The self-assembly of metallacarboranes, a peculiar family of compounds exhibiting surface activity and resembling molecular-scale Pickering stabilizers, has been investigated by comparison to the micellization of sodium dodecylsulfate (SDS). These studies have shown that molecules without classical amphiphilic topology but with an inherent amphiphilic nature can behave similarly to classical surfactants. As shown by NMR techniques, the self-assembly of both metallacarboranes and SDS obey a closed association model. However, the aggregation of metallacarboranes is found to be enthalpy-driven, which is very unusual for classical surfactants. Possible explanations of this fact are outlined.

In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes.

Polyhedral metallacarboranes are used mainly as ion-pairing agents and recently have been recognized as potent inhibitors of HIV protease. They are characterized by exceptional hydrophobicity, rigid geometry, delocalized negative charge, ion-pairing behavior, and strong acidity of their conjugated acids. The completely novel phenomenon, association of these promising pharmaceutical tectons in aqueous solutions, is described here. The behavior of two structural types of metallacarboranes, [bis(1,2-dicarbollide)cobaltate(1-)] and bis[(3)-1,2-dicarbollylcobalt]-(3,6)-1,2-dicarbacanastide(2-)], in aqueous solution was studied by a combination of static and dynamic light scattering and microscopy methods. Spherical aggregates with radii of ca. 100 nm and fairly monodisperse nanostructures were found in aqueous solutions. The behavior of nanoaggregates is fairly complex and depends on the concentration and aging of the solutions. The particles are stabilized in the solution by counterions. The formation of larger clusters upon dilution of bis(1,2-dicarbollide)cobaltate(1-) solutions was observed. The secondary aggregation can be suppressed by addition of NaCl. Gel permeation chromatography measurements of sodium bis(1,2-dicarbollide)cobaltate(1-) show that the majority of matallacarborane molecules form nanoaggregates and only a small amount of the metallacarborane remains molecularly soluble or forms small oligomers.

We prepared two fluorescein-[3-cobalt(III) bis(1,2-dicarbollide)](-) conjugates. They are sparingly soluble in water and form large aggregates in aqueous solutions. An extensive study on their spectral and aggregation behavior was carried out. To prepare their well-defined dispersion in aqueous systems, we studied the interaction of both probes with two biocompatible amphiphilic systems, cyclodextrins, which are frequently used in drug-delivery systems, and phospholipid membranes, which are the major constituents of cell barriers in living organisms. The presence of fluorescein in both conjugates allows us to study their behavior in detail by steady-state and time-resolved fluorometry, fluorescence correlation spectroscopy, and fluorescence lifetime imaging. The self-assembly of these metallacarboranes in aqueous solutions was studied by dynamic light scattering. The study shows that the compounds interact with cyclodextrins that increases their solubility in water, and they solubilize easily in phospholipid bilayers.