Zika Virus Inhibitors Based on a 1,3-Disubstituted 1H-Pyrazolo[3,4-d]pyrimidine-amine Scaffold

To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7H-pyrrolo[2,3-d]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound 5 with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound 5, we have exploited a 1H-pyrazolo[3,4-d]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1H-pyrazolo[3,4-d]pyrimidine scaffold but also generated anti-ZIKV compounds including 6 and 13, which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.     

Druggable exosites of the human kino-pocketome

Journal of Computer-Aided Molecular Design - Small molecules binding at any of the multiple regulatory sites on the molecular surface of a protein kinase may stabilize or disrupt the corresponding...     

Overview of DWDM/ODC Project

This article introduces the main achievements resulting from the DWDM/ODC project. The five areas of research activity within the DWDM/ODC project cover some of the main issues of design and development of dense wavelength division multiplexing systems for transparent optical networks. These issues are: performance assessment with arbitrary optical filtering; performance of signaling formats; dispersion compensation strategies for directly and externally modulated systems in presence of nonlinear transmission-induced degradation; and the impact of noise and crosstalk in the extent of transparent optical networks. All five areas of research activity have contributed significantly to a better understanding of the limitations present in dense wavelength division multiplexing systems.     

Charge‐induced modulation of magnetic interactions in a [2 × 2] metal‐organic grid complex

We investigate the magnetic state of a recently synthesized [2 × 2]‐metal‐organic grid complex as a function of its redox state. Our analysis of a phenomenological model for the relevant molecular orbitals reveals that additional electrons on the ligands can couple their spins via the bridging metal sites. We find that at certain stages of the reduction of the complex cation, a maximal total spin ground state of the complex (S = 3/2) can be stabilized by the Nagaoka mechanism. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006     

Comparison between the dissolution of whey protein gels and of synthetic polymers

The dissolution behavior of heat‐induced whey protein gels in alkali is compared with the literature on the dissolution of (1) uncrosslinked synthetic polymers with chemical reaction, (2) uncrosslinked polymers in a good solvent, and (3) crosslinked hydrogels. Diffusion of hydroxide and acid–base reactions, which are key processes in the dissolution of phenolic resins in alkali (Case 1), are found not to be very important with protein gels. The strong dependency of the dissolution rate on the free volume observed in protein gels is described by a large scaling factor, as predicted for Case 2 theory, indicating that the disentanglement of long chains before they are released is important. The cleavage of intermolecular crosslinks, which is important in Case 3, is also identified as a key dissolution step, where the complexity of protein chemistry comes into play. Synthetic polymer mechanisms are therefore able to elucidate several aspects of protein gel dissolution, but are not yet sufficient to explain all aspects of the process. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 1007–1021, 2008     

Applications of “Dry” Processing in the Microelectronics Industry Using Carbon Dioxide

Condensed carbon dioxide (CO₂) has emerged as a leading enabler of advanced semiconductor manufacturing processes. By exploiting the physical properties of CO₂, some of the current challenges encountered in microelectronics processing related to shrinking feature sizes and materials compatibility have been addressed. Furthermore, the potential for reduction of chemicals used in processing is realized. Applications of CO₂ in microelectronics operations such as wafer cleaning, spin-coating, development, and stripping of photoresists, drying, low-k film preparation and repair, etching, and metal deposition are discussed.     

A Bridged High-Spin Complex Bis-[Ni(II)( rac-5,5,7,12,12,14-hexamethyl- 1,4,8,11-tetraazacyclotetradecane)]-2,5-pyridinedicarboxylate Diperchlorate Monohydrate

A bridged high-spin complex,bis-[Ni(II)(rac-5,5,7,l2,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane)]-2,5-pyridinedicarboxylate diperchlorate monohydrate has been obtained by reaction of [Ni(II)(rac-5,5,7, 12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane)](ClO₄)₂ and 2,5-pyridinedicarboxylic acid in aqueousalkaline (NH₄OH) medium. C₃₉H₇₇Cl₂N₉Ni₂O₁₃, chemical formula weight 1068.42, orthorhombic, P2₁2₁2₁, a = 11 .423(3) Å,b = 14.770(6) Å, c = 31.608(7) Å, = = =90.00°, V = 5333(3) ų, Z = 4, D_calc = 1.331 g cm^-3, _calc = 0.869 mm^-1, F(000) = 2272, T = 293(2), R = 0.0870 for 2686 observed reflections [I > 2(I)]. The complexincludes two folded [Ni(rac- Me₆[14]aneN₄)]²⁺ units havingopposite diastereomeric configuration. They are bridged through a dianion of2,5-pyridinedicarboxylic acid, with one Ni-atom coordinated to the O-atom ofthe 2-carboxylic group and the pyridine N-atom (forming a 5-membered chelatering), and with the second Ni-atom coordinated to both O-atoms of the 5-carboxylic group (forming a 4-membered chelate ring). Hydrogen bonding involving macrocyclic NH groups, both 2- and 5-carboxylic groups, perchlorate anions and water molecules gives rise to the formation of an infinite supramolecular network in the title compound's crystals.     

Chemically patterned flat stamps for microcontact printing

Locally oxidized patterns on flat poly(dimethylsiloxane) stamps for microcontact printing were used as a platform for the transfer of a hydrophilic fluorescent ink to a glass substrate. The contrast was found to be limited. These locally oxidized patterns were conversely used as barriers for the transfer of hydrophobic n-octadecanethiol. In this case a good contrast was obtained, but the pattern was found to be susceptible to defects (cracks) in the barrier layer. Local stamp surface oxidation and subsequent modification with 1H,1H,2H,2H-perfluorodecyltrichlorosilane, for use as a barrier in the transfer of n-octadecanethiol, 16-mercaptohexadecanoic acid, and octanethiol, resulted in remarkably good contrast and stable patterns. The improved ink transfer control is ascribed to the reduction of undesired surface spreading and a superior mechanical stability of the stamp pattern. This new approach substantially expands the applicability of microcontact printing and provides a tool for the faithful reproduction of even extremely low filling ratio patterns.     

Cascade reactions leading to the mechanism of action of vinaxanthone and xanthofulvin,natural products that drive nerve repair

The natural products vinaxanthone and xanthofulvin promote regeneration in animal models of spinal cord injury and corneal transplant. However, inhibition of the initially described biological target of these compounds, semaphorin 3A, does not fully account for the recovery demonstrated in vivo following administration of the natural products. Through chemical synthesis substantial quantities of both natural products have been accessed with early reaction development paving the way for synthesizing both compounds. The success of a model system, first disclosed herein, translated to the syntheses of both natural products. Following from this we also report for the first time the discovery of a new target of the natural products, the succinate receptor 1 (SUCNR1). Both natural products function as positive allosteric modulators of SUCNR1. As the first known allosteric modulators of SUCNR1, the compounds represent powerful new tools to understand the pharmacology of SUCNR1 and its control of growth and cellular defense.