The synthesis and the structural characterization of dipeptides composed of unnatural fluorine-substituted β(2,3)-diarylamino acid and L-alanine are reported. Depending on the stereochemistry of the β amino acid, these dipeptides are able to self-assemble into proteolytic stable nanotubes. These architectures were able to enter the cell and locate in the cytoplasmic/perinuclear region and represent interesting candidates for biomedical applications.

The development of molecular carriers able to carry molecules directly into the cell is an area of intensive research. Cationic nanoparticles are effective delivery systems for several classes of molecules, such as anticancer agents, oligonucleotides and antibodies. Indeed, a cationic charge on the outer surface allows a rapid cellular uptake together with the possibility of carrying negatively charged molecules. In this work, we studied the self-assembly of an ultra-short ααβ-tripeptide containing an l-Arg-l-Ala sequence and an unnatural fluorine substituted β-diaryl-amino acid. The presence of the unnatural β-diaryl-amino acid allowed us to obtain a protease stable sequence. Furthermore, an arginine guanidinium group triggered the formation of spherical assemblies that were able to load small molecules and enter cells. These spherical architectures, thus, represent interesting candidates for the delivery of exogenous entities directly into cells.

A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations. Introduction g-Turns is a very short motif able to reverse the main chain of a peptide/protein. It is stabilized by the formation of a hydrogen bond between the C=O of residue i and the NH of residue i+2 forming a pseudo-seven-membered ring. Depending on the f and y angles, two different type of turns can be designed defined as inverse [φ (-75°); y (+65°)] and classical φ (+75°); y (-65°)] g-turns. In the first one, the R substituent of the a-amino acid lies in the equatorial position, while in the second one in axial position. Inverse g-turns are generally located at a position of reversal in chain direction (180°) and often within b-strands associated to b-sheets. On the other hand, classical g-turns are less common in proteins, and in most cases, they lie at the loop end of a β-hairpin. 1 A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations.

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies.