Marisa Martinelli

Efficient continuous flow synthesis of hydroxamic acids and suberoylanilide hydroxamic acid preparation.

A continuous flow tubing reactor can be used to readily transform methyl or ethyl carboxylic esters into the corresponding hydroxamic acids. Flow rate, reactor volume, and temperature were optimized for the preparation of a small collection of hydroxamic acids. Synthetic advantages were identified as an increased reaction rate and higher product purity. This method was also successfully applied to the multistep preparation of suberoylanilide hydroxamic acid, a potent HDAC inhibitor used in anticancer therapy.

Synthesis of (+)‐Dumetorine and Congeners by Using Flow Chemistry Technologies

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.

Electrochemical Study of a Dendritic Family at the Water/ 1,2-Dichloroethane Interface

The transfer of six dendritric molecules, DMs, across the water/1,2-dichloroethane interface was investigated using cyclic voltammetry. From the variation of peak potential with pH, two different mechanisms of transfer were postulated depending on the nature of the molecules. Voltammetric parameters were employed to evaluate the hydrophilic/hydrophobic character and calculate the acid dissociation constant of these molecules. The results were explained taking into account the nature and multiplicity of functional surface groups.

Synthesis and biological evaluation of novel dimiracetam derivatives useful for the treatment of neuropathic pain

Chemical modifications of dimiracetam, a bicyclic analogue of the nootropic drug piracetam, afforded a small set of novel derivatives that were investigated in in vivo models of neuropathic pain. Compounds 5, 7 and 8 displayed a very promising antihyperalgesic profile in rat models of neuropathic pain induced by both chronic constriction injury of the sciatic nerve and streptozotocin. The compounds completely reverted the reduction of pain threshold evaluated by the paw pressure test. Importantly these derivatives did not induce any behavioural impairment as evaluated by the rotarod test. These results suggest that compounds 5, 7 and 8 might represent novel and well-tolerated therapeutic agents for the relief of neuropathic pain.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films.

Rational design of dendritic thermoresponsive nanogels that undergo phase transition under endolysosomal conditions

In the last few decades, the synthesis of nanodevices has become a very active research field with many applications in biochemistry, biotechnology, and biomedicine. However, there is still a great need for smart nanomaterials that can sense and respond to environmental changes. Temperature- and pH-responsive nanogels (NGs), which are prepared in a one-pot synthesis from N-isopropylacrylamide (NiPAm) and a Newkome-type dendron (ABC) bearing carboxylic acid groups, are being investigated as multi-responsive drug carriers. As a result, NGs have been developed that are able to undergo a reversible volume phase transition triggered by acidic conditions, like the ones found in endolysosomal compartments of cancer cells. The NGs have been thoroughly characterized using dynamic light scattering and spectroscopies, such as infrared, nuclear magnetic resonance, UV-visible, and stimulated Raman. Strong hydrogen bonds have been detected when the ABC moieties are deprotonated, which has led to changes in the transition temperatures of the NGs and a reversible, pH-dependent aggregation. This pH-dependent phase change was exploited for the effective encapsulation and sustained release of the anticancer drug cisplatin and resulted in a faster release of the drug at endolysosomal pH values. The cisplatin-loaded NGs have exhibited high toxicities against A549 cells in vitro, while the unloaded NGs have been found to be not cytotoxic and hemocompatible.

Gelatin films dendronized selectively on one side: enhancing antimicrobial properties and water repellence

To develop a material with potential biomedical applications, novel gelatin films were prepared by cold-casting method using cerium(III) and genipin solution as cross-linking agents, and surface modified with dendritic molecules. The structure and properties of the synthesized gelatin films were investigated by ATR-FTIR, mechanical tests, swelling behavior and water vapor permeability (WVP). The results showed that cross-linking could improve the mechanical and microbiological properties and lower the hydrophilic property of gelatin films. According to ATR-FTIR analysis, it can be concluded that the dendronization took place on only one of the faces of the films. The results have shown that the experimental methodology performed allows one-surface modification, so a novel biomaterial was obtained in the form of a film with good properties and dendritic structure in one face (hydrophobic and hydrophilic faces), rendering a multivalent structure useful in biomedicine development.

The Cooperative Effect in Dendronized Chitosan Microbeads

The present study evaluates the cooperative effects of dendronized chitosan microbeads with tris- and hexa-functionalized dendrons for capturing copper and for further use as catalysts. The dendronized microbeads were characterized by infrared spectroscopy, scanning electron microscopy, thermogravimetry, swelling capacity analysis, and atomic absorption spectroscopy. A correlation between the number and type of functional groups at the dendritic surface of the dendronized microbeads and the retention of copper highlights structural features of the cooperative effect. It is demonstrated that covalently bound dendrons can modulate the properties of chitosan, which has shown potential as a catalyst for the development of a novel materials.

First generation newkome-type dendrimer as solubility enhancer of antitumor benzimidazole carbamate

A first generation dendrimer was evaluated as solubility enhancer of the antitumor compound methyl (5-[propylthio]-1H-benzimidazol-2-yl) carbamate. The dendrimer possess carboxylic acid as terminal groups, which provide high water solubility and a low cytotoxic character. The drug-dendrimer association significantly increases active compound solubility in water, avoiding aggregation. The formulation is stable several weeks in a wide temperature range. The formation of Langmuir monolayers in air–water interface of dendrimer-active compound blends evinces the viability of the complex to generate films for surface-mediated drug delivery systems.

DEHYDROHALOGENATION OF HALOALKANES PROMOTED BY METAL HALIDES. HYDROGEN HALOMETALATES FORMATION AND THEIR USE AS HYDROHALOGENATING AGENTS

Abstract In the dehydrohalogenation of 1,2-dihalo-1,1-diphenylethanes, 1, to 2-halo-1,1-diphenylethene, 2, either at 76°C or at 50°C, promoted by catalytic amount of the anhydrous bromides of Fe(III), Ru(III) and Al(III) and Fe(III) chloride the chemical transformation of the metal halides was observed. In reactions carried out in vacuum or under nitrogen atmosphere, the hydrogen halide eliminated from the organic substrate reacted with the metal halides rendering the unstable hydrogen perhalometalates H + n [MX 3+n ] n− . We demonstrate that these compounds behave as hydrogen halide donors in the hydrohalogenation of olefins at 4°C.