Francesca Leonelli

The interpretation of diffraction patterns of two prototypical protic ionic liquids: a challenging task for classical molecular dynamics simulations.

In this study, we discuss the performance of classical molecular dynamics in predicting the experimental X-ray diffraction patterns of liquid ethylammonium nitrate (one of the simplest protic room-temperature ionic liquid showing amphiphilic behavior) and of its hydroxy derivative (2-ethanolammonium nitrate, 2-HOEAN). Newly recorded energy-dispersive X-ray diffraction structure factors are compared with the corresponding quantities extracted from molecular dynamics simulations. Other useful theoretical and experimental indicators are used as a probe of the local structure of the title ionic liquids. We shall show that the use of a general purpose, two-body terms only, force field, such as OPLS/AA is able to describe most of the structural experimental data. However, we shall also point out that an improved description of some key structural features observed in the X-ray radial distribution function, can be obtained very easily by adding a general three-body potential energy term instead of changing the two-body potential parameters, in order to optimize the agreement with experimental data. This three-body term turns out to be naturally able to describe the complex polarization effects due to hydrogen bonding without requiring a quanto-mechanical treatment or a polarizable force field. In addition the present model turns out to be able to account for the presence of a low-Q peak in the scattering patterns of EAN, which has been commonly interpreted as a manifestation of the amphiphilic nature of this compound.

Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates†

Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatment of breast and ovarian cancer, suffers from significant disadvantages such as low solubility, certain toxicity and specific drug-resistance of some tumor cells. To overcome these problems extensive research has been carried out. Among the various proposed strategies, the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid (HA, 2), has also been considered. Coupling a bioactive compound to a biocompatible polymer offers, in general, many advantages such as better drug solubilization, better stabilization, specific localization and controlled release. Hereafter the design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview of HA-paclitaxel combinations is also given.

Two Different Models to Predict Ionic-Liquid Diffraction Patterns: Fixed-Charge versus Polarizable Potentials

This study reports the performance of classical molecular dynamics (MD) in predicting the X-ray diffraction patterns of butylammonium nitrate (BAN) and two derivatives, 4-hydroxybutan-1-ammonium nitrate (4-HOBAN) and 4-methoxybutan-1-ammonium nitrate (4-MeOBAN). The structure functions and radial distribution functions obtained from energy-dispersive X-ray diffraction spectra, recorded newly for BAN and for the first time for 4-MeOBAN and 4-HOBAN, are compared with the corresponding quantities calculated from MD trajectories, to access information on the morphology of these liquids. The different behavior of two force fields, a polarizable multipole force field and a fixed-charge one supplemented by an explicit three-body term, is shown. The three-body force field proves to be superior in reproducing the intermediate q range, for which the polarizable force field gives the wrong peak position and intensities. In addition, both models can correctly account for the presence or absence of a low q peak in the scattering patterns.

Interaction of a long alkyl chain protic ionic liquid and water.

A combined experimental/theoretical approach has been used to investigate the role of water in modifying the microscopic interactions characterizing the optical response of 1-butyl-ammonium nitrate (BAN) water solutions. Raman spectra, dominated by the signal from the protic ionic liquid, were collected as a function of the water content, and the corresponding spatial organization of the ionic couples, as well as their local arrangement with water molecules, was studied exploiting classical molecular dynamics calculations. High quality spectroscopic data, combined with a careful analysis, revealed that water affects the vibrational spectrum BAN in solution: as the water concentration is increased, peaks assigned to stretching modes show a frequency hardening together with a shape narrowing, whereas the opposite behavior is observed for peaks assigned to bending modes. Calculation results clearly show a nanometric spatial organization of the ionic couples that is not destroyed on increasing the water content at least within an intermediate range. Our combined results show indeed that small water concentrations even increase the local order. Water molecules are located among ionic couples and are closer to the anion than the cation, as confirmed by the computation of the number of H-bonds which is greater for water-anion than for water-cation. The whole results set thus clarifies the microscopic scenario of the BAN-water interaction and underlines the main role of the extended hydrogen bond network among water molecules and nitrate anions.

Role of ionic liquids in protein refolding: Native/fibrillar versus treated lysozyme

Several ionic liquids (ILs) are known to revert aggregation processes and to improve the in vitro refolding of denatured/fibrillar proteins. Here, Raman spectroscopy is exploited to verify the refolding capability of several ammonium-based ILs and to identify the microscopic signatures of the structural rearrangements induced by the interaction of ILs with fibrillar lysozyme. We collected and carefully analyzed spectra from native, fibrillar and ILs-treated fibrillar lysozyme to follow the microscopic process induced by ILs. These allowed us to identify different mechanisms of interaction depending on the length of the cation alkyl chain. A clear refolding effect was observed with EAN, as well as a tendency of the longer alkyl chain (PAN and BAN) of dissolving the fibril packing. A specific interaction mainly affecting the aromatic residues was identified for MEOAN (a long chain ILs with an ether group). The whole of the results, thus, provides new and detailed information on the ILs–protein interaction and shows Raman spectroscopy as a simple, reliable and effective diagnostic technique in this field.

Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2s ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.

Diastereoselective Total Synthesis of (+)-13-Stemarene by Fourth Generation Methods: A Formal Total Synthesis of (+)-18-Deoxystemarin

The problem of constructing diastereoselectively the C/D ring system of stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.

Regio- and diastereoselective synthesis and X-ray structure determination of (+)-2-deoxyoryzalexin S from (+)-podocarpic acid. Structural nonidentity with its nominal natural isolated enantiomer

(+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures.

Chiral HPLC Resolution of the Wieland–Miescher Ketone and Derivatives

Abstract The direct HPLC resolution of four structurally related compounds, the Wieland‐Miescher ketone, its C(5) homologue, and their C(1) dioxolane derivatives, was studied on commercially available polysaccharide‐based chiral stationary phases (CSPs) cellulose tris‐(3,5‐dimethylphenylcarbamate) (Chiralcel OD‐H), native β‐cyclodextrin (Cyclobond I), and acetylated, carboxymethylated and permethylated β‐cyclodextrins. The retention, resolution, and elution sequence of the enantiomeric couples were compared using different mobile phases. Baseline enantioseparation of all examined compounds was achieved only on the carboxymethyl‐derivatized β‐cyclodextrin stationary phase that appeared the most effective chiral selector for this class of compounds. Native, acetylated‐, and permethylated‐β‐cyclodextrin CSPs exhibited specific selectivity providing, in general, partial resolution of the compounds under investigation. On Chiralcel OD‐H, only two enantiomeric couples were fully separated. Elution orders depended on CSPs. To optimize chiral separation conditions, the influence of mobile phase composition on column retention and selectivity was also investigated.

Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment

Correction for ‘Inclusion of new 5-fluorouracil amphiphilic derivatives in liposome formulation for cancer treatment’ by M. Petaccia et al., Med. Chem. Commun., 2015, 6, 1639–1642.