Richard J. Hooley

Chemistry and Catalysis in Functional Cavitands

Biological macromolecules use binding forces to access unfavorable chemical equilibria and stabilize reactive intermediates by temporarily isolating them from the surrounding medium. Certain synthetic receptors, functional cavitands, share these abilities and allow for the direct observation of labile intermediates by conventional spectroscopy. The cavitands feature inwardly directed functional groups that form reversible, covalent bonds with small molecules held inside. Tetrahedral intermediates of carbonyl addition reactions--hemiaminals, hemiacetals, and hemiketals--show amplified concentrations and lifetimes of minutes under ambient conditions. Labile intermediates in addition reactions of carboxylic acids to isonitriles are also stabilized by isolation in the space of the cavitands. The restricted environments channel the reactions of intermediates in cavitands along a specific path and strengthen the parallels between functional synthetic cavitands and enzymes.

Steric effects control self-sorting in self-assembled clusters.

Endohedrally functionalized bis(pyridine) ligands show the ability to self-discriminate when treated with coordinating metals to form self-assembled clusters. Self-sorting between components is controlled by substitution on the interior of the complex. Tuning the size of the internal substituent allows selective heterocluster formation, determined by noncovalent and space-filling interactions. This novel method of self-sorting allows discrimination between ligands of identical geometry and donor type.

Protein and small molecule recognition properties of deep cavitands in a supported lipid membrane determined by calcination-enhanced SPR spectroscopy.

This paper details the incorporation of a water-soluble deep cavitand into a membrane bilayer assembled onto a nanoglassified surface for study of molecular recognition in a membrane-mimicking setting. The cavitand retains its host properties, and real-time analysis of the host:guest properties of the membrane:cavitand complex via surface plasmon resonance and fluorescence microscopy is described. The host shows selectivity for choline-derived substrates, and no competitive incorporation of substrate is observed in the membrane bilayer. A variety of trimethylammonium-derived substrates are suitable guests, displaying varied binding affinities in a millimolar range. The membrane:cavitand:guest complexes can be subsequently used to capture NeutrAvidin protein at the membrane surface if a biotin-derived guest molecule is used. The surface coverage of NeutrAvidin is affected by the spacer used to derivatize the biotin. Increased distance from the bilayer allows a higher concentration of protein to be immobilized, suggesting a diminishing detrimental steric effect when the binding event is shifted away from the surface.

Selective cavitand-mediated endocytosis of targeted imaging agents into live cells.

A water-soluble synthetic receptor molecule is capable of selective, controlled endocytosis of a specifically tagged target molecule in different types of living human cells. The presence of suitable choline-derived binding handles is essential for the molecular recognition and transport process, allowing selective guest transport and imaging of cancer cells.

Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis

Significance The exocyst complex is a conserved protein complex that tethers the secretory vesicles to the site of membrane fusion during exocytosis, an essential cellular process that transports molecules, such as protein, to the cell surface or extracellular space. We identified a small molecule that targets the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex to inhibit exocytosis. This compound made it possible to control the dynamics of the exocytosis process in a dosage-dependent manner in different organisms and overcame the mutant lethality and genetic redundancy issues in studying mechanisms of exocyst complex regulation. Further design of molecules with higher affinity and more potent activity may make it possible to use drugs to control human diseases related to exocytosis, such as cancer and diabetes. The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.

Synthesis and Properties of Metal–Ligand Complexes with Endohedral Amine Functionality

A series of tetracationic M(2)L(4) palladium-pyridyl complexes with endohedral amine functionality have been synthesized. The complexes were analyzed by NMR techniques (including Diffusion NMR and 2D NOESY), electrospray ionization (ESI) mass spectrometry, and X-ray crystallography. The solid state analysis shows a large change in crystal morphology upon introduction of the endohedral amine groups, caused by deleterious interactions between the amines and the triflate counterions from the coordination process. Combination of different ligands allows analysis of ligand exchange rates via NMR analysis, with half-lives on the order of 3 h, independent of the donor properties of the ligand. Self-sorting behavior is observed, with more electron-rich ligands being favored. The amine-containing and extended complexes are strongly fluorescent, giving quantum yields of up to 83%.

A Supramolecular Sorting Hat: Stereocontrol in Metal–Ligand Self-Assembly by Complementary Hydrogen Bonding†

A combination of self-complementary hydrogen bonding and metal-ligand interactions allows stereocontrol in the self-assembly of prochiral ligand scaffolds. A unique, non-tetrahedral M4L6 structure is observed upon multicomponent self-assembly of 2,7-diaminofluorenol with 2-formylpyridine and Fe(ClO4)2. The stereochemical outcome of the assembly is controlled by self-complementary hydrogen bonding between both individual ligands and a suitably sized counterion as template. This hydrogen-bonding-mediated stereoselective metal-ligand assembly allows the controlled formation of nonsymmetric discrete cage structures from previously unexploited ligand scaffolds.

Narcissistic Self‐Sorting in Self‐Assembled Cages of Rare Earth Metals and Rigid Ligands

Highly selective, narcissistic self-sorting can be achieved in the formation of self-assembled cages of rare earth metals with multianionic salicylhydrazone ligands. The assembly process is highly sensitive to the length of the ligand and the coordination geometry. Most surprisingly, high-fidelity sorting is possible between ligands of identical coordination angle and geometry, differing only in a single functional group on the ligand core, which is not involved in the coordination. Supramolecular effects allow discrimination between pendant functions as similar as carbonyl or methylene groups in a complex assembly process.

Self-Aggregating Deep Cavitand Acts as a Fluorescence Displacement Sensor for Lysine Methylation

A dual-mode aggregative host:guest indicator displacement sensing system has been created for the detection of trimethylated peptides and determination of histone demethylase activity. The combination of selective recognition of suitably sized trimethylammonium salts and reversible lipophilic aggregation of the host:guest complex provides a unique quenching mechanism that is not only dependent on affinity for sensitivity but the lipophilicity of the indicator. In addition, aggregation can be controlled by the application of chaotropic anions in the mixture, allowing a second level of discrimination between hard lysine groups and softer trimethyllysines.

Cooperative thermodynamic control of selectivity in the self-assembly of rare earth metal-ligand helices.

Metal-selective self-assembly with rare-earth cations is possible with suitable rigid, symmetrical bis-tridentate ligands. Kinetically controlled formation is initially observed, with smaller cations preferentially incorporated. Over time, the more thermodynamically favorable complexes with larger metals are formed. This thermodynamic control is a cooperative supramolecular phenomenon and only occurs upon multiple-metal-based self-assembly: single-metal ML3 analogues do not show reversible selectivity. The selectivity is dependent on small variations in lanthanide ionic radius and occurs despite identical coordination-ligand coordination geometries and minor size differences in the rare-earth metals.