Amedea Manfredi

Synthesis, characterization and catalytic oxidations of oxovanadium(IV), oxotitanium(IV) and dioxomolybdenum(VI) complexes with chiral imines of L-amino acids

Abstract Representative oxovanadium(IV), oxotitanium(IV), and dioxomolybdenum(VI) complexes of N-salicylidene-L-amino acids (the amino acids are: valine, leucine, except for Mo(VI), and histidine) have been synthesized and characterized by various spectroscopic techniques. It has been found that while in the histidine complexes of titanium(IV) and vanadium(IV) the amino acid residue is bound in the expected glycine-like mode, in the molybdenum(VI) complex it is bound in the unusual histamine-like mode. Also, the structure of this molybdenum(VI) complex contains imidazolate-bridged polymeric units in the solid state, while the carboxyl group of the amino acid residue is protonated. In solution the polymeric structure is cleaved and the monomers contain carboxylate and protonated imidazole groups at the histidine residue. The histamine-like structure of the histidine complex was probcd by comparison with that of the chiral dioxomolybdenum(VI) complex of N -salicylidene-L-histidinol. While the structure of the metal centers is six-coordinate for the dioxomolybdenum(VI) complexes and the histidine complexes of oxotitanium(IV) and oxovanadium(IV), it is likely that the complexes of the latter metals derived from nonpolar amino acids do not achieve coordination numbers higher than five. The present oxometal complexes are catalytically active in the sulfoxidation of sulfides and in the epoxidations of activated olefins by tert-butyl hydroperoxide, but in general exhibit a low degree of asymmetric induction in these reactions.

Use of poly(amidoamine) drug conjugates for the delivery of antimalarials to Plasmodium.

Current malaria therapeutics demands strategies able to selectively deliver drugs to Plasmodium-infected red blood cells (pRBCs) in order to limit the appearance of parasite resistance. Here, the poly(amidoamines) AGMA1 and ISA23 have been explored for the delivery of antimalarial drugs to pRBCs. AGMA1 has antimalarial activity per se as shown by its inhibition of the in vitro growth of Plasmodium falciparum, with an IC₅₀ of 13.7 μM. Fluorescence-assisted cell sorting data and confocal fluorescence microscopy and transmission electron microscopy images indicate that both polymers exhibit preferential binding to and internalization into pRBCs versus RBCs, and subcellular targeting to the parasite itself in widely diverging species such as P. falciparum and Plasmodium yoelii, infecting humans and mice, respectively. AGMA1 and ISA23 polymers with hydrodynamic radii around 7 nm show a high loading capacity for the antimalarial drugs primaquine and chloroquine, with the final conjugate containing from 14.2% to 32.9% (w/w) active principle. Intraperitoneal administration of 0.8 mg/kg chloroquine as either AGMA1 or ISA23 salts cured P. yoelii-infected mice, whereas control animals treated with twice as much free drug did not survive. These polymers combining into a single chemical structure drug carrying capacity, low unspecific toxicity, high biodegradability and selective internalization into pRBCs, but not in healthy erythrocytes for human and rodent malarias, may be regarded as promising candidates deserving to enter the antimalarial therapeutic arena.

Amphoteric Agmatine Containing Polyamidoamines as Carriers for Plasmid DNA in Vitro and in Vivo Delivery

In this paper we report on the investigation, as DNA nonviral carriers, of three samples of an amphoteric polyamidoamine bearing 4-aminobutylguanidine deriving units, AGMA5, AGMA10, and AGMA20, characterized by different molecular weights (M(w) 5100, 10100, and 20500, respectively). All samples condensed DNA in spherical, positively charged nanoparticles and protected it against enzymatic degradation. AGMA10 and AGMA20 polyplexes had average diameters lower than 100 nm. AGMA5 polyplexes were larger. All polyplexes showed negligible cytotoxicity and were internalized in cells. AGMA10 and AGMA20 performed differently from AGMA5 as nucleic acid carriers in vitro. AGMA10 and AGMA20 effectively promoted transfection, whereas AGMA5 was ineffective. FITC-labeled AGMA10 was prepared and the intracellular trafficking of its DNA polyplex was studied. DNA/AGMA10 polyplex was largely localized inside the nucleus, while AGMA10 concentrated in the perinuclear region. DNA/AGMA10 polyplex intravenously administered to mice promoted gene expression in liver but not in other organs without detectable toxic side effects.

Asymmetric Epoxidation of Alkenes in Fluorinated Media, Catalyzed by Second-Generation Fluorous Chiral (Salen)manganese Complexes

The synthesis of sterically hindered chiral (salen)manganese complexes bearing perfluoroalkyl ponytails and their use in asymmetric epoxidation reactions are described. For better understanding of the relative influences of steric and electronic effects on the enantioselectivity of the fluorous catalysts, the epoxidation of 1,2-dihydronaphthalene and benzosuberene was first studied under homogeneous conditions. It was shown that the presence of sterically demanding tert-butyl groups and, to a lesser degree, the displacement of the electron-withdrawing perfluoroalkyl substituents from the ligand core provide ees higher than those attainable with first generation fluorous chiral (salen)manganese complexes featuring perfluoroalkyl substituents in the key positions (3,3′ and 5,5′) in the ligand. Second generation catalysts (Mn-6)C7F15COO and (Mn-7)C7F15COO were successfully employed in the fluorous biphase epoxidation of alkenes with PhIO as the oxidant and pyridine N-oxide as an additive. Epoxide yields (68−98%) and ees (50−92%) were similar to those obtained with the same oxidizing system and standard (salen)manganese complexes under homogeneous conditions. When the reaction was complete, the fluorous layer in which the catalyst was immobilized was easily recoverable by simple phase separation at room temperature and could be used up to three times before significant decline in yield and enantioselectivity was observed.

Towards epoxidation catalysts for fluorous biphase systems: Synthesis and properties of two Mn(III)-tetraarylporphyrins bearing perfluoroalkylamido tails

Abstract Two new Mn(III)-tetraarylporphyrins Mn-1 and Mn-2 bearing one amido-bonded n-C7F15 chain on each meso-aryl group have been synthesized. The presence of four perfluoroalkyl tails strongly influences the solubility of these compounds in common organic solvents, but it is not sufficient to impart solubility in fluorocarbons. The catalytic activity of the new complexes was tested in alkene epoxidations employing aqueous NaOCl as oxygen donor. Results show that Mn-2 is more active than Mn(III)-5,10,15,20-tetrakis-(2,6-dichlorophenyl)porphyrin, one of the most efficient porphyrinic catalysts for hydrocarbon oxygenation.

Biological performance of a novel biodegradable polyamidoamine hydrogel as guide for peripheral nerve regeneration.

Polyamidoamines (PAAs) are a well-known family of synthetic biocompatible and biodegradable polymers, which can be prepared as soft hydrogels characterized by low interfacial tension and tunable elasticity. For the first time we report here on the in vivo performance of a PAA hydrogel implant as scaffold for tissue engineering. In particular, an amphoteric agmatine-deriving PAA hydrogel shaped as small tubing was obtained by radical polymerization of a soluble functional oligomeric precursor and used as conduit for nerve regeneration in a rat sciatic nerve cut model. The animals were analyzed at 30, 90, and 180 days post-surgery. PAA tubing proved to facilitate nerve regeneration. Good surgical outcomes were achieved with no signs of inflammation or neuroma. Moreover, nerve regeneration was morphologically sound and the quality of functional recovery satisfactory. In conclusion, PAA hydrogel scaffolds may represent a novel and promising material for peripheral nerve regeneration.

Synthesis of chiral Mn(III)-meso-tetrakis-[2.2]-p-cyclophanyl-porphyrin: a new catalyst for enantioselective epoxidation

Abstract The synthesis of Mn(III)-complexes of new chiral porphyrins 1a and 1b prepared by condensation of enantiomerically pure [2.2]- p -cyclophane-4-carbaldehyde and pyrrole are described. These compounds were used as catalysts in epoxidation reactions of prochiral alkenes, carried out in the presence of aqueous NaOCl at pH = 10.0 as oxygen donor and small amounts of 4-tert-butylpyridine as axial ligand, in CH 2 Cl 2 H 2 O two-phase conditions at 0°C. Results indicate a satisfactory catalytic efficiency (up to 700 overall turnovers), with enantiomeric excesses in the range 22–31%.

Arene-chromium-tricarbonyl complexes: stereoselective reactions with isocyanide

Abstract More than 98 % of A.I. is obtained during addition of TosMic with chiral complexes 2 and 3. The diastereoselectivity of the formation of the oxazolines is studied and the diastereomers clearly assigned. Orbital-interactions and electronic repulsions seem to be responsable for the presence of the cis isomers.

Stereoselective synthesis of β-hydroxyamino acids by aldol reaction of α-isocyanocarboxylate with arene-chromium-tricarbonyl complexes.

Abstract High diastereoselectivity is obtained during the addition of ethyl isocyanoacetate 1 to chiral complexes 2 and 3 . The 2-oxazoline-4-carboxylic esters are intermediates for the synthesis of β-substituted serines in a stereoconservative process.

Herringbone Infinite Networks Formed by Terpyridine and Haloperfluoroarene Modules

Abstract 4′-(4-Methylphenyl)-2,2′:6′,2″-terpyridine (1) self-assembles with dihaloperfluoroarenes (2). A chemo- and site-selective supramolecular synthesis occurs which preserves in the solid cocrystal the most stable s-trans, s-trans conformation of the pure terpyridine module. The single crystal X-ray structure of 3a, prepared from 1 and 1,4-diiodotetrafluorobenzene (2a) (monoclinic, a = 14.608(1), b = 13.276(1), c = 13.970(2) Å, β = 109.808(8)°, U = 2549.4 (4) Å3, T = 291 (1) K, space group C2/c Z = 4; μ(Mo-Kα) = 2.519 mm−1; d calc.: 1.890 g cm−3; 5748 reflections measured, 3715 unique (Rint = 0.024) which were used in all calculations; the final R and wR (F 2) were 0.043 and 0.069, respectively) shows the presence of infinite ribbons where the two modules alternate in a zigzag arrangement.