Alessandra Meli

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

Summary Cyclic N-propargyl α-peptoids of various sizes were prepared by way of macrocyclizations of linear N-substituted oligoglycines. These compounds were used as molecular platforms to synthesize a series of iminosugar clusters with different valency and alkyl spacer lengths by means of Cu(I)-catalysed azide–alkyne cycloadditions. Evaluation of these compounds as α-mannosidase inhibitors led to significant multivalent effects and further demonstrated the decisive influence of scaffold rigidity on binding affinity enhancements.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

Synthesis and complexing properties of cyclic benzylopeptoids - a new family of extended macrocyclic peptoids.

An efficient protocol for the solid-phase synthesis of six members of a new class of extended macrocyclic peptoids (based on ortho-, meta- and para-N-(methoxyethyl)aminomethyl phenylacetyl units) is described. Theoretical (DFT) and experimental (NMR) studies on the free and Na+-complexed cyclic trimers (3-5) and tetramers (6-8) demonstrate that annulation of the rigidified peptoids can generate new hosts with the ability to sequestrate one or two sodium cations with the affinities and stoichiometries defined by the macrocycle morphology. Ion transport studies have been also performed in order to better appreciate the factors promoting transmembrane cation translocation.

Ring size effect on the solid state assembly of propargyl substituted hexa- and octacyclic peptoids

The investigation of the solid state assembly of propargyl substituted hexa- and octacyclic peptoids highlights the effect of ring size in determining the packing arrangement of the macrocycles. A layered arrangement is obtained in the case of the hexacyclic peptoid 1 and a tubular arrangement in the case of the octacyclic peptoid 2. Guest molecules either intercalate between the layers as in 1 or are located within the peptoid nanotube as in 2.

Synthesis, crystallization, X-ray structural characterization and solid-state assembly of a cyclic hexapeptoid with propargyl and methoxyethyl side chains

The synthesis and the structural characterization of a cyclic hexapeptoid with four methoxyethyl and two propargyl side chains have disclosed the presence of a hydrate crystal form [form (I)] and an anhydrous crystal form [form (II)]. The relative amounts of form (I) and form (II) in the as-purified product were determined by Rietveld refinement and depend on the purification procedures. In crystal form (I), peptoid molecules assemble in a columnar arrangement by means of side-chain-to-backbone C=CH...OC hydrogen bonds. In the anhydrous crystal form (II), cyclopeptoid molecules form ribbons by means of backbone-to-backbone CH2...OC hydrogen bonds, thus mimicking β-sheet secondary structures in proteins. In both crystal forms side chains act as joints among the columns or the ribbons and contribute to the stability of the whole solid-state assembly. Water molecules in the hydrate crystal form (I) bridge columns of cyclic peptoid molecules, providing a more efficient packing.

Phakellistatins: An Underwater Unsolved Puzzle

A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1–19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility.

Molecular recognition and solvatomorphism of a cyclic peptoid: Formation of a stable 1D porous framework

Molecular recognition and the hydrophobic effect explain the solvatomorphic behavior of a hexameric α-cyclic peptoid. Either a pure non-porous crystal form or a stable one-dimensional porous framework is obtained using an appropriate choice of crystallization solvents.

Sense and flexibility: self-assembly, host-guest chemistry and solid state dynamic behaviour of cyclic peptoids

The design and synthesis of artificial systems able to mimic biological functions is the aim of extensive research activity in the field of molecular nanotechnology. Cyclic peptoids for their biostability and potential diversity seem to be the ideal candidates to evoke biological activities and novel chemical properties [1]. Peptoids differ from peptides in the backbone position of the side chains, which are attached to the nitrogen atoms. Due to the lack of the amide proton, CH···OC hydrogen bonds and CH-π interactions, play a key role in the solid-state assembly of cyclic α-peptoids: face to face or side by side arrangement of the macrocycles mimick β-sheet secondary structure in proteins [2,3]. Interestingly, the side chains may act as pillars: they may extend vertically with respect to the macrocycle plane and determine the columnar arrangement of the peptoid macrocycles [3]. Moreover, the peculiar conformational flexibility of cyclic peptoids is the key to their solid state dynamic behaviour. A cyclic peptoid compound, strategically decorated with propargyl and methoxyethyl side chains, undergoes a reversible single-crystal-to-single-crystal transformation upon guest release/uptake (see figure). The extensive and reversible alteration in the solid state is connected to the formation of an unprecedented “CH–π zipper”, which can reversibly open and close, thus allowing for guest sensing [4]. This contribution shows how easily tunable cyclic peptoids may lead to functional materials, that feature both robustness and adaptivity, at the frontier between materials science and biology. This research has received funding from the People Programme (Marie Curie Actions) FP7/2007-2013/ under REA grant agreement n°PIRSES-GA-2012-319011. [1] a) Schettini R., De Riccardis F., Della Sala G., Izzo I. J. Org. Chem. 81, 2494 (2016); b) Lepage M. L. et al. Chem. Eur. J. 22, 5151 (2016). [2] a) Izzo I., Ianniello G., De Cola C., Nardone B., Erra L., Vaughan G., Tedesco C., De Riccardis F. Org. Lett. 15, 598 (2013); b) Maulucci N. et al. Chem. Commun. 3927 (2008). [3] Tedesco C., Erra L., Izzo I., De Riccardis F. CrystEngComm 16, 3667 (2014). [4] Meli A., Macedi E., De Riccardis F., Smith V. J., Barbour L. J., Izzo I., Tedesco C. Angew. Chem. Int. Ed. Engl. 55, 4679 (2016).