A very large diversity space of synthetically accessible compounds for use with drug design programs

We have constructed a very large virtual diversity space containing more than 10¹³ chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.     

FLUORESCENCE LIFETIME STUDY OF THE DENATURATION OF RIBONUCLEASE-A

Abstract. Fluorescence quantum yield and lifetime measurements of the tyrosine residues in ribonuclease-A (RNase) were used to study the conformational changes involved in the denaturation of the enzyme. Measurements were done on RNase and on selectively acetylated RNase in the native, the partly denatured (reductive cleavage of S-S bridges or treatment with 8 M urea) and in the fully denatured state. The data were interpreted to mean that the opening of the S-S bridges causes large parts of the enzyme chain to unfold while leaving a hydrophobic region; including one of the tyrosine residues, intact. The biological activity of RNase is destroyed by this unfolding. Urea apparently does penetrate the protein coil but does not greatly affect the RNase structure since some of its biological activity is still retained. The opening of the S-S bridges in the presence of urea destroys the native conformation (and biological activity) completely leaving the protein in the form of an uncoiled polypeptide chain. It is suggested which parts of the protein structure might be affected by partial denaturation.     

Self-assembly of electron donor-acceptor dyads into ordered architectures in two and three dimensions: surface patterning and columnar "double cables"

We report the synthesis and characterization of covalent dyads and multiads of electron acceptors (A) and donors (D), with the purpose of exploiting their nanophase separation behavior toward (a) two-dimensional (2D) surface patterning with well-defined integrated arrays of dissimilar molecular electronic features and (b) bulk self-assembly to noncovalent columnar versions of the so-called "double cable" systems, the likes of which could eventually provide side-by-side percolation pathways for electrons and holes in solar cells. Soluble, alkylated hexa-peri-hexabenzocoronenes (HBCs) bearing tethered anthraquinones (AQs) are shown by scanning tunneling microscopy (STM) to self-assemble at the solution-graphite interface into either defect-rich polycrystalline monolayers or extended 2D crystalline domains, depending on the number of tethered AQs. In the bulk, the thermal stability of the room-temperature HBC columnar phase is increased, which is attributed to the desired nanotriphase separation of HBC columns, insulating alkyl sheaths, and AQ units. Homeotropic alignment (columns normal to surfaces), predicted to be ideal for potential exploitation of such "double cables" in photovoltaic devices, is demonstrated.     

Measurement of rheological properties of corn stover suspensions

Corn stover is currently being evaluated as a feedstock for ethanol production. The corn stover suspensions fed to reactors typically range between 10 and 40% solids. To simulate and design bioreactors for processing highly loaded corn stover suspensions, the rheologic properties of the suspension must be measured. In systems with suspended solids, rheologic measurements are difficult to perform owing to settling in the measurement devices. In this study, viscosities of corn stover suspensions were measured using a helical ribbon impeller viscometer. A calibration procedure is required for the impeller method in order to obtain the shear rate constant, k, which is dependent on the geometry of the measurement system. The corn stover suspensions are described using a power law flow model.     

The Structure of New Host Molecules that form Channel Inclusion Compounds

1,3-Benzenediamine,N,N′-bis(4,6-dichloro-1,3,5-triazine-2-yl) and 1,3,5-Triazine,2,2′-[2-methyl-1,3-phenylenebis(oxy)] bis(4,6-dichloro) were synthesized as host molecules. The inclusion compound of 1,3-Benzenediamine,N,N′-bis(4,6-dichloro-1,3,5-triazine-2-yl) crystallizes in the monoclinic crystal system in space group C2/c. The host molecule occupies the space group 2-fold special position and packed in the crystal lattice in such a manner as to leave channels running along the c axis of a rectangular cross-section. It crystallizes with two molecules of acetone that are hydrogen bonded to the amino nitrogen atoms. Molecules of 1,3,5-Triazine,2,2′-[2-methyl-1,3-phenylene bis(oxy)]bis(4,6-dichloro) are packed in the crystal in such a manner as to leave channels of a trapezoid cross-section that are running along the a axis. Guest molecules such as metanol, ethanol, and ethyl acetate can be used to fill the channels. The crystal structures of two inclusion compounds are described.     

Iron(III) dihydrogenphosphate(I)

The structure of rhombohedral (R) iron(III) tris­[di­hydrogen­phosphate(I)] or iron(III) hypophosphite, Fe(H₂PO₂)₃, has been determined by single‐crystal X‐ray diffraction. The structure consists of [001] chains of Fe³⁺ cations in octa­hedral sites with symmetry bridged by bidentate hypophosphite anions.     

Thermochemistry of C60 and C70 fullerene solvates

In an effort to improve understanding of dissolution behaviour of fullerenes and their simple chemical derivatives the binary systems of C₆₀, C₇₀ and the piperazine monoadduct of [60] fullerene C₆₀ N₂C₄H₈ with a series of aromatic solvents have been studied by means of DSC. In certain systems solid solvates have been found to be the thermodynamically stable phases relative to saturated solution at room temperature. Identified solid solvates were characterized by their compositions, temperatures and enthalpies of incongruent melting transitions. The regularities in thermodynamic stability of the solvated crystals have been discussed along with dissolution properties of fullerenes and the derivative. Certain correlations have been observed.     

A one-step route to azomethine ylides via chloroiminium salts

A new, one-step procedure for the generation of azomethine ylides, 4 and 20, via chloroiminium salts, 3 and 19, is reported. The generation of the azomethine ylides was confirmed by their trapping with dimethyl acetylenedicarboxylate (DMAD) which, upon spontaneous 1,4-dehydrochlorination, gave the corresponding pyrroles 17 and 21.     

Neighbouring-group Influence on the Ring Opening of Some 2-Alkyl-1,1,2-tribromocyclopropanes under Phase-transfer Conditions

Several 2-alkyl-1,1,2-tribromocyclopropanes were treated with sodium hydroxide and ethanol under phase-transfer conditions. Ring opening gave mixtures of the corresponding acetylenic diethyl ketals and acetals. When the steric bulk of the alkyl substituent was increased acetal formation dominated, and in the case of 1,1,2-tribromo-2-(tert-butyl)cyclopropane, the acetal was formed as the only product.     

The Effect of Solute Concentration on Equilibrium Partitioning in Polymeric Gels

The effect of solute concentration on the equilibrium partitioning of sphere-like, colloidal solutes in stiff polymer hydrogels is examined theoretically and experimentally. The theoretical development is a statistical mechanics approach, and allows quantitative calculations to be performed to determine the concentration-dependent partition coefficient correct to first order in solute concentration at specific surface charge densities. The theory predicts that repulsive steric and/or electrostatic solute-fiber interactions exclude solute from the gel phase, but that repulsive solute-solute interactions cause partitioning into the gel to increase with increasing solute concentration. These trends are enhanced for larger solutes, increased fiber volume fractions, or stronger electrostatic repulsion. Partition coefficients have also been measured for two proteins, bovine serum albumin (BSA) and alpha-lactalbumin (ALA), in a system consisting of a salt solution and cubes of agarose hydrogel. To investigate the effect of electrostatic interactions, the experiments were performed at 0.15 M KCl and 0.01 M KCl. The theory underpredicts the strong electrostatic repulsion between BSA macromolecules at the lower ionic strength. The experimental results for ALA show the influence of an attractive interaction between the protein macromolecules, in addition to hard-sphere repulsive and electrostatic interactions. Copyright 2001 Academic Press.