dye.