Irene Izzo

Ion transport through lipid bilayers by synthetic ionophores: modulation of activity and selectivity.

The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternate-calix[4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.

Size-dependent cation transport by cyclic α-peptoid ion carriers

N-Benzyloxyethyl macrocyclic peptoids 3 and 4 were synthesized and subjected to alkali metal binding studies; these compounds, plus the known 1 and 2, when subjected to ion transport studies, demonstrated size-dependent selectivity for the first group alkali metals cation transport.

Structural Effects of Proline Substitution and Metal Binding on Hexameric Cyclic Peptoids

L-Proline and N-methoxyethyl glycine have been included in novel cyclic hexameric peptoids. Supramolecular coordination with Na(+) triggered the formation of the first 1D metal-organic framework based on peptoids.

Structural revision of halipeptins: synthesis of the thiazoline unit and isolation of halipeptin C

Abstract The structural revision of the anti-inflammatory marine metabolites halipeptin A ( 1 ) and B ( 2 ) along with the isolation of the new related product halipeptin C ( 3 ) are reported. In particular, the heterocyclic portion of the molecule, incorrectly assigned as an oxazetidine ring, has now been characterised as a thiazoline unit by comparison of the spectral data of the natural products ( 1–3 ) with an appropriate synthetic model ( 10 ). GIAO calculated 13C NMR chemical shifts for oxazetidine and thiazoline model compounds provide additional support to the revised structure.

Design, synthesis and antimicrobial properties of non-hemolytic cationic α-cyclopeptoids

The synthesis and screening of neutral and cationic, linear and cyclic peptoids (N-alkylglycine peptidomimetics) is described. Structure-activity relationship studies show that the in vitro activities of the tested peptoids depend on both cyclization and decoration with cationic groups. The most powerful N-lysine cyclopeptoid derivatives showed good antifungal activity against Candida albicans (ATCC90029 and L21) and Candida famata (SA550, Amph B-resistant) and low hemolytic activity. The effects of the cyclic peptoids on membrane permeabilization were evaluated by the propidium iodide exclusion assay.

SYNTHESIS AND CYTOTOXIC ACTIVITY OF STEROID-ANTHRAQUINONE HYBRIDS

Abstract Synthesis of cytotoxic steroidal derivatives containing a quinone moiety is described. The synthetic strategy is based on an unsual A + CD → ABCD Diels-Alder approach which generates 9β-H cholestane analogs. The adducts formed are efficiently aromatized in basic media to give steroid-anthaquinones hybrids showing interesting cytotoxic activity on four tumor cell lines.

Solid state assembly of cyclic α-peptoids

The solid state assembly of free and metal coordinated cyclic α-peptoids has been examined with the aim to find common underlying features and to direct the design of new functional biomimetic materials with desired properties in terms of molecular recognition, drug delivery and catalysis. The lack of the amide proton prevents the formation of NH⋯OC hydrogen bonds and weaker interactions play a key role in the intermolecular recognition and assembly. Inter-annular CH⋯OC hydrogen bonds provide face to face or side by side arrangement of macrocycles in a way that can be considered the peptoid counterpart of β-sheet secondary structure in proteins. The choice of side chains is crucial for the solid state properties of α-cyclic peptoids. Side chains have a strong influence on the solid state assembly of peptoid macrocycles: they may provide competing interactions to CH⋯OC inter-annular hydrogen bonds, leading either to a T-shape or to a tubular arrangement of the peptoid macrocycles. The size of the macrocycle is another important factor influencing the tubular arrangement. In particular, a larger size of the macrocycle promotes side by side with respect to T-shape interactions. Hirshfeld surfaces and their fingerprint analysis allowed the analysis of the contributions of weak intermolecular interactions, such as weak CH⋯OC hydrogen bonds and CH–pi interactions, towards the crystal packing.

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.

SYNTHESIS OF (17R)-17-METHYLINCISTEROL, A HIGHLY DEGRADED MARINE STEROID

Abstract The synthesis of (17 R )-17-methylincisterol, a highly degraded marine steroid, has been achieved starting from vitamin D 2 in 8 steps and in 13% overall yield. Its O-demethyl analog, which is an intermediate in the synthetic sequence, is possibly the true naturally occurring molecule.

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.