Building Multivalent Iminosugar-Based Ligands on Calixarene Cores via Nitrone Cycloadditions

A novel and challenging approach for the construction of multivalent iminosugar architectures directly on calixarene scaffolds is presented, which exploits multiple cycloaddition reactions of a carbohydrate-derived nitrone on diversely functionalized calix[4]­arenes. Regardless of the 4-fold reiteration on a single calixarene, the reactions take place with high regio- and stereoselectivity, demonstrating this method as an appealing one for the synthesis of calixarene-based neoglycoconjugates

Ribonuclease Activity of an Artificial Catalyst That Combines a Ligated Cu^II Ion and a Guanidinium Group at the Upper Rim of a <i>cone</i>-Calix[4]arene Platform

A <i>cone</i>-calix­[4]­arene derivative, featuring a guanidinium group and a Cu^II ion ligated to a 1,4,7-triazacyclononane (TACN) ligand at the 1,3-distal positions of the upper rim, effectively catalyzes the cleavage of 2-hydroxypropyl <i>p</i>-nitrophenyl phosphate (HPNP) and a number of diribonucleoside 3′,5′-monophosphates (<i>N</i>p<i>N</i>′). Kinetic and potentiometric measurements support the operation of a general-base/general-acid mechanism and demonstrate that the hydroxo form of the ligated Cu^II ion is the sole catalytically active species. Rate enhancements relative to the background hydrolysis reaction at 1 mM catalyst concentration are 6 × 10⁵-fold for HPNP and cluster around 10⁷-fold with the most favorable catalyst–<i>N</i>p<i>N</i>′ combinations

Molecular Architecture and Symmetry Properties of 1,3-Alternate Calix[4]arenes with Orientable Groups at the Para Position of the Phenolic Rings

Two glycoclusters constituted by four fully acetylated β-acetylmannosamine residues linked through trimethylenethioureido spacers to a calix[4]­arene core and differing for the presence of methoxy or propoxy groups at the lower rim were synthesized. One of the two compounds is fixed in the 1,3-alternate geometry by the presence of the propoxy groups, while the other is potentially free to assume one of the different geometries allowed in calix[4]­arene. Their similar NMR spectra in chloroform clearly suggest the same 1,3-alternate geometry. Both compounds were submitted to a conformational investigation with the DFT approach at the standard B3LYP/6-31G­(d) level. The two glycocalixarenes showed a large conformational preference for the same geometry that put the mannosamine moiety of one substituent close to the thioureido group of the opposite substituent. This allows the formation of intramolecular hydrogen bonds and originates a series of through-space close contacts. A comparison with the NOESY maps evidence an excellent correspondence between experimental and theoretical data, thus giving an experimental validation of the highly symmetrical conformation that the two glycocalixarenes assume in apolar solvents

Phosphonated Calixarene as a “Molecular Glue” for Protein Crystallization

Protein crystallization remains a serious bottleneck to structure determination by X-ray diffraction methods. Compounds acting as “molecular glue” provide a promising strategy to overcome this bottleneck. Such molecules interact via noncovalent bonds with two or more protein surfaces to promote lattice formation. Here, we report a 1.5 Å resolution crystal structure of lysine-rich cytochrome <i>c</i> complexed with <i>p</i>-phosphonatomethyl-calix­[4]­arene (<b>pmclx</b>_<b>4</b>). Evidence for complex formation in solution was provided by NMR studies. Similar to <i>p</i>-sulfonato-calix­[4]­arene (<b>sclx</b>_<b>4</b>), the cavity of <b>pmclx</b>_<b>4</b> entrapped a single lysine side chain. Interesting features of protein recognition by the phosphonate substituents were identified in the crystal structure. A new calixarene binding site was identified at Lys54. The electron density at this site indicated two distinct calixarene conformers, suggesting a degree of ligand mobility. The role of <b>pmclx</b>_<b>4</b> in protein crystal packing (molecular glue and patchy particle model) as well as differences in protein-binding with respect to <b>sclx</b>_<b>4</b> are discussed

Lower Rim Guanidinocalix[4]arenes: Macrocyclic Nonviral Vectors for Cell Transfection

Guanidinium groups were introduced through a spacer at the lower rim of calix[4]­arenes in the cone conformation to give new potential nonviral vectors for gene delivery. Several structural modifications were explored, such as the presence or absence of a macrocyclic scaffold, lipophilicity of the backbone, length of the spacer, and nature of the charged groups, in order to better understand the factors which affect the DNA condensation ability and transfection efficiency of these derivatives. The most interesting compound was a calix[4]­arene unsubstituted at the upper rim and having four guanidinium groups linked at the lower rim through a three carbon atom spacer. This compound, when formulated with DOPE, showed low toxicity and transfection efficiency higher than the commercially available lipofectamine LTX in the treatment of human Rhabdomiosarcoma and Vero cells. Most of the investigated compounds showed a tendency to self-aggregate in pure water or in the presence of salts, as evidenced by NMR and AFM studies, and it was found that the ability to condense DNA plasmids in nanometric globules is a necessary but not sufficient condition for transfection. The superiority of macrocyclic vectors over linear Gemini-type analogues and of guanidinium compared to other ammonium head groups in determining the biological activity of the vectors was also ascertained

Actinide–lanthanide co-extraction by rigidified diglycolamides

<p>Within the actinide and lanthanide co-extraction strategy, three rigidified diglycolamides, namely 2,6-bis (<i>N</i>-dodecyl-carboxamide)-4-oxo-4<i>H</i>-pyran (<b>1</b>), 2,6-bis-[<i>N</i>-(4-<i>tert</i>-butylphenyl)carboxamide]-4-oxo-4<i>H</i>-pyran (<b>2</b>), 2,6-​bis[(<i>N</i>-docecyl-<i>N</i>-methyl)carboxamide]-​4-methoxy-​tetrahydro-pyran (<b>3</b>), were synthesized. Moreover, the effect of structural rigidification on Am(III) and Eu(III) extraction under different conditions was investigated. The carboxamide extractant <b>3</b> resembles the extracting behavior of <i>N,N,N</i>′,<i>N</i>′‐tetraoctyl diglycolamide (TODGA) in terms of efficiency and affinity within the lanthanide family, together with fast kinetics and satisfactory cation back-extraction. The presence of 1-octanol in the diluent mixture strongly affects the ligand stability. Moreover, despite the low extraction efficiency showed by <b>1</b> and <b>2</b>, all the three ligands exhibit a higher affinity for Am with respect to TODGA, resulting in a lower lanthanide/Americium separation factor, of around 4 for ligand <b>3</b> and close to 1 for ligands <b>1</b> and <b>2</b>.</p