Maria Cristina Bellucci

Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis

Psi[CH(CF(3))NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by stereoselective addition of alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY experiments, provided evidence that model Psi[CH(CF(3))NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calculations indicate a population of conformers which adopt folded beta turn structures for all the L-peptides; on the other hand, a D-stereochemistry at the Pro residue induces a natural folding towards a beta hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochemistry of the stereogenic peptide bond surrogate.

Synthesis of Multifunctional PAMAM−Aminoglycoside Conjugates with Enhanced Transfection Efficiency

The development of multifunctional vectors for efficient and safe gene delivery is one of the major challenges for scientists working in the gene therapy field. In this context, we have designed a novel type of aminoglycoside-rich dendrimers with a defined structure based on polyamidoamine (PAMAM) in order to develop efficient, nontoxic gene delivery vehicles. Three different conjugates, i.e., PAMAM G4-neamine, -paromomycin, and -neomycin, were synthesized and characterized by nuclear magnetic resonance (NMR) and MALDI analysis. The conjugates were found to self-assemble electrostatically with plasmid DNA, and unlike neamine conjugate, each at its optimum showed increased gene delivery potency compared to PAMAM G4 dendrimer in three different cell lines, along with negligible cytotoxicity. These results all disclosed aminoglycosides as suitable functionalities for tailoring safe and efficient multifunctional gene delivery vectors.

Synthesis of diverse spiroisoxazolidinohydantoins by totally regio- and diasteroselective 1,3-dipolar cycloadditions

5-Carboxymethylene hydantoins have been synthesized in high yield and under very mild conditions (20 °C, dichloromethane) through a highly (often totally) regio- and diastereoselective domino process involving readily accessible carbodiimides and acetylenedicarboxylic acid monoesters. Such compounds could be considered very intriguing intermediates for the preparation of spirohydantoins and other hydantoin derivatives. For instance, they react smoothly with either acyclic and cyclic nitrones to form spiroisoxazolidinohydantoins in high yield and with total control of the regio- and diastereoselectivity. Starting from an enantiomerically pure chiral pyrroline nitrone, the reaction was also enantiospecific. Both processes have been studied in detail and the diastereoselectivities seen have been rationalized upon examination of the alternative transition states and by density functional theory calculations of the cycloaddition step.

Diversity Oriented Combinatorial Synthesis of Multivalent Glycomimetics Through a Multicomponent Domino Process

Both multicomponent reactions and diversity oriented synthesis are indispensable tools for the modern medicinal chemist. However, their employment for the synthesis of multivalent glycomimetics has not been exploited so far although the importance that such compounds play in exploring multivalency on glycoside inhibition. Herein, we report the combinatorial synthesis of diversity oriented hetero di- and trivalent glycomimetics through a multicomponent domino process. The process is high yielding and very general, working efficiently with easily accessible sugar starting materials such as glycosylamines, glycosylazides, and glycosylisothiocyanates, having the reactive functional groups tethered either directly to the anomeric carbon, through a suitable linker, or to the primary 6 position of hexoses (or 5 position of pentoses), leading, in the latter case, to glycomimetics with artificial enzymatically stable backbone. The process has been also exploited for the multicomponent synthesis of aminoglycoside (neomycin) conjugates.

Dendrimeric Guanidinoneomycin for Cellular Delivery of Bio-macromolecules.

We present the synthesis of polymeric amino‐ and guanidinoglycosides prepared by tethering neomycin and guanidinoneomycin to PAMAM dendrimers of generations 2 and 4. The ability of these conjugates to promote cellular uptake of high‐molecular‐weight cargo is discussed, together with their cytotoxicity and mechanisms of entry. We demonstrate that the presence of multiple guanidinoneomycin carriers on the PAMAM surface plays an important role in promoting cellular uptake of the dendrimers, maintaining the heparan sulfate specificity and negligible cytotoxicity typical of monomeric guanidinoglycoside molecular transporters.

Carbodiimides-Mediated Multi Component Synthesis of Biologically Relevant Structures

Multi-component reactions are very popular because they offer a wealth of products, while requiring only a minimum effort combining many elements of an ideal synthesis, such as operational simplicity, atom economy, bond-forming efficiency, and the access to molecular complexity from simple starting materials. As such, multi-component reactions have become the cornerstones of both combinatorial chemistry and diversity-oriented synthesis and thus playing a central role in the development of modern synthetic methodology for pharmaceutical and drug discovery research. In this Insight we will highlight the development of novel multi-component reactions based on the reactivity of carbodiimides, paying particular attention on their mechanistic features. We will address our attention on the process developed by us and others groups, in these last years, for the synthesis of biologically relevant structures such as, for example, heterocycles and glyco-conjugates.