Alessandro Casnati

Calixarene-based multivalent ligands

Multivalency is a powerful concept which explains the strong binding observed in biological systems and guides the design and synthesis of ligands for self-assembly and molecular recognition in Chemistry. The phenol-formaldehyde cyclic oligomers, called calixarenes, have been used as scaffolds for the synthesis of multivalent ligands thanks to the fact that they have a variable number of reactive positions for attaching the ligating functions, well defined conformational properties and, in some cases, cavities of molecular dimensions eventually able to encapsulate guest species. This tutorial review illustrates the fundamental aspects of multivalency and the properties of calixarene-based multivalent ligands in lectin binding and inhibition, DNA condensation and cell transfection, protein surface recognition, self-assembly, crystal engineering, and nanofabrication.

Chloromethylation of calixarenes and synthesis of new water soluble macrocyclic hosts

Abstract The chloromethylation of calix[4]arene 1a and of the methyl ethers of calix[6]arene 1b and calix[8]arene 1c , using chloromethyl n-octyl ether and SnCl 4 in chloroform at room temperature has been performed in good yield for the first time. The chloromethylated products 2a–c have been used as intermediates to introduce on calixarenes phosphonic acid groups which render these macrocycles water soluble and potentially useful in Host Guest Chemistry.

Calix[n]arene-Based Glycoclusters: Bioactivity of Thiourea-Linked Galactose/Lactose Moieties as Inhibitors of Binding of Medically Relevant Lectins to a Glycoprotein and Cell-Surface Glycoconjugates and Selectivity among Human Adhesion/Growth-Regulatory Galectins

Growing insights into the functionality of lectin–carbohydrate interactions are identifying attractive new targets for drug design. As glycan recognition is regulated by the structure of the sugar epitope and also by topological aspects of its presentation, a suitable arrangement of ligands in synthetic glycoclusters has the potential to enhance their avidity and selectivity. If adequately realized, such compounds might find medical applications. This is why we focused on lectins of clinical interest, acting either as a potent biohazard (a toxin from Viscum album L. akin to ricin) or as a factor in tumor progression (human galectins‐1, ‐3, and ‐4). Using a set of 14 calix[n]arenes (n=4, 6, and 8) with thiourea‐linked galactose or lactose moieties, we first ascertained the lectin‐binding properties of the derivatized sugar head groups conjugated to the synthetic macrocycles. Despite their high degree of flexibility, the calix[6,8]arenes proved especially effective for the plant AB‐toxin, in the solid‐phase model system with a single glycoprotein (asialofetuin) and with human tumor cells in vitro. The bioactivity of the calix[n]arenes was also proven for human galectins. Notably, selectivity for the tested tandem‐repeat‐type galectin‐4 among the three subgroups was determined at the level of solid‐phase and cell assays, the large flexible macrocycles again figuring prominently as inhibitors. Alternate and cone versions of calix[4]arene with lactose units distinguished between galectins‐1 and ‐4 versus galectin‐3 in cell assays. The results thus revealed bioactivity of galactose‐/lactose‐presenting calix[n]arenes for medically relevant lectins and selectivity within the family of adhesion/growth‐regulatory human galectins.

Calixarenes: from biomimetic receptors to multivalent ligands for biomolecular recognition

Calixarenes are versatile platforms for the design and synthesis of molecular receptors and multivalent ligands that are able to mimic or affect specific biological functions. This review illustrates examples spanning the recognition of small peptides and carbohydrates to ion transport through membranes, biomimetic catalysis, DNA condensation and cell transfection, protein binding, sensing and inhibition, and gives perspectives for using calixarene macrocycles in bio-supramolecular chemistry.

Lanthanide complexes of encapsulating ligands: Luminescent devices at the molecular level

Lanthanide complexes of encapsulating ligands are studied as luminescent devices at the molecular level. The photophysical properties of the complexes which, up till now, showed the most intense luminescencepe reported. The luminescence intensity of these complexes is discussed,considering the efficiency of incident light-emitted light conversion, defined as the product of the absorption efficiency and the luminescence quantum yield. It is illustrated,how the metal luminescence intensity can be enhanced by adapting the ligands on basis of previously obtained experimental results. The possible application of these complexes in fluoroimmunoassays is examined.

A new chiral rigid cone water soluble peptidocalix[4]arene and its inclusion complexes with α-amino acids and aromatic ammonium cations

A remarkable influence of the rigidity of the calix[4]arene platform in determining the recognition properties of mobile 2 and rigid cone 6 water soluble peptidocalix[4]arene receptors towards α-amino acids and aromatic quaternary ammonium cations has been found.

Multivalent glycocalixarenes for recognition of biological macromolecules: glycocalyx mimics capable of multitasking

The glycoside cluster effect, a special case of multivalency involving carbohydrates, is a powerful tool exploited by Nature to make relatively weak interactions stronger and more specific. Organic and supramolecular chemists have been applying this concept and are devising a plethora of neo-glycoconjugates which can interfere with a series of pathological events such as infections due to viruses and bacteria, tumour progression and migration, and inflammation processes. In the present Tutorial Review, we will illustrate the factors that make calixarenes, the cyclic oligomers obtained by the condensation of phenols/resorcinols and aldehydes, unique scaffolds for the construction of multivalent glycosylated ligands, individually analysing how structural parameters such as the size, valency, conformation, self-assembling behaviour of the macrocycle and especially the topology of the saccharide presentation in space influence the biological properties. We will not only survey the most significant results obtained to date in the inhibition of carbohydrate binding proteins (lectins), but we will also try to paint a picture of the potential that multivalent glycocalixarenes might have in bionanotechnology and nanomedicine, that are especially related to their combined ability to load cargo and to specifically deliver that cargo to target cells.

Arginine clustering on calix[4]arene macrocycles for improved cell penetration and DNA delivery.

Cell-penetrating peptides are widely used as molecular transporters for the internalization inside cells of various cargo, including proteins and nucleic acids. A special role is played by arginine-rich peptides and oligoarginines covalently linked or simply mixed with the cargo. Here we report cell-penetrating agents in which arginine units are clustered on a macrocyclic scaffold. Instead of using long peptides, four single arginine units were covalently attached to either the upper or lower rim of a calix[4]arene, kept in the cone conformation building a ‘parallel’ cyclic array. These new macrocyclic carriers show high efficiency in DNA delivery and transfection in a variety of cell lines.

Syn-1,2-dialkylated calix[4]arenes: general intermediates in the NaH/DMF tetraalkylation of calix[4]arenes

In DMF or acetonitrile with NaH as a base at room temperature the tetraalkylation of calix[4]arenes 1a and 1b proceeds via the syn-1,2-disubstituted products to the tetraalkylated calix[4]arenes in the cone conformation. With KH as a base the tetraalkylated calix[4]arenes are predominantly formed in the partial cone conformation, and the reaction proceeds via both the syn-1,3-di and the syn-1,2-disubstituted products. Also the solvent influences the pathway via which tetraalkylation takes place. The syn-1,2-disubstituted calix[4]arenes 4-6 can be isolated in 15-55 % from the NaH/DMF or MeCN reactions when only 2.2 equiv of the electrophile are used.

Synthesis, antimicrobial activity and binding properties of calix[4]arene based vancomycin mimics

Abstract Biologically active Vancomycin antibiotic mimics have been synthesized by linking two opposite aromatic nuclei of a calix[4]arene derivative in the cone conformation with a polifunctional bridge containing D-or L-alanine units and diethylentriamine segment.