Federico Cisnetti

A platinum Chugaev carbene complex as a potent anticancer agent

A platinum Chugaev complex was synthesised and fully characterized by multinuclear NMR spectroscopy and X-ray crystallography. This cis bis acyclic diamino carbene complex acts as a cytotoxic compound and behaves as a cisplatin equivalent by interacting with supercoiled DNA and thiols. Stability of the ligand is also discussed.

Femtomolar Ln(III) affinity in peptide-based ligands containing unnatural chelating amino acids.

The incorporation of unnatural chelating amino acids in short peptide sequences leads to lanthanide-binding peptides with a higher stability than sequences built exclusively from natural residues. In particular, the hexadentate peptide P(22), which incorporates two unnatural amino acids Ada(2) with aminodiacetate chelating arms, showed picomolar affinity for Tb(3+). To design peptides with higher denticity, expected to show higher affinity for Ln(3+), we synthesized the novel unnatural amino acid Ed3a(2) which carries an ethylenediamine triacetate side-chain and affords a pentadentate coordination site. The synthesis of the derivative Fmoc-Ed3a(2)(tBu)(3)-OH, with appropriate protecting groups for direct use in the solid phase peptide synthesis (Fmoc strategy), is described. The two high denticity peptides P(HD2) (Ac-Trp-Ed3a(2)-Pro-Gly-Ada(2)-Gly-NH(2)) and P(HD5) (Ac-Trp-Ada(2)-Pro-Gly-Ed3a(2)-Gly-NH(2)) led to octadentate Tb(3+) complexes with femtomolar stability in water. The position of the high denticity amino acid Ed3a(2) in the hexapeptide sequence appears to be critical for the control of the metal complex speciation. Whereas P(HD5) promotes the formation of polymetallic species in excess of Ln(3+), P(HD2) forms exclusively the mononuclear complex. The octadentate coordination of Tb(3+) by both P(HD) leads to total dehydration of the metal ion in the mononuclear complexes with long luminescence lifetimes (>2 ms). Hence, we demonstrated that unnatural amino acids carrying polyaminocarboxylate side-chains are interesting building blocks to design high affinity Ln-binding peptides. In particular the novel peptide P(HD2) forms a unique octadentate Tb(3+) complex with femtomolar stability in water and an improvement of the luminescence properties with respect to the trisaquo TbP(22) complex by a factor of 4.

Stereocontrol by a Pair of Epimeric Sugar-Derived Ligands of the Coordination Sphere of Copper(II) Complexes

A pair of novel C3-epimeric sugar-derived ligands (glycoligands) with a neutral N4O donor set was synthesized. Copper(II) complexes of both ligands were obtained and characterized by X-ray crystallography. Cyclic voltammetry, electron paramagnetic resonance, and UV-vis spectroscopies showed similar electronic properties. Mirror-image CD spectra were obtained for the Cu(II) d-d band, indicating an enantiomeric character of the coordination sphere, which has been rationalized structurally. This example shows the possible predetermination of stereochemistry for complexes by ligands based on a glycoscaffold.

Entasis through Hook-and-Loop Fastening in a Glycoligand with Cumulative Weak Forces Stabilizing CuI

The idea of a possible control of metal ion properties by constraining the coordination sphere geometry was introduced by Vallee and Williams with the concept of entasis, which is frequently postulated to be at stake in metallobiomolecules. However, the interactions controlling the geometry at metal centers remain often elusive. In this study, the coordination properties toward copper ions—Cu(II) or Cu(I)—of a geometrically constrained glycoligand centered on a sugar scaffold were compared with those of an analogous ligand built on an unconstrained alkyl chain. The sugar-centered ligand was shown to be more preorganized for Cu(II) coordination than its open-chain analogue, with an unusual additional stabilization of the Cu(I) redox state. This preference for Cu(I) was suggested to arise from geometric constraints favoring an optimized folding of the glycoligand minimizing steric repulsions. In other words, the Cu(I) d(10) species is stabilized by valence shell electron pair repulsion (VSEPR). This idea was rationalized by a theoretical noncovalent interactions (NCI) analysis. The cumulative effects of weak forces were shown to create an efficient buckle as in a hook-and-loop fastener, and fine structural features within the glycoligand reduce repulsive interactions for the Cu(I) state. This study emphasizes that monosaccharide platforms are appropriate ligand backbones for a delicate geometric control at the metal center, with a network of weak interactions within the ligand. This structuration availing in glycoligands makes them attractive for metallic entasis.

[{Cu(IPr)}2(μ-OH)][BF4]: synthesis and halide-free CuAAC catalysis

The preparation under protic conditions of the first μ-hydroxo dicopper(I)-NHC complex is reported. Its application as a CuAAC catalyst was investigated, evidencing a remarkable enhancement of catalytic efficiency in the presence of 4,7-dichloro-1,10-phenanthroline and highlighting the beneficial effect of the absence of coordinating halides.

Synthesis and X-ray crystal structures of two transition metal complexes based on functionalised 1,5-anhydro-2-deoxy-D-galactitol and methyl 2-deoxy-α-D-galactopyranoside

Two new ligands of transition metal cations based on galactose-derived scaffolds were synthesised: 1,5-anhydro-2-deoxy-3,4,6-tri-O-(2-picolyl)-D-galactitol and methyl 2-deoxy-3,4,6-tri-O-(2-picolyl)-alpha-D-galactopyranoside. These ligands permitted the isolation as single crystals of a Co(II) and a Ni(II) complex, respectively. The structures of both complexes were determined by X-ray crystallography showing a coordination sphere including sugar-bound oxygen atoms. The sugar-derived ligands were found to be in both cases in high energy conformations in the crystal structures of the complexes. These conformations contain an arrangement of sugar-bound oxygen atoms similar to those observed in polyol-metal and carbohydrate-metal complexes.

Glycoligands and Co(II) glycocomplexes. Investigation of the variation of the sugar-scaffold on the structure and chirality measured by circular dichroism

Glycoligands using various monosaccharide platforms functionalised by three 2-picolyl groups and coordinated to Co(II) through the bidentate 2-picolyl ether moieties are interesting ligands as they efficiently induce chirality at the cobalt with a fine control of the structure through the central sugar scaffold.

Click 1,2,3-triazole derived fluorescent scaffold by mesoionic carbene-nitrene cyclization: an experimental and theoretical study

We describe a set of three fluorescent mesoionic benzo[4,5]imidazo-3-ide-[1,2-c]-2-alkyl-1,2,3-triazol-2-ium compounds obtained through a simple, concise and efficient synthetic sequence featuring a copper-catalyzed carbene–nitrene cyclization. The compounds were characterized by fluorescence spectroscopy highlighting promising photophysical properties in terms of quantum yields and Stokes shifts. Experimental properties were rationalized by a computational DFT and TD-DFT approach with excellent agreement with structural and spectroscopic data.