Biomedical subjects
Publications and source records attributed to J Rebek.
[formula: see text] A synthetic scheme for the selective functionalization of all-cis (rccc) resorcinarene platform at the "lower rim" was developed. Self-folding and self-complementary cavitands were prepared for molecular recognition and self-assembly, bearing functionality at remote sites. These molecules promise applications on solid support and as polymeric capsules.
Encapsulation complexes are reversibly formed assemblies in which small molecule guests are completely surrounded by large molecule hosts. The assemblies are held together by weak intermolecular forces and are dynamic: they form and dissipate on time scales ranging from milliseconds to days-long enough for many interactions, even reactions, to take place within them. Little information is available on the exchange process, how guests get in and out of these complexes. Here we report that these events can be slow enough for conventional kinetic studies, and reactive intermediates can be detected. Guest exchange has much in common with familiar chemical substitution reactions, but differs in some respects: no covalent bonds are made or broken, the substrate is an assembly rather than a single molecule, and at least four molecules are involved in multiple rate-determining steps.
Multiple copies of a molecule, held together in finite aggregates, give rise to properties and functions that are unique to their assembled states. Because these aggregates are held together by weak forces operating over short distances, a premium is placed on complementarity: The molecular surfaces must facilitate specific interactions that direct the assembly to one aggregate rather than another. Hydrogen-bonding preferences can be combined with molecular curvature to favor the assembly of four self-complementary subunits into a pseudo-spherical capsule. Filling the capsule with smaller, complementary molecules provides the final instruction for the assembly process.
Molecules with self-complementary surfaces interact through weak intermolecular forces to form assemblies, and the assembled states frequently exhibit distinctive properties. Described here are systems in which symmetrical molecules assemble through hydrogen bonding to produce capsules with dissymmetric cavities. The capsules form and dissipate on a time scale that permits their direct observation by nuclear magnetic resonance measurements, and they act as hosts for smaller molecular guests. Molecular recognition of chiral guests, such as naturally occurring terpenes, determines which dissymmetric cavities are preferentially formed in the assembly process.
The relatively new field of combinatorial chemistry has enabled researchers to create large mixtures of compounds that can be screened for leads in developing potential drug candidates. The new synthetic method has also created a need for better procedures to analyze the complex mixtures that are generated. The immediate goal in most cases is to verify the synthetic procedure and to determine the purity and completeness of the library sample before binding studies are initiated. We report here a method to rapidly characterize small-molecule combinatorial libraries in solution. All combinatorial library samples were synthesized by combining a core molecule bearing two acid chloride functionalities with various amino acids to generate libraries of 36, 78 and 120 components. Using electrospray ionization fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) we were able to identify 70-80% of the library components. All samples were analyzed as mixtures by direct infusion without chromatographic separation. Furthermore, nominally isobaric components could be resolved and identified through exact mass assignments without tandem mass spectrometery. ESI-FTICR-MS is a rapid and convenient tool for the characterization of small-molecule libraries. The method is especially useful for the analysis of larger libraries that contain many nominally isobaric components and impurities.
Five synthetic combinatorial libraries of 2,080 components each were screened as mixtures for inhibition of DNA binding to two transcription factors. Rapid, solution-phase synthesis coupled to a gel-shift assay led to the identification of two compounds active at a 5- to 10-microM concentration level. The likely mode of inhibition is intercalation between DNA base pairs. The efficient deconvolution through sublibrary synthesis augurs well for the use of large mixtures of small, nonpeptide molecules in biological screens.
Described are assemblies consisting of polymeric capsules, "polycaps," formed from two calix[4]arene tetraureas covalently connected at their lower rims. In these structures self-assembly leads to reversibly formed capsule sites along a chain, reminiscent of beads on a string. Their dynamic behavior is characterized by 1H NMR spectroscopy through encapsulation of guest species, reversible polymerization, and the formation of sharply defined hybrid capsules.
The interior of cage-like molecules can be considered to provide a new phase of matter, in which it becomes possible to stabilize reactive intermediates and to observe new forms of stereoisomerism. Cage-like molecular complexes that self-assemble through weak intermolecular forces are dynamic species, encapsulating guest molecules reversibly. They can persist over timescales ranging from microseconds to hours, long enough for chemical processes to take place within them. Here we report the acceleration of a Diels-Alder reaction by encapsulation of the reactants in a self-assembling molecular capsule. Although product inhibition (lack of dissociation) prevents the system from showing true catalytic behaviour, there is clear evidence for a rate increase of over two orders of magnitude owing to the effective enhancement of concentration inside the capsule.
The encapsulation of molecules within larger molecular or supramolecular cages (see ref. 1 for examples) brings about many interesting phenomena, among them the stabilization of reactive intermediates, new forms of stereoisomerism, and templating of the cage itself. Here we describe a self-assembling hydrogen-bonded molecular capsule that encapsulates guest molecules in a reversible, apparently entropy-driven process, giving rise to unusual temperature dependence of the formation process. The positive entropy of formation--at first sight unexpected--seems to be the result of the fact that more than one solvent molecule is included in the 'bare' cage, making their replacement by a single large molecule (here adamantane or ferrocene) entropically favourable.
By means of capillary electrophoresis coupled online to electrospray ionization MS, a library of theoretically 171 disubstituted xanthene derivatives was analyzed. The method allowed the purity and makeup of the library to be determined: 160 of the expected compounds were found to be present, and 12 side-products were also detected in the mixture. Due to the ability of capillary electrophoresis to separate analytes on the basis of charge, most of the xanthene derivatives could be resolved by simple capillary electrophoresis-MS procedures even though 124 of the 171 theoretical compounds were isobaric with at least one other molecule in the mixture. Any remaining unresolved peaks were resolved by MS/MS experiments. The method shows promise for the analysis of small combinatorial libraries with fewer than 1000 components.
A rigid dinitrile ligand was synthesized from two xanthene units condensed to a naphthalene-1,4,5,8-diimide spacer. The rigidity and C shape of the ligand gave exclusively trans complexes with Pd(II), Ag(I), and Au(I). Evidence for complexation, coordination geometry, and stoichiometry was provided by a combination of 1H NMR, 19F NMR, and IR spectroscopy. The AuBF4 and PdCl2 complexes were shown to have a 1:1 (metal-to-ligand) stoichiometry and the AgBF4 complex was shown to have a 1:2 stoichiometry in solution. The preorganization of the dinitrile ligand resulted in complexes much more stable than their monodentate counterparts.
Here, the synthesis of a bowl-shaped molecule is described and evidence of its reversible dimerization by means of hydrogen bonds is presented. The dimer features a flattened spherical cavity of peculiar symmetry and acts as a host for the encapsulation of guest molecules of complementary shape. Encapsulation of aromatic guests in chloroform solution and of cyclohexane in p-xylene solution was demonstrated by nuclear magnetic resonance experiments. The passage of guests into and out of the cavity is slow and occurs on a time scale of hours. The system was used to explore the effects of size, shape, and solvation on molecular recognition coupled with assembly.
Libraries of tetraureas tethered to a rigid core have been assembled. This simple, solution-phase methodology generates a defined, anticipated distribution of compounds. These conclusions are supported by synthesizing pure (homo) tetraurea xanthenes and by HPLC analysis of small 'microlibraries'.
The synthesis and characterization of a series of self-assembling capsules is described. Assembly takes place as a result of the self-complementary hydrogen bonding patterns on the subunit pieces and dimerization occurs in such a manner that the concave surfaces of the two subunits are directed at one another. This feature gives rise to close-shelled capsules which are shown to encapsulate smaller guest species. Selectivity is shown for guests ranging in size from methane to adamantane derivatives. Shape selectivity is shown in special capsules capable of recognizing disc-like molecules such as benzene and cyclohexane. Disproportionation reactions are shown to exist between capsules of slightly different sizes, and these are shown to be controlled by the nature of the guest species. The use of these capsules as reaction chambers is proposed.
Several di- and tripeptides containing protected purine (adenine) and pyrimidine (thymine) residues on their side chains were synthesized. The parent amino acids alpha, alpha-dialkylated in a symmetrical manner. An effective coupling procedure was developed for these sterically hindered amino acids: the fluoren-9-ylmethyloxycarbonyl-protected amino acid was dehydrated to its oxazolinone form, which was coupled in good yields with amino esters in hot tetrachloroethane.
A calix[4]arene was designed to reversibly dimerize and form an egg-shaped enclosure. Adhesive interactions in the assembly were provided by four self-associating ureas, which form a cyclic array containing 16 hydrogen bonds. The synthesis was completed in four steps from the previously described O,O',O",O"'-tetrabenzylcalix[4]arene. Evidence for dimerization of the calixarene tetraurea was provided by H NMR, mass spectrometry, and the observation of encapsulated molecules. The resulting cavity was of sufficient size to capture guests such as ethyl benzene and p-xylene.
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.