3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity.

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson's disease that has been repurposed as a TTR stabiliser.

Cationic Calix[4]arene Vectors to Efficiently Deliver AntimiRNA Peptide Nucleic Acids (PNAs) and miRNA Mimics.

One of the most appealing approaches for regulating gene expression, named the "microRNA therapeutic" method, is based on the regulation of the activity of microRNAs (miRNAs), the intracellular levels of which are dysregulated in many diseases, including cancer. This can be achieved by miRNA inhibition with antimiRNA molecules in the case of overexpressed microRNAs, or by using miRNA-mimics to restore downregulated microRNAs that are associated with the target disease. The development of new efficient, low-toxic, and targeted vectors of such molecules represents a key topic in the field of the pharmacological modulation of microRNAs.

A Combined Solution and Solid-State Study on the Tautomerism of an Azocalix[4]arene Chromoionophore.

Azocalixarenes functionalized with cation binding sites are popular chromoionophores due to the ease of synthesis and the large complexation-induced shifts of their absorption band that originate from an azo-phenol-quinone-hydrazone tautomerism. Despite their extensive use, however, a thorough investigation of the structure of their metal complexes has not been reported. We describe herein the synthesis of a new azocalixarene ligand () and the study of its complexation properties with the Ca cation.

Multivalent calix[4]arene-based mannosylated dendrons as new FimH ligands and inhibitors.

We report the synthesis and biological characterization of a novel class of multivalent glycoconjugates as hit compounds for the design of new antiadhesive therapies against urogenital tract infections (UTIs) caused by uropathogenic E. coli strains (UPEC). The first step of UTIs is the molecular recognition of high mannose N-glycan expressed on the surface of urothelial cells by the bacterial lectin FimH, allowing the pathogen adhesion required for mammalian cell invasion.

Complex Formation between Cytochrome and a Tetra-alanino-calix[4]arene.

Owing to their remarkable features, calix[n]arenes are being exploited to study different aspects of molecular recognition, including protein complexation. Different complexation modes have been described, depending on the moieties that complement the aromatic cavity, allowing for function regulation and/or controlled assembly of the protein target. Here, a rigid cone calix[4]arene, bearing four anionic alanine units at the upper rim, was tested as a ligand for cytochrome .

Intra- and Intermolecular Cooperativity in the Catalytic Activity of Phosphodiester Cleavage by Self-Assembled Systems Based on Guanidinylated Calix[4]arenes.

The calix[4]arene scaffold, blocked in the cone conformation through alkylation with long alkyl chains, and decorated at the upper rim with four guanidine or arginine units, effectively catalyzes the cleavage of the phosphodiester bond of DNA and RNA model compounds in water. An exhaustive kinetic investigation unequivocally points to the existence of spontaneous aggregation phenomena, driven by hydrophobic effect, occurring at different critical concentrations that depend on the identity of the compound. A pronounced superiority of the assembled structures compared with the monomers in solution was observed.

Temporal Control of the Host-Guest Properties of a Calix[6]arene Receptor by the Use of a Chemical Fuel.

The host-guest interaction of a 1,3,5-trisaminocalix[6]arene receptor with -methylisoquinolinium trifluoromethanesulfonate ( of 500 ± 30 M in CDCl) can be dissipatively driven by means of 2-cyano-2-(4'-chloro)phenylpropanoic acid used as a convenient chemical fuel. When the fuel is added to a dichloromethane solution containing the above complex, the host is induced to immediately release the guest in the bulk solution. Consumption of the fuel allows the guest to be re-uptaken by the host.

Calixarenes Incorporating Sulfonamide Moieties: Versatile Ligands for Carbonic Anhydrases Inhibition.

Carbonic anhydrases (CAs) continue to represent a relevant pharmaceutical target. The need of selective inhibitors and the involvement of these metalloenzymes in many multifaceted diseases boost the search for new ligands able to distinguish among the different CA isoforms, and for multifunctional systems simultaneously able to inhibit CAs and to interfere with other pathological events by interacting with additional targets. In this work, we successfully explored the possibility of preparing new CAs ligands by combining calixarenes with benzensulfonamide units.

Dissipative control of the fluorescence of a 1,3-dipyrenyl calix[4]arene in the cone conformation.

The temporal control (ON/OFF/ON) of the fluorescence of a dichloromethane/acetonitrile 1 : 1 solution of calixarene 3 decorated with two pyrenyl moieties at the upper rim is attained by the addition of CClCOH used as a convenient chemical fuel.

Calixarene-decorated liposomes for intracellular cargo delivery.

Amphiphilic calix[4]arenes, functionalized with guanidinium groups, are used to decorate the outer surface of liposomes and significantly improve the cellular uptake of a cargo compared to plain liposomes. The improved uptake is elicited and mediated by the interaction between the cationic polar heads of the macrocycle units embedded in the liposome bilayer and anionic heparan-sulfate proteoglycans surrounding the exterior of cells.

Delivery of Peptide Nucleic Acids Using an Argininocalix[4]arene as Vector.

The importance of peptide nucleic acids (PNAs) for alteration of gene expression is nowadays firmly established. PNAs are characterized by a pseudo-peptide backbone composed of N-(2-aminoethyl)glycine units and have been found to be excellent candidates for antisense and antigene therapies. Recently, PNAs have been demonstrated to alter the action of microRNAs and thus can be considered very important tools for miRNA therapeutics.

Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin.

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine and retinol in blood and cerebrospinal fluid. TTR stabilizers, such as tolcapone, an FDA approved drug for Parkinson's disease, are able to interact with residues of the thyroxine-binding sites of TTR, both wild type and pathogenic mutant forms, thereby stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on the synthesis of 3-deoxytolcapone, a novel stabilizer of TTR.

Time Programmable Locking/Unlocking of the Calix[4]arene Scaffold by Means of Chemical Fuels.

In this work, we report that 2-cyano-2-phenylpropanoic acid and its p-Cl, p-CH and p-OCH derivatives can be used as chemical fuels to control the geometry of the calix[4]arene scaffold in its cone conformation. It is shown that, under the action of the fuel, the cone calix[4]arene platform assumes a "locked" shape with two opposite aromatic rings strongly convergent and the other two strongly divergent ("pinched cone" conformation). Only when the fuel is exhausted, the cone calix[4]arene scaffold returns to its resting, "unlocked" shape.

Probing the determinants of porosity in protein frameworks: co-crystals of cytochrome c and an octa-anionic calix[4]arene.

Sulfonato-calix[n]arenes (sclxn) are promising tools to generate crystalline protein frameworks. We report, for the first time, a lower rim functionalised octa-anionic calix[4]arene (sclx4mc) in complex with proteins. Two crystal structures of sclx4mc bound to yeast or horse heart cytochrome c (cytc) are described.

Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle.

MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e.

Activation of the Aromatic Core of 3,3'-(Pyridine-2,6-diylbis(1-1,2,3-triazole-4,1-diyl))bis(propan-1-ol)-Effects on Extraction Performance, Stability Constants, and Basicity.

The "CHON" compatible water-soluble ligand 3,3'-(pyridine-2,6-diylbis(1-1,2,3-triazole-4,1-diyl))bis(propan-1-ol) (PTD) has shown promise for selectively stripping actinide ions from an organic phase containing both actinide and lanthanide ions, by preferential complexation of the former. Aiming at improving its complexation properties, PTD-OMe was synthesized, bearing a methoxy group on the central pyridine ring, thus increasing its basicity and hence complexation strength. Unfortunately, solvent extraction experiments in the range of 0.

A calix[4]arene with acylguanidine units as an efficient catalyst for phosphodiester bond cleavage in RNA and DNA model compounds.

A calix[4]arene scaffold, blocked in the cone conformation and decorated at the upper rim with two acylguanidine units, effectively catalyzes the cleavage of phosphodiester bonds of HPNP and BNPP under neutral pH conditions. The catalyst performance is discussed in terms of acceleration over background hydrolysis and effective molarity (EM). The combination of potentiometric acid-base titrations with pH-rate profiles for HPNP and BNPP cleavage in the presence of 2·2HCl additives points to a marked synergic action of an acylguanidine/acylguanidinium catalytic dyad in 2H, via general base-electrophilic bifunctional catalysis.

Efficient cell penetration and delivery of peptide nucleic acids by an argininocalix[4]arene.

The application of Peptide Nucleic Acids (PNAs), mimics of DNA lacking the sugar-phosphate backbone, for antisense/anti-gene therapy and gene editing is limited by their low uptake by cells. Currently, no simple and efficient delivery systems and methods are available to solve this open issue. One of the most promising approach is the modification of the PNA structure through the covalent linkage of poliarginine tails, but this means that every PNA intended to be internalized must be modified.

Inherently chiral cone-calix[4]arenes via a subsequent upper rim ring-closing/opening methodology.

Access to chiral calix[4]arenes can unlock novel supramolecular architectures for enantioselective catalysis and molecular recognition. However, accessibility to these structures has been significantly hindered so far. We report herein the synthesis and characterization of di- and trifunctionalized cone-calix[4]arenes featuring a lactone moiety spanning the distal positions at the upper rim.

Complete tetraglycosylation of a calix[4]arene by a chemo-enzymatic approach.

Polyglycosylated calixarenes are efficient and selective multivalent ligands for lectins. However, the chemical decoration of these macrocyclic scaffolds with saccharides of increasing complexity is hampered by the highly complex chemistry of carbohydrates. An alternative to the conventional approach is the enzymatic diversification of simple glycocluster-presented glycans.

Mannosylcalix[n]arenes as multivalent ligands for DC-SIGN.

DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC-SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers.

Guanidinium Promoted Cleavage of Phosphoric Diesters: Kinetic Investigations and Calculations Provide Indications on the Operating Mechanism.

The catalytic activity of the guanidinium units toward the cleavage of phosphoric diesters is deeply investigated both with kinetic experiments and DFT calculations. The first part of the investigation aims to determine how the structure of the substrate (phenyl or alkyl esters) is able to influence the guanidinium-catalyzed hydrolysis changing the mechanism from AD to A+D. In the cleavage of the DNA model bis(4-nitrophenyl)phospate (BNPP), experimental kinetic data highlight the operation of a guanidine-guanidinium catalytic dyad that can act both intermolecularly and intramolecularly on different molecular scaffolds exhibiting notable values of effective molarity.

Docetaxel-Loaded Nanoparticles Assembled from β-Cyclodextrin/Calixarene Giant Surfactants: Physicochemical Properties and Cytotoxic Effect in Prostate Cancer and Glioblastoma Cells.

Giant amphiphiles encompassing a hydrophilic β-cyclodextrin (βCD) component and a hydrophobic calix[4]arene (CA) module undergo self-assembly in aqueous media to afford core-shell nanospheres or nanocapsules, depending on the nanoprecipitation protocol, with high docetaxel (DTX) loading capacity. The blank and loaded nanoparticles have been fully characterized by dynamic light scattering (DLS), ζ-potential measurements and cryo-transmission electron microscopy (cryo-TEM). The data are compatible with the distribution of the drug between the nanoparticle core and the shell, where it is probably anchored by inclusion of the DTX aromatic moieties in βCD cavities.

Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling.

We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells.