Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform

Diversity-oriented synthesis of structurally complex and diverse small molecules can be used as the first step in a process to explore cellular and organismal pathways. The success of this process is likely going to be dependent on advances in the synthesis of small molecules having natural product-like structures in an efficient and stereoselective manner. The development, scope, and mechanism of the oxidation of organocuprates was investigated and exploited in the atropdiastereoselective synthesis of biaryl-containing medium rings (9-, 10-, and 11-membered rings). The methodology was performed on high-capacity, large polystyrene beads by metalating aryl bromides with i-PrBu(2)MgLi, followed by transmetalating with CuCN x 2LiBr and then oxidizing with 1,3-dinitrobenzene, and was used in a diversity-oriented synthesis of biaryl-containing medium rings (library total theoretical maximum 1412 members). The high capacity beads were arrayed into 384-well plates and, using a process optimized during the development of a one bead/one stock solution technology platform, converted into arrays of stock solutions, with each stock solution containing largely one compound. These stock solutions were used in numerous phenotypic and protein-binding assays. The process described outlines a pathway that we feel will contribute to a comprehensive and systematic chemical approach to exploring biology (chemical genetics).     

Globular Polymer Grafts Require a Critical Size for Efficient Molecular Sieving of Enzyme Substrates

A series of 2,2‐bis(hydroxymethyl)propionic acid dendrons of generation 2 through 8 having a strained cyclooctyne at the core and hydroxy groups at the periphery were prepared by a divergent method and used to functionalize azide‐decorated α‐chymotrypsin. The ability of the appended dendrons to selectively block enzyme activity (through a molecular sieving effect) was investigated using a small molecule substrate (benzoyl‐l ‐tyrosine p‐nitroanilide), as well as two proteins of different size (casein and bovine serum albumin). Additionally, the ability of dendrons to block complexation with a chymotrypsin antagonist, α‐antichymotrypsin, was investigated, and it was found that the dendron coating effectively prevented inhibition by this antagonist. We found that a critical generation is required to achieve efficient sieving with bis‐MPA dendrons, which illustrates the importance of macromolecular architecture and size in the shielding of proteins.     

Self-Assembly and Fluorescence of Tetracationic Liquid Crystalline Tetraphenylethene

A series of tetraguanidinium tetraphenylethene (TPE) arylsulfonates with different chain lengths was prepared via ionic self-assembly of tetraguanidinium TPE chloride and the respective methyl arylsulfonates. Liquid crystalline properties were studied by differential scanning calorimetry, polarizing optical microscopy and X-ray diffraction. Tetraguanidinium TPE arylsulfonates with chain lengths of C₈–C₁₂ displayed hexagonal columnar mesophases over a broad temperature range, while derivatives with longer chains showed oblique columnar phases. In solution all compounds displayed aggregation-induced emission behaviour. Temperature-dependent luminescence spectra of the bulk phase of the tetraguanidinium TPE arylsulfonate with C₁₄ side chains revealed a strong luminescence both in the solid state and the oblique columnar mesophase. The emission behaviour was rationalized by a unique combination of restriction of intramolecular rotation of the TPE core, Coulomb interaction between the guanidinium cations and π–π interactions of the anionic arylsulfonate moieties.     

Are J(Si-H) NMR coupling constants really a probe for the existence of nonclassical H-Si interactions?

A series of hydridosilyl complexes of tantalum, Cp(ArN)Ta(PMe3)(H)(SiClnR3-n) (n = 0-3), was prepared and studied by 29Si NMR, X-ray diffraction, and DFT calculations. An unprecedented increase of the J(Si-H) coupling constant between the hydride and silyl ligands from 14 Hz for n = 0 to 50 Hz n = 3 was observed, which however, according to DFT calculations, does not correspond to stronger bonding interaction between silicon and hydride ligands, with the strongest interaction being for n = 1.     

Energy transfer from a fluorescent hydrogel to a hosted fluorophore

The fluorescent properties of a new 1,3,5-cyclohexyltricarboxamide-based low-molecular-weight hydrogelator (1) derivatized with one hydrophobic fluorophore and two hydrophilic substituents have been investigated. Gels of 1 are composed of long, nonbranched fibers of uniform diameter, as shown by cryo-transmission electron microscopy (cryo-TEM). The aggregation of the naphthalene fluorophore moieties of the gelator molecules in the gel fibers favors the occurrence of a fast energy migration process that allows a very efficient sensitization of the fluorescence of a hosted fluorophore. Such processes have been investigated by the addition of propyldansylamide (PDNS), at two different concentrations, to gels of 1. Around 30% of the total PDNS added to the gels was found to be incorporated in the gel fibers, as confirmed by deconvolution of the fluorescence spectrum, excited-state lifetime measurements, and steady-state and time-resolved fluorescence anisotropy measurements. Moreover, anisotropy measurements show that the fluorophore that is incorporated within the gel fibers is almost completely immobilized, indicating that the interactions of PDNS with the gelator moieties are very strong. This particular configuration of donor (1) and acceptor (PDNS) molecules leads to a very efficient antenna effect, where 50% of the absorbed photons are funneled through to the dansyl derivative when one PDNS molecule is incorporated in the gel fibers for every 100 gelator molecules. A 5-fold higher concentration of PDNS increases the percentage of funneled photons to 75%.     

Surface forces,supramolecular polymers,and inversion symmetry

The effects of supramolecular equilibrium polymers on surface forces are studied by both a phenomenological Landau type analysis and a molecular model based on a Bethe-Guggenheim approximation. We point out that surface forces brought about by equilibrium polymers may be completely different from what can be found with "ordinary" polymers. The new feature is the role of inversion (a)symmetry or "directionality" of the associating unit molecules ("monomers"). Symmetric B-B monomers (where B denotes a self-complementary binding group) give rise to nondirectional chains and lead to attractive forces between similar surfaces. Asymmetric A-D monomers (where A and D denote complementary acceptor and donor groups, respectively) produce directional chains and can cause strong repulsion. The range of the attractive force has a maximum at intermediate concentration, while the range of the repulsive force increases over the whole concentration range.     

Stereochemically controlled synthesis of unsaturated acids via diphenylphosphinoyl (Ph2PO) -ketoacids

Acylation of phosphine oxide anions with derivatives of cyclic anhydrides or oxidative cleavage of cyclic allyl phosphine oxides gives Ph₂PO-ketoacids: reduction, separation of diastereoisomers, and completion of the Horner-Wittig reaction gives single isomers ($\text{E}$) or ($\text{Z}$) of unsaturated acids.     

Surface Functionalization Methods to Enhance Bioconjugation in Metal-Labeled Polystyrene Particles

Lanthanide-encoded polystyrene particles synthesized by dispersion polymerization are excellent candidates for mass cytometry based immunoassays, however they have previously lacked the ability to conjugate biomolecules to the particle surface. We present here three approaches to post-functionalize these particles, enabling the covalent attachment of proteins. Our first approach used partially hydrolyzed poly(N-vinylpyrrolidone) as a dispersion polymerization stabilizer to synthesize particles with high concentration of -COOH groups on the particle surface. In an alternative strategy to provide -COOH functionality to the lanthanide-encoded particles, we employed seeded emulsion polymerization to graft poly(methacrylic acid) (PMAA) chains onto the surface of these particles. However, these two approaches gave little to no improvement in the extent of bioconjugation. In our third approach, seeded emulsion polymerization was subsequently used as a method to grow a functional polymer shell (in this case, poly(glycidyl methacrylate) (PGMA)) onto the surface of these particles, which proved highly successful. The epoxide-rich PGMA shell permitted extensive surface bioconjugation of NeutrAvidin, as probed by an Lu-labeled biotin reporter (ca. 7 × 10(5) binding events per particle with a very low amount of non-specific binding) and analyzed by mass cytometry. It was shown that coupling agents such as EDC were not needed, such was the reactivity of the particle surface. These particles were stable and the addition of a polymeric shell was shown did not affect the narrow lanthanide ion distribution within the particle interior as analyzed by mass cytometry. These particles represent the most promising candidates for the development of a highly multiplexed bioassay based on lanthanide-labeled particles to date.     

Combinatorial Synthesis and Multidimensional NMR Spectroscopy: An Approach to Understanding Protein–Ligand Interactions

Combinatorial chemistry is a laboratory emulation of natural recombination and selection processes. Strategies in this developing discipline involve the generation of diverse, molecular libraries through combinatorial synthesis and the selection of compounds that possess a desired property. Such approaches can facilitate the identification of ligands that bind to biological receptors, promoting our chemical understanding of cellular processes. This article illustrates that the coupling of combinatorial synthesis, multidimensional NMR spectroscopy, and biochemical methods has enhanced our understanding of a protein receptor used commonly in signal transduction, the Src Homology 3 (SH3) domain. This novel approach to studying molecular recognition has revealed a set of rules that govern SH3–ligand interactions, allowing models of receptor–ligand complexes to be constructed with only a knowledge of the polypeptide sequences. Combining combinatorial synthesis with structural methods provides a powerful new approach to understanding how proteins bind their ligands in general.