Receptor-bound conformation of an alpha(5)beta(1) integrin antagonist by (15)N-edited 2D transferred nuclear overhauser effects

We report the results of (15)N-edited 2D transferred NOE experiments of the partially (15)N-labeled alpha(5)beta(1) antagonist c[Mpa(15)N-Arg-(15)N-Gly-(15)N-Asp-(15)N-Asp-(15)N-Val-Cys]-NH(2) (Mpa denotes mercaptopropionic acid) in the presence of the native alpha(5)beta(1) receptor. The alpha(5)beta(1) integrin receptor is believed to be involved in tumor metastasis and the rational design of alpha(5)beta(1) integrin antagonist is therefore of considerable interest. Our experiments provide insight into the alpha(5)beta(1) receptor-bound conformation of the antagonist c[MpaRGDDVC]-NH2 and will be important for the design of novel antagonists.     

Versatile solid-phase synthesis of secondary amines from alcohols. Development of an N-Boc-(o-nitrobenzene)sulfonamide linker

The development of a versatile amine releasing linker based on the modified o-nitrobenzene sulfonamide protective group is described. This new N-Boc-o-nitrobenzenesulfonamide (Boc-ONBS) linker enables the elaboration on resin of primary and secondary amines by sequential substitution of the sulfonamide moiety using the Mitsunobu reaction. A 16-member array of secondary and Boc protected primary amines was then prepared using this linker.     

Proton spin-lattice relaxation studies. N-aryl-1-isoindolinones

Proton spin-lattice relaxation rates (R₁ values) have been measured, at 270 MHz, for a series of N-aryl isoindolinones. A normalization procedure has been used to enable comparison of R₁ values in different compounds by minimizing the effects on relaxation rates of changes in motional correlation times accompanying changes in substitution patterns. A substantial (4.3-fold) dynamic range of R₁ values has been observed, and individual values have been correlated with the molecular environments of the nuclei. There is evidence for an interring relaxation process.     

X-ray photoelectron spectroscopy and magnetic studies on the effect of pore size, wall thickness, and wall composition on superparamagnetic cobaltocene mesoporous Nb, Ta, and Ti composites

Recent results in our group demonstrated that mixed oxidation state mesoporous niobium oxide cobaltocene composites display superparamagnetism at certain composition ratios. This was the first report of superparamagnetism in nanoscale molecular ensembles. A series of mesoporous niobium oxide materials were synthesized in order to understand the role of pore size and thickness of the walls in the mesostructure on the magnetic properties. Mesoporous Ti oxide and Ta oxide composites were also synthesized in order to investigate the effect of changing the wall composition on the magnetic properties of this new series of materials. All samples were characterized by X-ray diffraction, nitrogen adsorption, ultraviolet spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and superconducting quantum interference device magnetometry. The results of this study showed that variation of wall thickness or pore size in the Nb system had little effect on the properties and that superparamagnetism most likely arises from mixed oxidation state cobaltocene grains residing in the individual pores and not from the free electrons in the mesostructure or much larger domains. The Langevin function was applied to the isothermal magnetic data from the Nb composites and gave mean superparamagnetic particle sizes of ca. 14 nm in each system. The Co(II) to Co(III) ratios in these materials were approximately 1:1. The Ti and Ta materials showed no sign of superparamagnetism and only very low levels of neutral cobaltocene in the pores. This suggests that a critical amount of cobaltocene is required to bring about superparamagnetic behavior.     

Some diels—alder reactions of η1-bonded cyclopentadienylmetal compounds

Bis(cyclopentadienyl)mercury readily undergoes Diels—Alder reactions with RCCR (R = CO₂Me or CF₃), CF₃CFCFCF₃, CF₃CFCF₂, (CF₃)₂CC(CN)₂, C₂(CN)₄ and Ph$\text{NCONNC}$O to give stable adducts characterised by¹H, ¹⁹F and ¹³C NMR, spectroscopy. Similar reactions of CF₃CCCF₃ and CF₃CFCFCF₃ with the cyclopentadiene derivatives Me₃MC₅H₅ and (Me₃M)₂C₅H₄ (M = Si, Sn) are also described.     

Computational strategies for evaluating barrier heights for gas-phase reactions of lithium enolates

Gas-phase activation energies were calculated for three lithium enolate reactions by using several different ab initio and density functional theory (DFT) methods to determine which levels of theory generate acceptable results. The reactions included an aldol-type addition of an enolate to an aldehyde, a proton transfer from an alcohol to a lithium enolate, and an S(N)2 reaction of an enolate with chloromethane. For each reaction, the calculations were performed for both the monomeric and dimeric forms of the lithium enolate. It was found that transition state geometry optimization with B3LYP followed by single point MP2 calculations generally provided acceptable results compared to higher level ab initio methods.     

Synthesis of cationic dialkylgold(III) complexes: nature of the facile reductive elimination of alkane

A series of gold(III) cations of the type cis-[CH₃)₂AuL₂]⁺ X^? where L  Ph₃, PMePh₂, PMe₂Ph, PMe₃, AsPh₃, AsPh₃, SbPh₃, $\text{1}\text{2}$H₂NCH₂CH₂NH₂, $\text{1}\text{2}$ Ph₂PCH₂CH₂-PPh₂, $\text{1}\text{2}$ Ph₂AsCH₂CH₂AsPh₂, and $\text{1}\text{2}$o-C₆H₄(AsMe₂)₂ and X  BF₄^?, PF₆^?, ClO₄^?, and F₃CSO₃^? has been prepared. In addition, the cis complexes [(CH₃)(CD₃)-Au(PPh₃)₂]F₃CSO₃, [(C₂H₅)₂Au(PPh₃)₂]F₃CSO and [(n-C₄H₉)₂Au(PPh₃)₂]F₃-CSO₃ have been synthesized. All have been characterized by PMR, Raman and infrared spectroscopy. These [R₂AuL₂]X compounds yield only ethane, butane, or octane via reductive elimination, and no disproportionation is observed. The alkane eliminations have been studied in CHCl₃, CH₃Cl₂, and CH₃COCH₃ solution as a function of temperature, concentration of the complex, and concentration of added ligand L. Elimination is fastest when L is bulky (PPh₃ > PMePh₂ > PMe₂Ph > PMe₃), decreases in the sequence SbPh₃ > AsPh₃ > PPh₃, is slow with chelating ligands, is inhibited by excess ligand, and there is small anion effect as X is varied. As R is varied, the rate of elimination decreases Bu ? Et > Me. An intramolecular dissociative mechanism is proposed which involves rapid elimination of alkane from an electron deficient dialkylgold(III) complex with nonequivalent gold—carbon bonds and produces the corresponding [AuL₂]X complex.     

ESR STUDY OF ORIENTED TRIPLET MOLECULES GENERATED BY EXCITATION WITH POLARIZED LIGHT

Abstract— The lowest-lying triplet states of a variety of aromatic molecules and complexes have been generated by the irradiation of these compounds in solvent glasses with plane-polarized light. Measurements of the allowed (Δ M=± 1) ESR transitions clearly demonstrate that the triplets so formed are oriented with respect to the external magnetic field. By this method the triplet zero-field splitting parameters, D and E , can be evaluated simply and reliably. Intramolecular energy transfer is postulated to explain the triplet spectra of Zn( o -phen)₂(NO₃)₂ and Zn( o -phen)₃(NO₃)₂. It was observed that in triplet-triplet energy transfer from benzophenone to naphthalene there is no apparent orientation requirement between the donor and acceptor molecules. Further areas of significance and application of this technique are suggested.     

New approach to molecular docking and its application to virtual screening of chemical databases

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.     

Ion atmosphere relaxation and percolative electron transfer in Co bipyridine DNA molten salts

Polypyridyl complexes of Co decorated with 350-Da polyether chains (Co(350)(2+)) form molten phases of nucleic acids when paired with DNA counterions (Co(350)DNA) or 25-mer oligonucleotides. Analysis of voltammetry and chronoamperometry of mixtures of these phases with complexes having ClO(4)(-) counterions (Co(350)(ClO(4))(2)) and no other diluent provides charge transport rates from the oxidation and reduction currents for the complexes. As the mole fraction of the Co(350)(ClO(4))(2) complex in the mixture is varied from ca. 0.25 to 1, the physical diffusion constants derived from the Co(III/II) wave increase from 1 x 10(-11) cm(2)/s to 5 x 10(-10) cm(2)/s, and apparent diffusion constants dominated by the Co(II/I) electron self-exchange increase from 1 x 10(-10) cm(2)/s to 2 x 10(-8) cm(2)/s. Pure Co(350)DNA melts, containing no Co(350)(ClO(4))(2) complex, do not exhibit recognizable voltammetric waves; DNA suppresses the Co(II/I) electron transfer reactions of Co complexes for which it is the counterion. There are therefore two microscopically distinct kinds of Co(350) complexes, those with DNA and those with ClO(4)(-) counterions, with respect to their Co(II/I) electron-transfer dynamics, leading to percolative behavior in their mixtures. The electron-transfer rates of the Co(II/I) couple are controlled by the diffusive relaxation of the ionic atmosphere around the reaction pair, and the inactivity of the bound Co complexes can be attributed to the very low mobility of the anionic phosphate groups in the DNA counterion. Substitution of sulfonated polystyrene for DNA produced similar results, suggesting that this phenomenon is general to other polymer counterions of low mobility. We conclude that the measured Co(II/I) charge transport and electron-transfer rate constants reflect more the diffusive mobility of the perchlorate counterion than the intrinsic Co(II/I) electron hopping rate.