Sulfonates-PMMA nanoparticles conjugates: A versatile system for multimodal application

a b s t r a c t We report herein the viability of a novel nanoparticles (NPs) conjugated system, namely the attachment, based on ionic and hydrophobic interactions, of different sulfonated organic salts to positively charged poly(methylmethacrylate) (PMMA)-based core-shell nanoparticles (EA0) having an high density of ammonium groups on their shells. In this context three different applications of the sulfonates@EA0 systems have been described. In detail, their ability as cytotoxic drugs and pro-drugs carriers was evaluated in vitro on NCI-H460 cell line and in vivo against human ovarian carcinoma IGROV-1 cells. Besides, 8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt (HPTS) was chosen for NPs loading, and its internalization as bioimaging probe was evaluated on Hep G2 cells. Overall, the available data support the interest for these PMMA NPs@sulfonates systems as a promising formulation for theranostic applications. In vivo biological data strongly support the potential value of these core-shell NPs as delivery system for negatively charged drugs or biologically active molecules. Additionally, we have demonstrated the ability of these PMMA core-shell nanoparticles to act as efficient carriers of fluorophores. In principle, thanks to the high PMMA NPs external charge density, sequential and very easy post-loading of different sulfonates is achievable, thus allowing the preparation of nanocarriers either with bi-modal drug delivery behaviour or as theranostic systems

Sintesi di 4-bromo-pirazoli quali precursori di sistemi eterociclici condensati. Sintesi della 3a,4,5,6,7,7a-esaidro-N-metil-1H-1,4,6-(epietano-1,1,2-triil)indeno-4,8-dicarbossimmide e di composti relazionati tramite reazione Diels-Alder intramolecolare.

Il progetto di tesi specialistica svolto durante questo anno accademico si è suddiviso in due parti: un primo periodo, da settembre 2010 a gennaio 2011, presso il dipartimento di Chimica Organica “A. Mangini” della Facoltà di Chimica Industriale dell’Università di Bologna e un secondo periodo in Spagna, da marzo ad agosto 2011, presso la Unitat de Química Farmacèutica de la Facultat de Farmàcia de la Universitat de Barcelona. Nel primo periodo a Bologna mi sono occupato della sintesi di 4-bromo-pirazoli da utilizzare come precursori di composti eterociclici condensati. Inizialmente è stato sintetizzato un pirazolo 1,3,5-trisostituito tramite cicloaddizione 1,3-dipolare tra un acetilene e una nitril immina generata in situ da un idrazonoil cloruro. Il pirazolo è stato poi bromurato facendo uno screening di diversi agenti bromuranti e condizioni di reazione per ottenere la migliore resa e chemoselettività. Infine è stata studiata la ciclizzazione intramolecolare del prodotto bromurato tramite reazione di cross-coupling catalizzata da metalli di transizione. Nel secondo periodo a Barcellona mi sono occupato della sintesi di dicarbossimmidi tricicliche con struttura a gabbia con il fine di creare alcheni altamente piramidalizzati e di studiarne la dimerizzazione ad un derivato del dodecaedrano. La strategia sintetica è stata impostata utilizzando come reagente di partenza una semplice succinimmide per giungere, dopo numerosi passaggi, al precursore del prodotto triciclico, del quale è stata studiata la ciclizzazione tramite reazione Diels-Alder intramolecolare

Preparation of polychlorinated isoxazoles and application to organic synthesis

The work behind my doctoral thesis has been focused on the study of reactivity of 3,5-dimethyl-4-nitroisoxazole. This compound shows a peculiar reactivity compared to other isoxazole derivatives due to the presence of the nitro group in 4-position. The chemical behavior of 3,5-dimethyl-4-nitroisoxazole has been extensively studied in the last decade with the development of important applications in pharmaceutical chemistry in the preparation of valuable biologically active compounds. The investigation has been focused in the development of novel procedures for the electrophilic chlorination of 3,5-dimethyl-4-nitroisoxazole. We envisaged that the introduction of one or more chlorine atoms on the methyl group in 5-position of the nitroisoxazole core could bring to the formation of polyfunctional derivatives bearing multiple nucleophilic and electrophilic functionalities on the same molecule. The polyfunctional reactivity of these new type of isoxazole derivatives could then be exploited by means of different kind of reactions to produce important building blocks. In particular the use of 3-methyl-4-nitro-5- trichloromethylisoxazole in haloform-type reactions with different nucleophiles would produce 5-aminoisoxazoles via transition metal-free heteroaromatic amination. On the other hand, reaction of 3-methyl-4-nitro-5- chloromethylisoxazole with aldehydes and ketones would furnish α,β- epoxisoxazoles and α,β-epoxiesters through Darzens condensation. Moreover we decided to study the possibility of expanding the typical reactivity exhibited by the 4-nitroisoxazole core to other heterocyclic compounds like indoles in order to prepare valuable functionalized indoles. Thus, the preparation of these new classes of isoxazole derivatives and their application in the development of novel chemical transformations could serve as new efficient methodologies in the synthesis of important bioactive compounds in different industrial pharmaceutical fields.</p

Vinylogous nitro-haloform reaction enables aromatic amination

The first example of an aromatic haloform reaction is reported, defining a conceptually new haloform-type approach to the metal-free functionalization of arenes. We demonstrated that heteroarenes bearing a vinylogous nitromethane system, via the stage of a trichloromethane derivative, could undergo aromatic amination to produce N-functionalized arenes in quantitative yields and without the need for transition-metal catalysis. The haloform-type amination was implemented in the development of effective orthogonal N-protection strategies, establishing a new promising N-protecting reagent. </p

Development and Scale-up of an Organocatalytic Enantioselective Process to Manufacture (<i>S</i>)‑Pregabalin

Herein is reported the development of a new process to manufacture (<i>S</i>)-pregabalin. The method comprises six steps, run under the catalysis of a recyclable polymer bound phase transfer catalyst, and afforded (<i>S</i>)-pregabalin in overall 54% yield, starting from building blocks acetylacetone, isovaleraldehyde, and nitromethane