Celebrating Maurizio Prato's Passion, Talent and Imagination.

This Editorial introduces a Special Collection of papers dedicated to Maurizio Prato, featuring prominent examples of his team's efforts to integrate complex frontier research with pioneering achievements in the field of carbon nanostructures and molecular nanoscience.

Naphthalimide-Dyes Bearing Phosphine and Phosphorylamide Moieties: Synthesis and Optical Properties.

1,8-Naphthalimides (NIs) represent a class of organic dyes with interesting optical properties that has been extensively explored in the last decades in lighting devices, chemosensors, optical probes or medicinal chemistry. However, despite their remarkable potential, reports on organometallic dyes bearing NIs are scarce and virtually inexistent regarding palladium(II) complexes. Herein, we report the synthesis of NIs bearing phosphine and amine chelating moieties and the characterization of their optical properties both as single molecules and when complexed on Pd(II) ions. It is shown that the introduction of phosphine moieties in the naphthalimide core results in a marked increase in non-radiative processes, leading to a significant reduction of the emission efficiency and lifetime of these dyes, compared to amine-bearing counterparts. The complexation to Pd(II) sequesters the electronic contribution of chelating moieties, with complexes assuming an optical behavior similar to that of unsubstituted 1,8-naphthalimide. The complexation significantly increases the acidity of chelating secondary amines, giving rise to an unexpected intramolecular reaction that results in the formation of a novel 1,8-naphthalimide dye bearing a cyclic phosphorylamide moiety. The new dye exhibits good emission quantum yield, long fluorescence lifetime and sensitivity to basic media, evidencing potential for application in optical imaging and sensing scenarios.

Probing Peripheral H-Bonding Functionalities in BN-Doped Polycyclic Aromatic Hydrocarbons.

The replacement of carbon atoms at the zigzag periphery of a benzo[fg]tetracenyl derivative with an NBN atomic triad allows the formation of heteroatom-doped polycyclic aromatic hydrocarbon (PAH) isosteres, which expose BN mimics of the amidic NH functions. Their ability to form H-bonded complexes has never been touched so far. Herein, we report the first solution recognition studies of peripherally NBN-doped PAHs to form H-bonded DD·AA- and ADDA·DAAD-type complexes with suitable complementary H-bonding acceptor partners. The first determination of Ka in solution showed that the 1:1 association strength is around 27 ± 1 M-1 for the DD·AA complexes in C6D6, whereas it rises to 1820 ± 130 M-1 for the ADDA·DAAD array in CDCl3. Given the interest of BN-doped polyaromatic hydrocarbons in supramolecular and materials chemistry, it is expected that these findings will open new possibilities to design novel materials, where the H-bonding properties of peripheral NH hydrogens could serve as anchors to tailor the organizational properties of PAHs.

Toward Fractioning of Isomers through Binding-Induced Acceleration of Azobenzene Switching.

The E/Z isomerization process of a uracil-azobenzene derivative in which the nucleobase is conjugated to a phenyldiazene tail is studied in view of its ability to form triply H-bonded complexes with a suitably complementary 2,6-diacetylamino-4-pyridine ligand. UV-vis and 1H NMR investigations of the photochemical and thermal isomerization kinetics show that the thermal Z → E interconversion is 4-fold accelerated upon formation of the H-bonded complex. DFT calculations show that the formation of triple H-bonds triggers a significant elongation of the N═N double bond, caused by an increase of its πg* antibonding character. This results in a reduction of the N═N torsional barrier and thus in accelerated thermal Z → E isomerization. Combined with light-controlled E → Z isomerization, this enables controllable fractional tuning of the two configurational isomers.

Cyclic Peptoids as Mycotoxin Mimics: An Exploration of Their Structural and Biological Properties.

Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

Hydrolytic Metallo-Nanozymes: From Micelles and Vesicles to Gold Nanoparticles.

Although the term nanozymes was coined by us in 2004 to highlight the enzyme-like properties of gold nanoparticles passivated with a monolayer of Zn(II)-complexes in the cleavage of phosphate diesters, systems resembling those metallo-nanoparticles, like micelles and vesicles, have been the subject of investigation since the mid-eighties of the last century. This paper reviews what has been done in the field and compares the different nanosystems highlighting the source of catalysis and frequent misconceptions found in the literature.

Guanine-based amphiphiles: synthesis, ion transport properties and biological activity.

Novel amphiphilic guanine derivatives, here named Gua1 and Gua2, have been prepared through few, simple and efficient synthetic steps. In ion transport experiments through phospholipid bilayers, carried out to evaluate their ability to mediate H(+) transport, Gua2 showed high activity. When this compound was investigated for ion-selective transport activities, no major differences were observed in the behaviour with cations while, in the case of anions, selective activity was observed in the series I(-)>Br(-)>Cl(-)>F(-). The bioactivity of these guanine analogues has been evaluated on a panel of human tumour and non-tumour cell lines in preliminary in vitro cytotoxicity assays, showing a relevant antiproliferative profile for Gua2.

Helical peptide-polyamine and -polyether conjugates as synthetic ionophores.

Two new synthetic ionophores in which the hydrophobic portion is represented by a short helical Aib-peptide (Aib=α-amino-isobutyric acid) and the hydrophilic one is a poly-amino (1a) or a polyether (1b) chain have been prepared. The two conjugates show a high ionophoric activity in phospholipid membranes being able to efficiently dissipate a pH gradient and, in the case of 1b, to transport Na(+) across the membrane. Bioactivity evaluation of the two conjugates shows that 1a has a moderate antimicrobial activity against a broad spectrum of microorganisms and it is able to permeabilize the inner and the outer membrane of Escherichia coli cells.

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.

New meso-substituted trans-A(2)B(2) di(4-pyridyl)porphyrins as building blocks for metal-mediated self-assembling of 4 + 4 Re(I)-porphyrin metallacycles.

The reaction between 5-(4-pyridyl)dipyrrylmethane and aromatic aldehydes affords meso-arylsubstituted trans-A2B2 di(4-pyridyl)porphyrins which are key building blocks in the metal-mediated self-assembling of supramolecular structures. A careful optimization of the reaction conditions allowed us to obtain 5,15-diphenyl-10,20-di(4-pyridyl)porphyrin (P1), and two analogues bearing on the meso-phenyl substituents two dipropyl- (P4) or dihexyl-alkyl chains (P5), with yields ranging from 53 to 63%. Porphyrin P1 reacts with Re(CO5)Br to give the expected 4 + 4 Re(I)-porphyrin metallacycle which has been fully characterized by means of infrared, NMR and UV-Vis (absorption and emission) spectroscopies and by guest inclusion studies. Unexpectedly the addition of alkyl chains to the porphyrin fragment, which increase the solubility of the porphyrin in organic solvents, has the opposite effect on the adduct with Re(I). Indeed, the reaction between Re(CO5)Br and porphyrins P4,5 gives very insoluble materials, hampering their complete characterization.

Metal-organic transmembrane nanopores.

A stable tetraporphyrin metallacycle with Re(I) corners (1) is capable of forming nanopores in a liposomial membrane, provided that the porphyrin units are properly functionalized with peripheral carboxylic acid residues that, by establishing an hydrogen bond network, allow the formation of dimers that span the depth of the membrane.

Design, synthesis and characterisation of guanosine-based amphiphiles.

A small library of sugar-modified guanosine derivatives has been prepared, starting from a common intermediate, fully protected on the nucleobase. Insertion of myristoyl chains and of diverse hydrophilic groups, such as an oligoethylene glycol, an amino acid or a disaccharide chain, connected through in vivo reversible ester linkages, or of a charged functional group provided different examples of amphiphilic guanosine analogues, named G1-G7 herein. All of the sugar-modified derivatives were positive in the potassium picrate test, showing an ability to form G-tetrads. CD spectra demonstrated that, as dilute solutions in CHCl(3), distinctive G-quadruplex systems may be formed, with spatial organisations dependent upon the structural modifications. Two compounds, G1 and G2, proved to be good low-molecular-weight organogelators in polar organic solvents, such as methanol, ethanol and acetonitrile. Ion transportation experiments through phospholipid bilayers were carried out to evaluate their ability to mediate H(+) transportation, with G5 showing the highest activity within the investigated series. Moreover, G3 and G5 exhibited a significant cytotoxic profile against human MCF-7 cancer cells in in vitro bioassays.

Cholate Conjugated Polymeric Amphiphiles as Efficient Artificial Ionophores.

A family of amphiphilic copolymers containing hydrophobic cholate pendants has been prepared by copolymerization of cholic acid-based monomer 2-(methacryloxy)-ethyl cholate (MAECA) with polyethylene glycol methyl ether methacrylate (PEGMA). The polymers differ for the content of MAECA that increases from 0 to 35%. The copolymers partition within liposomes and display potent ionophoric activity forming large pores in the membrane and allowing the leakage of small inorganic ions (H+, Na+) and of large polar organic molecules (calcein). Their activity is strictly correlated to the content of cholic acid subunits, increasing as the fraction of cholate moiety increases.

Design, synthesis and characterisation of a fluorescently labelled CyPLOS ionophore.

A novel fluorescently labelled synthetic ionophore, based on a cyclic phosphate-linked disaccharide (CyPLOS) backbone and decorated with four tetraethylene glycol tails carrying dansyl units, has been synthesised in 12 steps in 26% overall yield. The key intermediate in the synthetic strategy is a novel glucoside building block, serving through its 2- and 3-hydroxy groups as the anchor point for flexible tetraethylene glycol tentacles with reactive azido moieties at their ends. To test the versatility of this glucoside scaffold, it was preliminarily functionalised with a set of diverse probes--as fluorescent, redox-active or hydrophobic tags--either by reduction of the azides followed by condensation with activated carboxylic acid derivatives, or by a direct coupling with a terminal alkyne in a Cu(I)-promoted 1,3-dipolar cycloaddition. Tagging of the monomeric building block with dansyl residues allowed us to prepare a fluorescent, amphiphilic macrocycle, which was investigated for its propensity to self-aggregate in CDCl(3)--studied by means of concentration-dependent (31)P NMR spectroscopy experiments--and in aqueous solution, in which combined dynamic light scattering (DLS) and small-angle neutron scattering (SANS) measurements provided a detailed physico-chemical analysis of the self-assembled systems, mainly organised in the form of large vesicles. Its ion-transport properties through phospholipid bilayers, determined by HPTS fluorescence assays, showed this compound to be more active than the previously synthesised CyPLOS congeners. Solvent-dependent fluorescence changes for the labelled ionophore in liposome suspension established that the dansyl moieties are dispersed in environments with polarity intermediate between those of CH(2)Cl(2) and propan-2-ol, suggesting that the CyPLOS tentacles infiltrate the mid-polar region of the membranes.

Configurational Selection in Azobenzene-Based Supramolecular Systems Through Dual-Stimuli Processes.

Azobenzene is one of the most studied light-controlled molecular switches and it has been incorporated in a large variety of supramolecular systems to control their structural and functional properties. Given the peculiar isomeric distribution at the photoexcited state (PSS), azobenzene derivatives have been used as photoactive framework to build metastable supramolecular systems that are out of the thermodynamic equilibrium. This could be achieved exploiting the peculiar E/Z photoisomerization process that can lead to isomeric ratios that are unreachable in thermal equilibrium conditions. The challenge in the field is to find molecular architectures that, under given external circumstances, lead to a given isomeric ratio in a reversible and predictable manner, ensuring an ultimate control of the configurational distribution and system composition. By reviewing early and recent works in the field, this review aims at describing photoswitchable systems that, containing an azobenzene dye, display a controlled configurational equilibrium by means of a molecular recognition event. Specifically, examples include programmed photoactive molecular architectures binding cations, anions and H-bonded neutral guests. In these systems the non-covalent molecular recognition adds onto the thermal and light stimuli, equipping the supramolecular architecture with an additional external trigger to select the desired configuration composition.

CyPLOS: a new family of synthetic ionophores.

The ion transport properties of a new family of synthetic ionophores based on cyclic phosphate-linked oligosaccharide (CyPLOS) macrocycles are described.

Size-dependent cation transport by cyclic alpha-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.

Cationic calix[4]arenes as anion-selective ionophores.

1,3-Alternate cationic calix[4]arene proved highly selective for proton/halogens symport transport and showed antiproliferative activity against murine monocyte/macrophage J774.A1 cancer cells.

Artificial anion transporters in bilayer membranes.

Anion transport across phospholipid membrane is a typical supramolecular function involving dynamic recognition of the substrate during the whole translocation process. Supramolecular chemists, taking inspiration by the natural anion transporters, have designed artificial systems able to mimic, at the functional level, several features of the natural ion channels. The scope of this research is twofold: on one hand to get insight on the molecular basis of recognition and transport, and on the other hand to get control of the biomedical relevant processes. The present review focuses on the synthetic systems promoting anion transport, covering both artificial channels and carriers that operate in phospholipid membrane. The design principles of such systems will be discussed together with the potential biomedical applications.

Biological Activity of Trans-Membrane Anion Carriers.

Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article, an overview of the recent results on the study of aniontransporters, mainly acting with a carrier-type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived from dysregulation of natural anion channels.