Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis,Biological Activity,and X‐Ray Crystal‐Structure Analysis

A new class of nonpeptidic inhibitors of the Zn^II‐dependent metalloprotease neprilysin with IC₅₀ values in the nanomolar activity range (0.034–0.30 μM ) were developed based on structure‐based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo[4,5‐c]pyridine moieties as central scaffolds to undergo H‐bonding to Asn542 and Arg717 and to engage in favorable π‐π stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn^II ion and an aryl residue to occupy the hydrophobic S1′ pocket, but lack a substituent for binding in the S2′ pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)‐ 1 , (+)‐ 2 , (+)‐ 25 , and (+)‐ 26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors (+)‐ 2 and (+)‐ 26 with an imidazo[4,5‐c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)‐ 1 and (+)‐ 25 ) (Table 1). The predicted binding mode was established by X‐ray analysis of the complex of neprilysin with (+)‐ 2 at 2.25‐Å resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn^II ion, and the benzyl residue occupies the S1′ pocket. The 1H‐imidazole moiety of the central scaffold forms the required H‐bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes π‐π stacking with the side chain of His711 as well as edge‐to‐face‐type interactions with the side chain of Trp693. According to the X‐ray analysis, the substantial advantage in biological activity of the imidazo‐pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N‐atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1′ pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.     

Two Unusual Carbohydrate Reactions: Nucleophilic Ring Opening of an Anhydrosugar and Reductive Elimination with Co‐occurring Hydrogenation

Treatment of the 1,6‐anhydrosugar epoxide 5 with a cyano‐Gilman cuprate [(CuCN (6 eq.), MeLi (12 eq.)] surprisingly led to the open chain rearranged (2S,3R)‐1,2‐dihydroxy‐3,6‐dimethylheptan‐4‐one (7), structurally confirmed by conversion to the corresponding diacetate 8. Another unusual reaction was found by hydrogenation of the 2‐tosyl‐1‐bromosugar 11, leading in one operation to the twofold deoxygenated chiral pyran derivative 14. This procedure might prove to be useful in the rapid deoxygenation of sugar derivatives.     

Open Chain Chiral Macrolide Building Blocks by Opening of Deoxygenated 1,6-Anhydrosugars with 1,3-Propanedithiol

Chiral building blocks for macrolides and related natural products are obtained from 1,6-anhydrosugars by conversion of the bicyclic acetals 2 or 12 into the open chain chiral 1,3-dithianes 6 and 13. Branched precursors can be obtained by opening of the ?erný epoxide 1 with the 1,3-dithiane anion to yield 7, followed by ring opening with 1,3-propanedithiol to the bis-1,3-dithiane 8.     

New Cytotoxic Laurene‐, Cuparene‐, and Laurokamurene‐Type Sesquiterpenes from the Red Alga Laurencia obtusa

Three new sesquiterpene alcohols, laur‐2‐ene‐3,12‐diol ( 1 ), cuparene‐3,12‐diol ( 2 ), and 8,11‐dihydro‐1‐methoxylaurokamuren‐12‐ol ( 3 ), along with one known diterpene, kahukuen‐10‐ol ( 4 ) have been isolated from the organic extract of the red alga Laurencia obtusa. The chemical structures were elucidated on the basis of spectroscopic analysis. The cytotoxicity of the isolated compounds were evaluated against three cancer cell lines, i.e., KB, HepG2, and MCF‐7. Compound 4 exhibited a wide range of cytotoxic activity against KB, HepG2, and MCF‐7 cell lines with IC₅₀ of 0.100, 0.057, and 0.054 μm, respectively. In addition, 1 showed moderate activities towards KB and MCF‐7 cell lines with IC₅₀ values of 0.171 and 0.184 μM , respectively and 2 exhibited a moderate activity against KB cell line at a concentration of 0.213 μg/ml. On the other hand, compound 3 exhibited no cytotoxic activity against any of the three cell lines.     

A nonlinear circuit model for studying the frequency response in buried heterostructure lasers

An equivalent-circuit model of a semiconductor laser is developed. The model includes diffusion and uses the parabolic gain approximation. It can be applied to various buried heterostructure (BH) devices to simulate optical response characteristics. The values of the circuit elements versus injection current clearly indicate that the parabolic gain approximation and carrier diffusion play an important role in obtaining a more accurate frequency response, especially for (BH) lasers with stripe widths greater than the diffusion length.     

Elaboration and electrochemical characterization of LaZr2Cr4Ni5-based metal hydride alloys

The elaboration of LaZr₂Cr₄Ni₅-based intermetallic compound was performed by mechanical alloying from LaNi₅ and ZrCr₂ precursors and characterized as active materials of negative electrodes in nickel-metal hydride (Ni-MH) batteries. The effect of the milling duration on the phase composition was investigated. The structural properties of the formed phases were determined by X-ray diffraction and quantified from the Rietveld refinement data. The increase of the milling time up to 40 h leads to the highest abundance of the LaZr₂Cr₄Ni₅ phase, estimated at a weight content of 60.6 %, and a complete elimination of the LaNi₅ intermetallic precursor. The chronopotentiometry, cyclic voltammetry, and chronoamperometry techniques were applied to characterize the electrochemical behavior of prepared LaZr₂Cr₄Ni₅-based compounds. The maximum discharge capacity was 152 mAh g⁻¹, and a high electrochemical stability was obtained in the alkaline solution. The value of the hydrogen diffusion coefficient is equal to 2.1 × 10⁻⁸ cm² s⁻¹, reflecting an appropriate electrochemical hydrogenation kinetic in the LaZr₂Cr₄Ni₅-based compounds.

     

Characterization of a dielectric microdroplet thermal interface material with dispersed nanoparticles

Gold nanoparticles (NPs) with a size close to 1.5?nm, coated with organic ligands bearing Si(OEt)₃ groups, were synthesized and used to obtain self-standing films by a sol?Cgel process catalyzed by formic acid. Using FESEM images, FTIR, and UV?Cvisible spectra, it was observed that very small gold NPs self-assembled by Si?CO?CSi covalent bonds forming crosslinked clusters with sizes up to about 50?nm in which NPs preserve their individuality. The possibility of fixing very small gold NPs in a crosslinked film opens a variety of potential applications based on the specific properties of small-size particles. As an example, we illustrated the way in which one can take advantage of the low melting temperature of these NPs to generate tiny gold crystals partially embedded at the surface, a process that might be used for the development of catalysts or sensors. Besides, the shift and change in the intensity of the plasmon band produced by heating to 100?°C may be employed to develop an irreversible sensor of undesirable temperature excursions during the life-time of a specific product.     

Instabilities in quantum-dot spin-VCSELs

A modified spin-flip model is used to investigate the stability of optically-pumped quantum-dot spin-vertical cavity surface-emitting lasers. in terms of pump intensity and polarization. The stability maps exhibit pronounced polarization switching in the stable regions. Periodic oscillations in unstable regions are attributed to competition between spin relaxation and birefringence.     

Boiling Stability in a Porous Medium Heated From Below

Boiling in a porous layer heated from below at constant heat flux and cooled at constant temperature from the upper permeable surface leads below the critical flux of appearance of a vapor zone at the bottom in the approximation of dominated reservoirs to two solutions: a liquid-dominated one and a vapor-dominated one. The stability of these two situations is analyzed. The approach allows to understand the respective roles played by the gravitational instability, natural convection in the liquid upper layer, and movement of the interface between the two regions. Taking into account the confinement allows the comparison of these theoretical results with experimental results obtained in the laboratory.