Luisa Maria Migneco

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.

In vivo 19F MRI and 19F MRS of 19F- labelled boronophenylalanine-fructose complex on a C6 rat glioma model to optimize boron neutron capture therapy (BNCT)

Boron neutron capture therapy (BNCT) is a promising binary modality used to treat malignant brain gliomas. To optimize BNCT effectiveness a non-invasive method is needed to monitor the spatial distribution of BNCT carriers in order to estimate the optimal timing for neutron irradiation. In this study, in vivo spatial distribution mapping and pharmacokinetics evaluation of the (19)F-labelled boronophenylalanine (BPA) were performed using (19)F magnetic resonance imaging ((19)F MRI) and (19)F magnetic resonance spectroscopy ((19)F MRS). Characteristic uptake of (19)F-BPA in C6 glioma showed a maximum at 2.5 h after compound infusion as confirmed by both (19)F images and (19)F spectra acquired on blood samples collected at different times after infusion. This study shows the ability of (19)F MRI to selectively map the bio-distribution of (19)F-BPA in a C6 rat glioma model, as well as providing a useful method to perform pharmacokinetics of BNCT carriers.

On the Diastereoselectivity of the Aqueous‐Acid‐Catalyzed Intramolecular Aldol Condensation of 3‐Oxocyclohexaneacetaldehydes

The factors responsible for the diastereoselective formation of the 6-endo-hydroxybicyclo[2.2.2]octan-2-one by acid-catalyzed intramolecular aldol reaction of 3-oxocyclohexaneacetaldehydes have been investigated. This study, carried out on (1SR,4RS,6RS)-6-hydroxybicyclo[2.2.2]octan-2-one 1a, (1SR,4RS,6SR)-6-hydroxybicyclo[2.2.2]octan-2-one 1b, and 3,3-(ethylenedioxy)cyclohexaneacetaldehyde 2a, allowed to demonstrate the absence of intramolecular H-bonding in 1a as a stabilizing factor, and to ascertain the presence of unfavorable steric interactions in 1b.

In vivo 19F MR imaging and spectroscopy for the BNCT optimization

The aim of this study was to evaluate in vivo the boron biodistribution and pharmacokinetics of 4-borono-2-fluorophenylalanine ((19)F-BPA) using (19)F MR Imaging ((19)F MRI) and Spectroscopy ((19)F MRS). The correlation between the results obtained by both techniques, (19)F MRI on rat brain and (19)F MRS on blood samples, showed the maximum (19)F-BPA uptake in C6 glioma model at 2.5h after infusion determining the optimal irradiation time. Moreover, the effect of L-DOPA as potential enhancer of (19)F-BPA tumour intake was assessed using (19)F MRI.

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.

Multi-nuclear MRS and 19F MRI of 19F-labelled and 10B-enriched p-boronophenylalanine-fructose complex to optimize boron neutron capture therapy: phantom studies at high magnetic fields

Reaction yield optimization for the synthesis and the complexation of a boron neutron capture therapy agent (19)F-labelled, (10)B-enriched p-boronophenylalanine-fructose ((19)F-BPA-fr) complex was obtained. (1)H, (19)F, (13)C and (10)B magnetic resonance spectroscopy (MRS) of the (19)F-BPA-fr complex in aqueous and rat blood solution phantoms and its spatial distribution mapping using (19)F magnetic resonance imaging (MRI) results are reported. 7 T and 9.4 T magnetic fields were used to perform MRI and MRS respectively. Our in vitro results suggest that in vivo studies on (19)F-BPA through (19)F NMR will be feasible.

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.

Antimicrobial activity of catechol functionalized-chitosan versus Staphylococcus epidermidis

Protein mussel-inspired adhesive polymers, characterized by the presence of catechol groups, possess superior muco-adhesive properties and have great potentiality in wound healing. Suitable materials for wound dressing should properly combine muco-adhesiveness and antimicrobial activity. In this work, catechol-functionalized chitosan was obtained by reaction with hydrocaffeic acid (HCAF), in order to investigate how catechol introduction at different content could affect the intrinsic antimicrobial activity of the polymer itself. Unexpectedly, an enhancement of chitosan antimicrobial activity was observed after catechol functionalization, with a fourfold reduction in the polymer minimum inhibitory concentration versus Staphylococcus epidermidis. Additionally, a commercial wound dressing coated with one of the synthesized CS-HCAF derivatives showed a significant reduction in the adhesion of S. epidermidis compared to the uncoated dressing (3-log reduction). The CS-HCAF derivatives also showed an interesting antioxidant property (EC50 ranging from 20 to 60μg/mL), which further confirms the potentiality of these materials as wound dressings.