Polycyclic N-Heterocyclic compounds. 50. Synthesis and pharmacological evaluation of 2,3,6,7-Tetrahydrothieno[2,3-H]-imidazo[2,1-f][1,6]naphthyridines,3,4,7,8-Tetrahydro-2H-thieno-[2,3-h]pyrimido[2,1-f][1,6]naphthyridines and their precursor

Some novel 5-hydroxyalkylamino-1,2-dihydrothieno[2,3-h][1,6]naphthyridines were prepared by the reaction of 5-chloro-1,2-dihydrothieno[2,3-h][1,6]naphthyridine derivatives with some aminoalcohols in the presence of base. These derivatives were cyclized to the corresponding imidazo or pyrimido derivatives. The bronchodilatory activity of these compounds was evaluated on the basis of their relaxation activity to tracheal contraction induced by carbamylcholine chloride as a primary in vitro assays. Effect of some naphthyridines on carbamylcholine chloride-induced contractions of trachea in the presence or absence of milrinone or 4-(3-butoxy-4-methoxyphenyl)imidazolidin-2-one, which is inhibitor of phosphodiesterase III or IV, were also evaluated.     

Novel synthesis of electroconducting polymers from simple monomers with transition metal complex catalysts

Electroconductive polyaromatics or polyarylenes have been successfully prepared by the oxidative polymerization of the corresponding simple monomers over the transition metal complex catalyst. For example, poly(1,4-phenylene) was prepared from benzene by using oxygen as an oxidant and a copper(I) chloride-aluminum chloride double complex as the catalyst. The same catalytic system was applied to the preparation of poly(2,5-pyrrolylene) and poly(2,5-thienylene) from pyrrole and 2,2′-bithiophen, respectively. The electrochemical oxidative polymerization was also carried out for the preparation of the poly(1,4-phenylene) and poly(1,4-naphthylene) films in the presence of copper(I) chloride and aluminum chloride.     

Cryo-EM structure of acylpeptide hydrolase reveals substrate selection by multimerization and a multi-state serine-protease triad

The first structure of tetrameric mammalian acylaminoacyl peptidase, an enzyme that functions as an upstream regulator of the proteasome through the removal of terminal N-acetylated residues from its protein substrates, was determined by cryo-EM and further elucidated by MD simulations. Self-association results in a toroid-shaped quaternary structure, guided by an amyloidogenic β-edge and unique inserts. With a Pro introduced into its central β-sheet, sufficient conformational freedom is awarded to the segment containing the catalytic Ser587 that the serine protease catalytic triad alternates between active and latent states. Active site flexibility suggests that the dual function of catalysis and substrate selection are fulfilled by a novel mechanism: substrate entrance is regulated by flexible loops creating a double-gated channel system, while binding of the substrate to the active site is required for stabilization of the catalytic apparatus – as a second filter before hydrolysis. The structure not only underlines that within the family of S9 proteases homo-multimerization acts as a crucial tool for substrate selection, but it will also allow drug design targeting of the ubiquitin-proteasome system.

The structure of tetrameric mammalian acylaminoacyl peptidase – a key upstream regulator of the proteasome – was determined by cryo-EM (and elucidated by MD), showing a “shutters-and-channels” substrate selection apparatus created by oligomerization.     

Revealing hydrogen spillover pathways in reducible metal oxides

Hydrogen spillover, the migration of dissociated hydrogen atoms from noble metals to their support materials, is a ubiquitous phenomenon and is widely utilized in heterogeneous catalysis and hydrogen storage materials. However, in-depth understanding of the migration of spilled hydrogen over different types of supports is still lacking. Herein, hydrogen spillover in typical reducible metal oxides, such as TiO₂, CeO₂, and WO₃, was elucidated by combining systematic characterization methods involving various in situ techniques, kinetic analysis, and density functional theory calculations. TiO₂ and CeO₂ were proven to be promising platforms for the synthesis of non-equilibrium RuNi binary solid solution alloy nanoparticles displaying a synergistic promotional effect in the hydrolysis of ammonia borane. Such behaviour was driven by the simultaneous reduction of both metal cations under a H₂ atmosphere over TiO₂ and CeO₂, in which hydrogen spillover favorably occurred over their surfaces rather than within their bulk phases. Conversely, hydrogen atoms were found to preferentially migrate within the bulk prior to the surface over WO₃. Thus, the reductions of both metal cations occurred individually on WO₃, which resulted in the formation of segregated NPs with no activity enhancement.

The hydrogen spillover pathway in typical reducible metal oxides, such as TiO₂, CeO₂, and WO₃, was investigated by combining various in situ characterization techniques, kinetic analysis, and density functional theory calculations.     

Novel Fluorescent Probes for Singlet Oxygen

The first fluorescent chemical traps for ¹ O ₂ have been developed. DPAXs react specifically with ¹O₂ to yield the corresponding endoperoxides, DPAX-EPs (see scheme; X = H, Cl, F). DPAXs scarcely fluoresce, while DPAX-EPs are strongly fluorescent. Since the fluorescence of these probes is unaffected by H₂O₂, superoxide, and nitric oxide, they are useful for the selective detection of ¹O₂ in biological systems.     

Nanoscopic structure and function of polymer‐protected metal clusters

Colloidal dispersion of polymer‐protected metal clusters were prepared by heat treatment of macromolecule‐metal complexes, composed of water‐soluble polymer and noble metal ions. The mixtures of two kinds of noble metal ions can provide polymer‐protected bimetallic nanoclusters with a core/shell structure by the same procedure. In contrast, bimetallic clusters with the inverted core/shell structure are difficult to be prepared by the similar procedure. A sacrificial hydrogen strategy has been successfully proposed for the preparation of the inverted ones. When copper or nickel ions were used as one of the elements to prepare bimetallic clusters, rather random alloy structured nanoparticles were produced. The catalytic activity of these bimetallic clusters is, in general, higher than that of the corresponding monometallic ones.