Javier de Mendoza

Molecular recognition of oxoanions based on guanidinium receptors

Guanidinium is a versatile functional group with unique properties. In biological systems, hydrogen-bonding and electrostatic interactions involving the arginine side chains of proteins are critical to stabilise complexes between proteins and nucleic acids, carbohydrates or other proteins. Leading examples of artificial receptors for carboxylates, phosphates and other oxoanions, such as sulfate or nitrate are highlighted in this tutorial review, addressed to readers interested in biology, chemistry and supramolecular chemistry.

Autoencapsulation through intermolecular forces : a synthetic self-assembling spherical complex

The synthesis and characterization of a system for the study of molecular recognition phenomena are described. The system involves a tetraurea molecule that is capable of assembly into various associated states through hydrogen bonding. In organic solvents, the dynamic transition between a low-ordered (aggregate) state and a highly ordered dimeric assembly can be induced by the introduction of smaller molecules of appropriate size and shape. These smaller molecules, such as benzene, adamantanes, and ferrocenes, act as guests that occupy the pseudospherical capsule formed by the dimeric host. Among various guests, those that best fill the cavity and offer chemical complementarity to the host are preferentially encapsulated.

Tripodal exTTF-CTV Hosts for Fullerenes

A receptor for fullerenes featuring three exTTF units linked to a CTV scaffold is described. The exTTF-CTV host forms remarkably stable complexes with both C(60) (log K(a) = 5.3 +/- 0.2) and C(70) (log K(a) = 6.3 +/- 0.6). Light-induced ESR spectra demonstrate that intracomplex PET processes take place in solution.

Binding to protein surfaces by supramolecular multivalent scaffolds.

Multivalency plays a pivotal role in biological recognition, particularly at protein-protein and protein-carbohydrate interaction sites. Scaffolds of diverse structure, flexibility, and valency are gaining increasing biomedical importance in the development of artificial multivalent ligands for these interfaces. Relevant examples range from small C(4) symmetric calix[4]arenes and porphyrin ligands, which may achieve nanomolar affinity for protein surfaces of pharmaceutical interest, to large-sized dendrimers that provide promising adherence-inhibition for toxins and other relevant lectins. In addition, highly flexible supramolecular platforms like rotaxanes and polymers have been proposed as challenging alternatives to more rigid designs. Finally, nanoparticles are being exploited for this aim as they present important advantages from the biological and synthetic points of view.

Resorcinarenes with 2-benzimidazolone bridges: self-aggregation, self-assembled dimeric capsules, and guest encapsulation.

The synthesis and spectroscopic characterization of self-assembled dimeric resorcinarenes 1a–d containing four 2-benzimidazolone (cyclic urea) bridges are reported. The nanometer-size capsules are held together by a cyclic array of complementary hydrogen bonds. Unlike the related imide-bridged resorcinarenes reported by Rebek and coworkers [Heinz, T., Rudkevich, D. M. & Rebek, J., Jr. (1998) Nature (London) 394, 764–766], these strongly bound dimers aggregate in chloroform solutions yielding different self-organized structures, depending on the nature and length of the four carbon chains attached at the bottom of each resorcinarene platform, as revealed by transmission electron microscopy. Thus, phenethyl groups (dimer 1c⋅1c) produce long fibers, probably arising from tail to tail contacts and subsequent threading of the resulting linear self-assembled polymers, whereas long alkyl chains (dimers 1a⋅1a and 1b⋅1b) induce formation of large reverse vesicles of 0.8–2.2 μm diameter through side to side extensive stacking. Presumably, the rigidity of the dimer precludes folding of the aggregate into smaller vesicles. On the contrary, dimer 1d⋅1d, containing four nine-carbon chains and a cis-double bond, does not substantially aggregate and gives rise to reasonably resolved 1H NMR spectra. The compound was shown to be dimeric either by matrix-assisted laser desorption ionization–time-of-flight and vapor pressure osmometry. Encapsulation studies were followed by NMR. Propionic or pivalic acid was included in the capsules, probably as head to head hydrogen-bonded dimers in mesitylene-d12, a solvent too big to be a guest by its own. Longer dimeric carboxylic acids or larger substrates, like 2-adamantyl azide or cyclohexylcarbodiimide, do not encapsulate, but mixtures of a long and a short carboxylic acid (i.e., propionic-adamantyl or propionic-cyclohexyl) yield pairwise complexes.

Molecular recognition of organic acids and anions — Receptor models for carboxylates, amino acids, and nucleotides

The roots of synthetic molecular recognition and supramolecular chemistry itself lie in the investigation of organic ligands for metal cations, and the amount of research done in this field is overwhelming. For a long time, however, far less interest has been focussed on the complexation of anions even if the primal strategies were comparable, and only in recent years have the advances made been increasingly dynamic. In particular receptor molecules for biorelevant species such as amino acids and nucleotides are primary research targets, not least for their potential applications in medicine. In this article the developments which have been made here so far will be summarized and the attentive reader might notice that most of the primary literature cited is less than five years old. The emphasis has not been laid upon structural characteristics or synthetic strategies but rather on the effects the new host molecules give rise to and the functions they may have.

Self‐Assembling Cavities: Present and Future

The prohibitive difficulty of the covalent bond approach to the construction of artificial hosts for medium-size substrates can be circumvented by designing hosts that assemble by hydrogen bonding of smaller, simpler fragments. The calixarene dimer shown on the right is held together by interdigitating urea groups.

Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand

Protein p53 is a transcription factor crucial for cell cycle and genome integrity. It is able to induce both cell arrest when DNA is damaged and the expression of DNA repair machinery. When the damage is irreversible, it triggers apoptosis. Indeed, the protein, which is a homotetramer, is mutated in most human cancers. For instance, the inherited mutation p53-R337H results in destabilization of the tetramer and, consequently, leads to an organism prone to tumor setup. We describe herein a rational designed molecule capable of holding together the four monomers of the mutated p53-R337H protein, recovering the tetramer integrity as in the wild-type structure. Two ligand molecules, based on a conical calix[4]arene with four cationic guanidiniomethyl groups at the wider edge (upper rim) and hydrophobic loops at the narrower edge (lower rim), fit nicely and cooperatively into the hydrophobic clefts between two of the monomers at each side of the protein and keep the tetrameric structure, like molecular templates, by both ion-pair and hydrophobic interactions. We found a good agreement between the structure of the complex and the nature of the interactions involved by a combination of theory (molecular dynamics) and experiments (circular dichroism, differential scanning calorimetry and 1H saturation transfer difference NMR).

Selective complexation of adenosine monophosphate nucleotides by rigid bicyclic guanidinium abiotic receptors

Abstract Extraction of AMP nucleotides by receptors 2 and 3 from water to chloroform takes place selectively to a 0–50% extent. Receptor 5 binds AMP nucleotides by simultaneous ion-pairing, Hoogsteen H-bonding and aromatic π-π stacking.

A Synthetic Cation‐Transporting Calix[4]arene Derivative Active in Phospholipid Bilayers

One order of magnitude: The transport of Na+ and K+ ions through a phospholipid bilayer occurs with much higher conductance levels with 1 and 2 than with typical Na+ -transporting proteins or gramicidin. However, the cations do not appear to pass through the calix[4]arene ring, which has a rigid 1,3-alternate conformation. diazacrown=10-benyzl-1,10-diaza[18]crown-6 group.