No abstract

The synthetic potentialities of cerium(III) chloride are demonstrated by the synthesis of a nine-membered ring heterocycle component of Griseoviridin (3) in optically active form. The key step involves the stereospecific formation of the alpha-carbalkoxy alkenyl sulfide moiety using a combination system of cerium(III) chloride heptahydrate and sodium iodide.

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.

A process featuring a sequential multicomponent reaction followed by a regioselective postcyclization strategy was implemented for the facile synthesis of N,N′-disubstituted dihydroorotic acid amides under mild conditions. We obtained, for the first time, a library of 29 derivatives, encompassing 19 N α-substituted-N 4-dihydroorotyl-4-aminophenylalanine derivatives, a key residue of gonadotropin-releasing hormone antagonist Degarelix. The corresponding products were prepared from easily accessible starting materials in good to excellent yields with broad substrate scope.

The decoration of polyamidoamine (PAMAM) dendrimers with some functional moieties holds promises for improving the gene-delivery behavior of the resulting polyplexes. Herein, we reported the synthesis and the development of nonviral gene vectors built on an array of PAMAMs, spanning generation 2 (G2), G4, and G7, specifically tethered with multivalent neomycin (Neo) or guanidinoneomycin (GNeo). Following a thorough chemical characterization by means of NMR and MALDI analyses, the ability of PAMAM−(G)Neo conjugates to serve as transfectants was investigated. First, we demonstrated that every PAMAM, whether or not tethered with Neo (or GNeo), exhibited greater DNA packing ability than the gold standard transfectant 25 kDa bPEI. Measurements of the colloidal properties showed that PAMAMs, when mixed with plasmid DNA (pDNA) as a function of the nitrogen-to-phosphate ratio (N/P), allowed preparing complexes of ≈150−300 nm in diameter with a positive surface charge of ≈+20−35 mV, strictly dependent on the PAMAM generation. The conjugation with Neo affected the DNA release behavior from PAMAM-based polyplexes and their ultimate transfection efficiency. When low generation PAMAM G2 was tethered with Neo, we obtained the most efficient transfectants, with remarkable antibacterial activity against Gram negative bacteria. It is worth noting that pDNA/PAMAM−(G)Neo nanoassemblies, which were tested at the optimal N/P, invariably showed better transfection efficiency than 25 kDa bPEI, along with low cytotoxicity in both HeLa and COS-7 cells. Altogether, these results underline the potential of such PAMAM−(G)Neo dendrimers as promising vehicles for efficient gene delivery into cells.