Synthesis of a new class of uridine phosphorylase inhibitors

A new series of potent uridine phosphorylase inhibitors have been prepared from barbituric acid. Among them, 1-[(2-hydroxyethoxy)methyl]-5-)(m--benzyloxy)benzylbarbituric acid ( 37 , BBBA) is the most promising having a K_i value of 1.1 ± 0.2 nM with uridine phosphorylase from human liver. The new inhibitors are easily synthesized and are better inhibitors of human uridine phosphorylase than their uracil counterparts.     

A semiclassical reactive flux method for the calculation of condensed phase activated rate constants

A semi classical reactive flux algorithm for calculating thermally activated rate constants is presented which is based on a semi-classical transition state theory due to Chapman, Garrett and Miller [J. Chem. Phys. 63 (1975) 2710]. This reactive flux technique, when combined with the semiclassical TST, enables one to describe dynamical recrossings of the transition state on the same footing as tunneling effects. Most importantly, the method is readily applied to nonlinear multidimensional systems over a wide range of temperatures. It will be shown that the method works very well for a variety of existing models.     

On the Role of Mixed Strategies in Elementary Decision Analysis and Related Decision-Support-System Treatments

We first demonstrate that mixed strategies are relevant in decision analysis for a maximin decision-maker quite apart from any game-theory considerations. This rectifies the apparent misconception that results from MS/OR textbooks which discuss mixed strategies only in the game-theory setting. Next we show an example of an implementable mixed strategy, by which we mean a mixed decision strategy which does not require randomization for its implementation. This application is to portfolio construction.     

Rhodathiaboranes with `anomalous' electron counts: synthesis, structure and reactivity

Analysis of the structures of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 9,9-(PPh₃)₂-9,7,8-nido-RhC₂B₈H₁₁ by RMS misfit calculations has confirmed that these rhodaheteroboranes possess nido 11-vertex cluster geometries in apparent contravention of Wade's rules. However, examination of the molecular structures of both species shows that the {RhP₂} planes are inclined by ca. 66° with respect to the metal-bonded SB₃ or CB₃ faces, and that two weak ortho-CHRh agostic interactions occupy the vacant co-ordination position thereby created. As a consequence of these agostic bonds the Rh atom, and hence the overall cluster, is provided with an additional electron pair, meaning that their nido structures are now fully consistent with Wade's rules. The chelated diphosphine compound 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ is similar to the PPh₃ compound in showing the same agostic bonding. Attempts to prepare a bis-P(OMe)₃ analogue result in ligand scavenging and the formation of 8,8,8-{P(OMe)₃}₃-8,7-nido-RhSB₉H₁₀. Similarly, reaction between Cs[6-arachno-SB₉H₁₂] and RhCl(dmpe)CO does not result in CO loss but in formation of 8,8-(dmpe)-8-(CO)-8,7-nido-RhSB₉H₁₀, shown to exist as a mixture of two of three possible rotamers. Deprotonation of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ with MeLi yields the anions [1,1-(PPh₃)₂-1,2-closo-RhSB₉H₉]⁻ and [1,1-dppe-1,2-closo-RhSB₉H₉]⁻, respectively, with octadecahedral cage structures. It is argued that anion formation causes the agostic bonding to be `switched-off' and results in the cluster adopting the closo architecture predicted by Wade's rules. This structural change is fully reversible on reprotonation, and if reprotonation of [1,1-(dppe)-1,2-closo-RhSB₉H₉]⁻ is carried out in MeCN, the product 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ forms. Interestingly, 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ reconverts to 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ on standing in CDCl₃, suggesting that the agostic bonding is sufficiently strong to displace co-ordinated MeCN. All new compounds are fully characterised by multinuclear NMR spectroscopy and, in many cases, by single crystal X-ray diffraction.     

The ICP-MS approach to environmental studies

The certification of marine materials for trace metals is a process which challenges every technique involved, especially if a technique is as recent as inductively coupled plasma mass spectrometry (ICP-MS), Developmental work was required for several materials (natural waters, biological materials, marine sediments). It is reviewed here, in an attempt to show how one can take full advantage of ICP-MS. This includes a review of the digestion procedures developed for the multielement analysis of biological materials and marine sediments in order to minimize spectroscopic interferences. The multielement analysis of natural waters is also reviewed, in particular that of saline waters which requires a separation of the analytes from the alkali and alkaline earths elements and a preconcentration of the analytes on a column of silicaimmobilized 8-hydroxyquinoline. The potential of performing this separation/preconcentration procedure on-line is showed using both published and original results. Finally, the application of ICP-MS to speciation is illustrated by the determination of methylmercury in biological materials after extraction, and by the determination of arsenic species by high performance liquid chromatography coupled to ICP-MS.Presented in part at the 1989 European Winter Conference on Plasma Spectrochemistry, Reutte, AustriaThe work described was carried out while the author was a Research Associate at the Analytical Chemistry Section, Chemistry Division, National Research Council of Canada, Ottawa, K1A OR9, Canada     

Kinetic and structural characterization of human manganese superoxide dismutase containing 3-fluorotyrosines

Incorporation of 3-fluorotyrosine and site-specific mutagenesis have been used with stopped-flow spectrophotometry and pulse radiolysis to investigate the catalytic properties of human manganese superoxide dismutase (MnSOD). All of the nine tyrosine residues in each of the four subunits of the homotetramer of human MnSOD were replaced with 3-fluorotyrosine. Previous studies showed that the crystal structures of the unfluorinated and fluorinated human MnSOD are nearly superimposable with the root-mean-square deviation for 198 -carbon atoms at 0.3 Å. However, the catalytic activity k_cat/K_m of the fluorinated MnSOD at 30 μM⁻¹ s⁻¹ was less than unfluorinated wild type at 800 μM⁻¹ s⁻¹. Comparison of the values of k_cat/K_m for fluorinated and unfluorinated wild-type andY34F MnSOD showed that this decrease for the fluorinated enzyme was in significant part due to 3-fluorotyrosine residues distant (>7 Å) from the active-site metal, not to 3-fluorotyrosine at position 34 close (5 Å) to the metal. Although many rate constants for the catalysis are decreased by this fluorination, the rate of dissociation of the product-inhibited complex appears unchanged by the presence of fluorinated tyrosines. These results suggest that Tyr34 is not a proton donor in the release of the product-inhibited complex, which involves protonation of a peroxo complex of the metal with release of hydrogen peroxide.     

Synthesis and characterization of 3-phenylethynyl endcapped matrix resins

The synthesis of 3-phenylethynylphenol, and its applicability as a high temperature cross-linking endcap for high T_g polyarylene ethers is described. It was synthesized in high yields and purity using the palladium catalyzed coupling reaction between the protected 3-bromo or iodo phenol and phenylacetylene. The yield of the reaction was found to be highly dependent on the structure of the halide used, the reaction temperature, and the concentration of phenylacetylene. The use of the protected phenol in the palladium catalyzed reaction was also extended to the high yield synthesis of 3-ethynylphenol and protected 4-ethynylphenols. The complete synthesis of 3-phenylethynylphenol, 3-ethynylphenol, and protected 4-ethynylphenol in high yields has been demonstrated and is discussed herein. Three new phenylethynyl functionalized arylene ether matrix resins have been synthesized in high yields and purity by reacting 3-phenylethynylphenol with 4,4′-dichlorodiphenyl sulfone, 4,4′-difluorobenzophenone, and bis(4-fluorophenyl)phenyl phosphine oxide, via nucleophilic poly(arylene ether) synthesis conditions. These low molecular weight materials undergo thermally induced chain extension/branching to yield an insoluble three-dimensional network at reaction temperatures of around 380°C. The low molecular weight arylene ethers endcapped with the phenylethynyl group demonstrate excellent flow characteristics and a wide processing window of about 250°C. Crosslinking of the 4,4′-bis(3-phenylethynyl phenoxy)diphenyl sulfone system for 30 min at 350°C in air afforded a T_g value of 265°C by differential scanning calorimetry measurements. Trace metal analysis for palladium and copper showed absence of these metals that would otherwise detract from the excellent thermal stability. The synthesis and characterization of these phenylethynyl endcapped arylene ether matrix resins is discussed. © 1995 John Wiley & Sons, Inc.     

A subjective Bayesian approach to the theory of queues II — Inference and information in M/M/1 queues

This is a sequel to Part I of A Subjective Bayesian Approach to the Theory of Queues. The focus here is on inference and a use of Shannon's measure of information for assessing the amount of information conveyed by the various types of data from queues. The notation and terminology used here is established in Part I.