Polyoxometalate HIV-1 protease inhibitors. A new mode of protease inhibition.

Nb-containing polyoxometalates (POMs) of the Wells-Dawson class inhibit HIV-1 protease (HIV-1P) by a new mode based on kinetics, binding, and molecular modeling studies. Reaction of alpha(1)-K(9)Li[P(2)W(17)O(61)] or alpha(2)-K(10)[P(2)W(17)O(61)] with aqueous H(2)O(2) solutions of K(7)H[Nb(6)O(19)] followed by treatment with HCl and KCl and then crystallization affords the complexes alpha(1)-K(7)[P(2)W(17)(NbO(2))O(61)] (alpha(1)()1) and alpha(2)-K(7)[P(2)W(17)(NbO(2))O(61)] (alpha(2)()1) in 63 and 86% isolated yields, respectively. Thermolysis of the crude peroxoniobium compounds (72-96 h in refluxing H(2)O) prior to treatment with KCl converts the peroxoniobium compounds to the corresponding polyoxometalates (POMs), alpha(1)-K(7)[P(2)W(17)NbO(62)] (alpha(1)()2) and alpha(2)-K(7)[P(2)W(17)NbO(62)] (alpha(2)()2), in moderate yields (66 and 52%, respectively). The identity and high purity of all four compounds were confirmed by (31)P NMR and (183)W NMR. The acid-induced dimerization of the oxo complexes differentiates sterically between the cap (alpha(2)) site and the belt (alpha(1)) site in the Wells-Dawson structure (alpha(2)()2 dimerizes in high yield; alpha(1)()2 does not). All four POMs exhibit high activity in cell culture against HIV-1 (EC(50) values of 0.17-0.83 microM), are minimally toxic (IC(50) values of 50 to >100 microM), and selectively inhibit purified HIV-1 protease (HIV-1P) (IC(50) values for alpha(1)()1, alpha(2)()1, alpha(1)()2, and alpha(2)()2 of 2.0, 1.2, 1.5, and 1.8 microM, respectively). Thus, theoretical, binding, and kinetics studies of the POM/HIV-1P interaction(s) were conducted. Parameters for [P(2)W(17)NbO(62)](7)(-) were determined for the Kollman all-atom (KAA) force field in Sybyl 6.2. Charges for the POM were obtained from natural population analysis (NPA) at the HF/LANL2DZ level of theory. AutoDock 2.2 was used to explore possible binding locations for the POM with HIV-1P. These computational studies strongly suggest that the POMs function not by binding to the active site of HIV-1P, the mode of inhibition of all other HIV-1P protease inhibitors, but by binding to a cationic pocket on the "hinge" region of the flaps covering the active site (2 POMs and cationic pockets per active homodimer of HIV-1P). The kinetics and binding studies, conducted after the molecular modeling, are both in remarkable agreement with the modeling results: 2 POMs bind per HIV-1P homodimer with high affinities (K(i) = 1.1 +/- 0.5 and 4.1 +/- 1.8 nM in 0.1 and 1.0 M NaCl, respectively) and inhibition is noncompetitive (k(cat) but not K(m) is affected by the POM concentration).     

Reactions of Cp Ru(η-C6H5CHO) OSO2CF3 (Cp = C5Me5) with substituted anilines forming ruthenium Schiff base complexes

Cp^* Ru(η⁶-C₆H₅CHO)⁺OSO₂CF₃⁻ (1) (Cp^* = C₅Me₅) reacts with substituted anilines forming ruthenium Schiff base complexes containing an η⁶-coordinated Cp^* Ru⁺ group. The 2:1 reaction of 1 with 1,4-phenylenediamine yielded only the monocondensation product, whereas the 2:1 reaction of 1 with 1,4-xylylenediamine yielded the dicondensation product.     

Temperature-induced changes in chain-folded lamellar crystals of aliphatic polyamides. Investigation of nylons 2 6, 2 8, 2 10, and 2 12

Four members of the even-even nylon 2 Y series, for Y = 6, 8, 10, and 12, have been crystallized in the form of chain-folded lamellar single crystals from 1,4-butanediol and studied by transmission electron microscopy (imaging and diffraction), x-ray diffraction, and thermal analysis. The structures of these 2 Y nylons are different from those of nylon 6 6 and many other even-even nylons. At room temperature, two strong diffraction signals are observed at spacings 0.42 and 0.39 nm, respectively; these values differ from the 0.44 and 0.37 nm diffraction signals observed for nylon 6 6 and most even-even nylons at ambient temperature. Detailed analyses of the diffraction patterns show that all these 2 Y nylons have triclinic unit cells. The diamine alkane segments of 2 Y nylons are too short to sustain chain folds; thus, the chain folds must be in the diacid alkane segments in all cases. On heating the crystals from room temperature to the melt, the triclinic structures transform into pseudohexagonal structures and the two diffraction signals meet at the Brill transition temperature which occurs significantly below the melting point. The room temperature structures of these 2 Y nylons are similar to the unit cell of nylon 6 6 at elevated temperature, but below its Brill temperature. The room temperature structures and behavior on heating of the nylon 2 Y family is noticeably different from that of the even-even nylon X 4 family, although the only difference between these families of polyamides is the relative disposition of the amide groups within the chains. The results show that in order to understand the structure, behavior and properties of crystalline nylons, especially as a function of temperature, the detailed stereochemistry needs to be taken into account. © 1997 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys, 35: 675–688, 1997     

Fine coal dewatering using pH- and temperature-sensitive superabsorbent polymers

Water is a necessary medium in most coal preparation processes, but its presence in the final product has a negative impact on transporation costs, handling and specific energy value. A major contribution to the total moisture content may be attributed to the proportion of fine coal in the total product, which presents the greatest dewatering problem. This paper describes a novel process that seeks to reduce the moisture content of fine coal cakes to a level comparable to that achieved by thermal drying. In this process, superabsorbent polymers, which are granular highly crosslinked synthetic copolymers with excellent water-absorbing properties, are employed to draw water from moist fine coal. The drying or dewatering process is characterized by three main stages: (a) contacting of superabsorbents with high-moisture fine coal; (b) separation of dried fine coal from superabsorbents by screening; and (c) regeneration of used superabsorbent polymer, taking advantage of its response to changes in such conditions as pH, temperature or electric field. Depending on the polymer type, the dosage and the polymer/coal contact time, the moisture content of coal filter cake can readily be reduced from, say, 25% to 10% by mass or less. The results of laboratory and pilot scale tests conducted using pH- and temperature-sensitive superabsorbent polymers are discussed in this paper. © 1997 John Wiley & Sons, Ltd.     

Frattini subgroups and supernilpotent groups

In the context of the problem of which nonabelianp-groups can occur as normal subgroups contained in Frattini subgroups, the family of supernilpotent groups (all maximal subgroups characteristic) is investigated. Results of this investigation are applied to the Frattini-embedding problem, incorporating recent work of A. R. Makan. The groups of order 2ⁿ (n ≦ 6) have been examined with respect to supernilpotence and their occurrence as normal subgroups contained in Frattini subgroups. Results of this examination are presented.     

Abelian group pairs having a trivial coGalois group

Torsion-free covers are considered for objects in the category q ₂. Objects in the category q ₂ are just maps in R-Mod. For R = ℤ, we find necessary and sufficient conditions for the coGalois group G(A → B), associated to a torsion-free cover, to be trivial for an object A → B in q ₂. Our results generalize those of E. Enochs and J. Rado for abelian groups.     

Strongly segregated cubic microdomain morphology consistent with the double gyroid phase in high molecular weight diblock copolymers of polystyrene and poly(dimethylsiloxane)

We report the observation of a cubic phase consistent with the double gyroid structure in strongly segregated diblock copolymers of PS‐b‐PDMS over a volume fraction (φ_PDMS) range of ～0.39 to 0.45. The samples have respective molecular weights of 127 kg/mol and 73 kg/mol and degree of segregation Nχ equal to 187 and 106, respectively, at annealing temperature of 130 °C. It is important to highlight that two out of the total four samples investigated, exhibited hexagonally close packed cylindrical domains of PDMS and alternating lamellae at φ_PDMS = 0.39 and 0.45, respectively, indicating the possible narrow range of the DG morphology for the specific diblock copolymers. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 2419–2427, 2009     

Generic dealkylation: a tool for increasing the hit‐rate of metabolite rationalization,and automatic customization of mass defect filters

The use of exact mass liquid chromatography/mass spectrometry (LC/MS) for drug metabolism studies has increased significantly in recent years. Firstly, exact mass measurements facilitate identification of standard biotransformations through the use of narrow window extracted ion chromatograms, which are typically highly selective relative to signals from matrix or dosing components. Secondly, novel metabolites can be characterized via elemental formula calculations and high‐resolution product ion spectra. Furthermore, biological background ions can be removed by the use of mass defect filters (MDFs) which filter out ions based on the decimal component of their m/z value. Here, we describe an approach which we term ‘generic dealkylation’ that in association with other data interpretation tools adds significant value to the assignment process. Generic dealkylation uses a simple strategy to identify those bonds which have the potential to be cleaved by metabolism. In combination with standard phase 1 and phase 2 biotransformations, this allows creation of a chemically intelligent MDF which balances the need to remove matrix background with the requirement of avoiding filtering true metabolites. Secondly, generic dealkylation increases the hit‐rate at which non‐trivial (i.e. not covered by simple phase 1 oxidations or direct phase 2 conjugations) metabolites can be directly rationalized. The value of the generic dealkylation approach is illustrated by its application to determination of in vitro metabolic routes for two commercial drugs, nefazodone and indinavir. Copyright © 2009 John Wiley & Sons, Ltd.     

Fluoride-containing bioactive glasses: Fluoride loss during melting and ion release in tris buffer solution

Melt-derived bioactive glasses (SiO₂-P₂O₅-CaO-Na₂O-CaF₂; CaF₂ 0 to 17.76 mol%) lost fluoride during melting, but nominal and analysed CaF₂ contents in the glass correlated linearly. Analysed CaO contents were increased, showing that fluoride was lost as hydrofluoric acid after reaction with atmospheric water during melting. Weight loss on ignition reduced linearly with increasing CaF₂, suggesting that CaF₂ impedes absorption of atmospheric water. pH changes in tris buffer solution showed that pH is controlled by the silicate matrix (via ion exchange processes), and fluoride release contributes less to the overall pH. Glasses formed apatite in tris buffer; phosphate concentration of the glass was the limiting factor, resulting in fluorite formation for increasing fluoride content in the glass and calcite formation for the fluoride-free composition. These results allow for tailoring of novel fluoride-containing bioactive glasses to address specific needs, particularly in dentistry and for remineralising toothpastes.