Nicola Castellucci

Conformational Studies of Phe-Rich Foldamers by VCD Spectroscopy and ab Initio Calculations

Employing VCD spectroscopy, we demonstrate that the structural behavior of the oligomers Boc-(L-Phe-L-Oxd)(n)-OBn is similar from n = 2 to n = 6; ab initio calculations for the n = 1 case provide physical insight into the conformational properties. Further information is gained by IR, (1)H NMR, and ECD spectroscopies. ECD spectra suggest the presence of different conformations between n = 1 on one side and longer chain foldamers on the other side. VCD and absorption IR spectra in methanol solutions can be interpreted as indicative of a PPII structure. In the case of Boc-L-Phe-L-Oxd-OBn, VCD spectra in CCl(4) and detailed DFT computational analysis allow one to demonstrate that the most populated conformers exhibit backbone dihedral angles similar to those of a PPII geometry. This is a remarkable outcome, as we had previously demonstrated that the Boc-(L-Ala-D-Oxd)(n)-OBn series folds in a β-band ribbon spiral that is a subtype of the 3(10) helix.

α,ε-Hybrid Foldamers with 1,2,3-Triazole Rings: Order versus Disorder

Two epimeric series of foldamers characterized by the presence of a repeating α,ε-dipeptide unit have been prepared and characterized by (1)H NMR and ECD spectroscopies together with X-ray diffraction. The first series contains L-Ala and D-4-carboxy-5-methyl-oxazolidin-2-one (D-Oxd). The other series contains L-Ala and L-Oxd. The L,D series of oligomers forms ordered β-turn foldamers, characterized by a 311 pattern. The L,L series is not ordered. Simulations show that an ordered L,L trimer lies more than 2 kcal/mol higher than the more stable nonfolded extended conformations. Cu(2+) forms complexes with both series but is not able to order the L,L series. Analysis of the EPR spectra shows that the L,D foldamers bear two types of complexation sites that are assigned as a nitrogen donor of the triazole ring and a carboxylate ligand. The L-Ala-D-Oxd-Tri-CO motif may be introduced in any peptide sequence requiring the presence of a stable β-turn conformations, like in the study of protein-protein interactions.

A peptidic hydrogel that may behave as a “Trojan Horse”

Summary A physical hydrogel prepared with the low-molecular-weight hydrogelator (LMWHG) CH2(C3H6CO-L-Phe-D-Oxd-OH)2 and water/ethanol mixture was applied as a potential “Trojan Horse” carrier into cells. By SEM and XRD analysis we could demonstrate that a fibrous structure is present in the xerogel, making a complex network. The gelator is derived from α-amino acids (Thr, Phe) and a fatty acid (azelaic acid) and is biocompatible: it was dosed to IGROV-1 cells, which internalized it, without significantly affecting the cell proliferation. To check the internalization process by confocal microscopy, fluorescent hydrogels were prepared, introducing the fluorescent dansyl moiety into the mixture.

Shaping calcite crystals by customized self-assembling pseudopeptide foldamers

Two pseudopeptide foldamers with similar backbones, one containing a D-4-carboxy-5-methyl-oxazolidin-2-one moiety (1) and the other a D-proline moiety (2), self-assembled in a 9 : 1 water–ethanol mixture. Molecule 1 formed fibres that generated a highly viscous sol or a gel by increasing its concentration; molecule 2 assembled in nanoparticles that aggregated in bigger particles by increasing its concentration. This behaviour was conserved in the presence of 10 mM CaCl2. Both foldamers, which exposed carboxylate groups, were able to modify the shape of single crystals of calcite. The presence of molecule 1 favoured the formation of rhombohedral calcite showing additional crystalline faces, while molecule 2 induced the formation of cavities and curvatures. Thus, pseudopeptide foldamers diversely act as crystal growth modifiers according to minor structural changes that mutate their self-assembly. This result is of general interest for the design of new molecules affecting the crystallization process and has implications in understanding how biological molecules control the growth of mineral phases.

Pseudopeptide Foldamers designed for photoinduced intramolecular electron transfer

We have designed and prepared three pseudopeptide foldamers, called dyads 1, 2 and 3, equipped with a donor and an acceptor unit to promote intramolecular electron transfer after light excitation. All the three dyads contain the same donor and acceptor, which are a derivative of 1,5-dihydroxynaphthalene and a derivative of pyromellitic diimide, respectively. The donor and acceptor units are separated by hybrid foldamers of different length in order to vary both their distance and relative orientation. Specifically, one, two or three L-Ala-D-Oxd (Ala = alanine, Oxd = 4-carboxy-5-methyl-oxazolidin-2-one) units are contained in dyads 1, 2, and 3, respectively. Dyad 1 folds in a bent conformation in which the donor and acceptor units lie one close to the other, while dyads 2 and 3 preferentially assume an extended conformation. In all the three dyads both the donor and acceptor emissions are efficiently quenched via intramolecular electron transfer, as suggested by photophysical and electrochemical investigations. Because of its bent conformation dyad 1 exhibits a charge-transfer (CT) band at 410 nm in CH2Cl2 solution and a photoinduced electron transfer that occurs more efficiently than in dyads 2 and 3. Upon dissolving dyad 1 in DMSO, a competitive solvent for hydrogen bonds that establish in the pseudopeptide linker, the CT band disappears and the efficiency of electron transfer slightly decreases, in agreement with an unfolded conformation in which donor and acceptor units are no longer in close contact.

β-Peptoids: synthesis of a novel dimer having a fully extended conformation

Chiral imines 1a,b, already synthesized in our laboratory, were converted in good yield by reduction into the corresponding N-benzyl-γ-lactams 2a,b. Desilylation followed by oxidation of the hydroxymethyl functionality gave the N-benzyl-β-amino acids 5a,b in good yield and high purity. Starting from compound 6a, the corresponding β-peptoid dimer 8 was prepared, together with its derivatives 9 and 10, these latter displaying conformational restriction about the peptide bond, as evidenced by NMR data.