Human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT) coordinates DNA polymerization and ribonuclease H (RNase H) activities using two discrete active sites embedded within a single heterodimeric polyprotein. We have identified a novel thiophene diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid, that selectively inhibits polymeraseindependent RNase H cleavage (IC 50 ‫؍‬ 3.2 M) but has no effect on DNA polymerization (IC 50 > 50 M). The activity profile of the diketo acid is shown to be distinct from previously described compounds, including the polymerase inhibitor foscarnet and the putative RNase H inhibitor 4-chlorophenylhydrazone. Both foscarnet and the hydrazone inhibit RNase H cleavage and DNA polymerization activities of RT, yet neither inhibits the RNase H activity of RT containing a mutation in the polymerase active site (D185N) or an isolated HIV-1 RNase H domain chimera containing the ␣-C helix from Escherichia coli RNase HI, suggesting these compounds affect RNase H indirectly. In contrast, the diketo acid inhibits the RNase H activity of the isolated RNase H domain as well as full-length RT, and inhibition is not affected by the polymerase active site mutation. In isothermal titration calorimetry studies using the isolated RNase H domain, binding of the diketo acid is independent of nucleic acid but strictly requires Mn 2؉ implying a direct interaction between the inhibitor and the RNase H active site. These studies demonstrate that inhibition of HIV-1 RNase H may occur by either direct or indirect mechanisms, and they provide a framework for identifying novel agents such as 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid that specifically targets RNase H.

We investigate the viscosity dependence on concentration and molecular weight of semiflexible polyelectrolyte sodium carboxymethylcellulose (NaCMC) in aqueous saltfree and NaCl solutions. Combining new measurements and extensive literature data, we establish relevant power laws and crossovers over a wide range of degree of polymerisation (N ), polymer (c) and salt (c s ) concentration. In salt-free solution, the overlap concentration shows the expected c * ∝ N −2 dependence, and the entanglement crossover scales as c e ∝ N −0.6±0.3 , in strong disagreement with scaling theory for which c e ∝ c * is expected, but matching the behaviour found for flexible polyelectrolytes. A second crossover, to a steep concentration dependence for specific viscosity 1 (η sp ∝ c 3.5±0.2 ), commonly assigned to the concentrated regime, is shown to follow c * * ∝ N −0.6±0.2 (with c * * /c e 6) which thus suggests instead a dynamic crossover, possibly related to entanglement. The scaling of c * and c e in 0.01M and 0.1M NaCl shows neutral polymer in good solvent behaviour, characteristic of highly screened polyelectrolyte solutions. This unified scaling picture enables the estimation of viscosity of ubiquitous NaCMC solutions as a function of N , c and c s and establishes the behaviour expected for a range of semiflexible polyelectrolyte solutions.

We report a small angle neutron scattering (SANS) and rheology study of cellulose derivative polyelectrolyte sodium carboxymethyl cellulose with a degree of substitution of 1.2. Using SANS, we establish that this polymer is molecularly dissolved in water with a locally stiff conformation with a stretching parameter. We determine the cross sectional radius of the chain ( 3.4 Å) and the scaling of the correlation length with concentration (ξ = 296 c−1/2Å for c in g/L) is found to remain unchanged from the semidilute to concentrated crossover as identified by rheology. Viscosity measurements are found to be in qualitative agreement with scaling theory predictions for flexible polyelectrolytes exhibiting semidilute unentangled and entangled regimes, followed by what appears to be a crossover to neutral polymer concentration dependence of viscosity at high concentrations. Yet those higher concentrations, in the concentrated regime defined by rheology, still exhibit a peak in the scattering function that indicates a correlation length that continues to scale as. © 2014 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 492–501

A total of 21 complexes of CuX (X = Cl, Br, I) with bridging ligand (B = 4,4'-dipyridyl (Bpy), pyrazine (Pyz), quinoxaline (Quin), phenazine (Phz), 1,4-diazabicyclo[2.2.2]octane (DABCO), and hexamethylenetetramine (HMTA)) have been synthesized. The products show two stoichiometries: [CuXB] (type 1) and [(CuX)2B] (type 2). Both types can be obtained for B = Bpy, depending on the conditions of preparation. In these cases, the type 2 stoichiometry is the kinetic product. Type 2 complexes only are found for B = Pyz (X = I), Quin, Phz, DABCO, and HMTA. Type 1 complexes form for Pyz (X = Cl, Br). Thermogravimetic analyses of the complexes reveal the general decomposition trend: 1 --> 2 --> [(CuX)2B(1/2)] --> CuX. The X-ray crystal structure of [CuBr(Pyz)] (type 1) features copper atoms bridged by Br and Pyz, forming 2D sheets of fused rectangular Cu4Br2(Pyz)2 units. The X-ray structure of [(CuI)2(Quin)] (type 2) shows 2D layers composed of [Cu2I2]infinity "stair step" chains which are cross-linked by Quin ligands. A total of 16 complexes of CuXL (L = P(OPh)3) with bridging ligand (B = those above and 1,4-dimethylpiperazine (DMP)) have also been prepared. All of these products, except those of HMTA, are of type 3 formulation, [(CuXL)2B]. The HMTA products have the formula [CuX(HMTA)], type 4. Thermal decomposition of the type 3 and 4 complexes occurs with initial loss of B, L, or both. The X-ray structures of [(CuBrL)2(Bpy)] and [(CuBrL)2(Pyz)] (type 3) reveal 1D chains formed from rhomboidal (LCu)2Br2 units linked by the B ligand. The type 4 structure of [CuBrL(HMTA)] is shown by X-ray to be a simple halide-bridged dimer.

The first group VI η 2 -coordinated benzene complex, TpW(NO)(PMe 3 )(η 2 -benzene), is reported. The bound arene is activated toward Diels-Alder cycloaddition, and substitution of the arene with DMF yields a rare example of a η 2 -coordinated amide.Over the past decade, we have endeavored to develop π-basic metal fragments with the ability to bind aromatic molecules and activate them toward otherwise inaccessible organic transformations, with the ultimate goal of expanding the array of reactions available for this ubiquitous class of molecules. 1-3 These electronrich transition-metal fragments such as {Os(NH 3 ) 5 } 2+ and {TpRe(CO)(MeIm)} (Tp ) hydridotris(pyrazolyl)-borate, MeIm ) 1-methylimidazole) coordinate aromatic molecules across only two atoms of the aromatic ring and thereby localize the π-bonds of the uncoordinated portion, rendering the molecule highly nucleophilic. 2,4,5 Recently, the first group VI dearomatization fragment, {TpMo(NO)(MeIm)}, was synthesized 6 by using a strategy of matching d 5 /d 6 reduction potentials with previously developed rhenium(I) and osmium(II) systems. Although this complex forms stable η 2 complexes with naphthalene and furan, complexes of benzene or pyrrole could not be isolated. We hypothesized that a heavymetal analogue of the form {TpW 0 (NO)(L)} could more effectively back-bond with aromatic molecules, thereby strengthening the metal-arene bond to the point that a full range of complexes with aromatic molecules could be isolated and characterized.The difference in d 5 /d 6 reduction potentials between TpRe(CO) 3 7 and TpW(NO)(CO) 2 8 suggests that the fragment {TpW(NO)} is approximately 300 mV more reducing than {TpRe(CO)}. 9 This observation, along with a comparison of electrochemical data for the series of complexes {TpRe(CO)(L)} (L ) NH 3 , MeIm, py, PMe 3

. 66:7414-7419, 1992). This observation suggests that chemical inhibitors of integrase may prevent the spread of HIV in infected individuals. In our search for such potential chemotherapeutic agents, we observed that ␤-conidendrol inhibits both the sequence-dependent and sequenceindependent endonucleolytic activities of integrase with comparable potencies in vitro (50% inhibitory concentration, 500 nM). Structurally related compounds tested for their abilities to inhibit integrase generated a limited structure-activity analysis which demonstrated that potency is associated with the bis-catechol structure: two pairs of adjacent hydroxyls on separate benzene rings. ␤-Conidendrol did not inhibit several other endonucleases and/or phosphoryltransferases. Although ␤-conidendrol was not effective in preventing HIV-1 infection in cell culture, the in vitro data demonstrate that it is possible to identify selective agents targeted against this essential HIV-1 function.

The isoquinuclidine (2-azabicyclo[2.2.2]octane) core is found in numerous molecules of biological and medicinal importance, including the widely investigated Iboga alkaloids and their related bisindole Cantharanthus alkaloids (Sundberg, R. J.; Smith, S. Q. Alkaloids (San Diego, CA, United States) 2002, 59, 281-386). A diverse range of synthetic methods for the stereoselective construction of this architecture is required for the efficient development of related pharmaceuticals. Here, we report a fundamentally new methodology that constructs the isoquinuclidine core directly from pyridines, using a pi-basic tungsten complex to disrupt the aromatic stabilization of these otherwise inert heterocycles. By this approach, common pyridines are found to undergo stereoselective Diels-Alder reactions with electron-deficient alkenes under mild reaction conditions, thus providing access to a broad range of functionalized isoquinuclidines. Further, by using the common terpene alpha-pinene, a single enantiomer of the tungsten fragment can be isolated and used to provide access to enantio-enriched isoquinuclidines from pyridines.

Thermolysis of Cp*W(NO)(CH2CMe3)(eta(3)-CH2CHCHMe) (1) at ambient temperatures leads to the loss of neopentane and the formation of the eta(2)-diene intermediate, Cp*W(NO)(eta(2)-CH2=CHCH=CH2) (A), which has been isolated as its 18e PMe3 adduct. In the presence of linear alkanes, A effects C-H activations of the hydrocarbons exclusively at their terminal carbons and forms 18e Cp*W(NO)(n-alkyl)(eta(3)-CH2CHCHMe) complexes. Similarly, treatments of 1 with methylcyclohexane, chloropentane, diethyl ether, and triethylamine all lead to the corresponding terminal C-H activation products. Furthermore, a judicious choice of solvents permits the C-H activation of gaseous hydrocarbons (i.e., propane, ethane, and methane) at ambient temperatures under moderately elevated pressures. However, reactions between intermediate A and cyclohexene, acetone, 3-pentanone, and 2-butyne lead to coupling between the eta(2)-diene ligand and the site of unsaturation on the organic molecule. For example, Cp*W(NO)(eta(3),eta(1)-CH2CHCHCH2C(CH2CH3)2O) is formed exclusively in 3-pentanone. When the site of unsaturation is sufficiently sterically hindered, as in the case of 2,3-dimethyl-2-butene, C-H activation again becomes dominant, and so the C-H activation product, Cp*W(NO)(eta(1)-CH2CMe=CMe2)(eta(3)-CH2CHCHMe), is formed exclusively from the alkene and 1. All new complexes have been characterized by conventional spectroscopic and analytical methods, and the solid-state molecular structures of most of them have been established by X-ray crystallographic analyses. Finally, the newly formed alkyl ligands may be liberated from the tungsten centers in the product complexes by treatment with iodine. Thus, exposure of a CDCl3 solution of the n-pentyl allyl complex, Cp*W(NO)(n-C5H11)(eta(3)-CH2CHCHMe), to I2 at -60 degrees C produces n-C5H11I in moderate yields.