Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis

Enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are therapeutic targets for the treatment of important infectious diseases. Whereas this pathway is absent in humans, it is used by plants, many eubacteria and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis. Herein, we report on the design, preparation and biological evaluation of a new series of ligands for IspE protein, a kinase from this pathway. These inhibitors were developed for the inhibition of IspE from Escherichia coli, using structure-based design approaches. Structure-activity relationships (SARs) and a co-crystal structure of Aquifex aeolicus IspE bound to a representative inhibitor validate the proposed binding mode. The crystal structure shows that the ligand binds in the substrate-rather than the adenosine 5'-triphosphate (ATP)-binding pocket. As predicted, a cyclopropyl substituent occupies a small cavity not used by the substrate. The optimal volume occupancy of this cavity is explored in detail. In the co-crystal structure, a diphosphate anion binds to the Gly-rich loop, which normally accepts the triphosphate moiety of ATP. This structure provides useful insights for future structure-based developments of inhibitors for the parasite enzymes.     

Thermal oxidation of oxynitride perovskites in different atmospheres

Oxynitride perovskites with bright and variable colour have the potential to be employed as non-toxic pigments, and to substitute colourants that contain harmful heavy metals. For this application it is extremely important to have a precise knowledge about the materials stability. The thermal stability of oxynitride perovskites in different atmospheres was measured by thermogravimetry in combination with mass spectroscopy (MS). The studied compounds, namely LaTiO₂N, SrNbO₂N and SrTaO₂N, were heated up to 1200 °C in argon–oxygen mixtures with varying oxygen contents. It was found that the thermal behaviour of the studied oxynitrides changes drastically with the oxygen concentration. When heated up in pure argon the oxynitrides transform to oxides containing transition metals of lower oxidation state and/or binary nitrides. For oxygen contents between 0.5% and 20% the samples were completely oxidised. The oxidation rate increases with oxygen content. MS analysis of the gaseous products (including N₂, NO and NO₂) reveals a complex reaction mechanism, which is strongly modified by the composition of the atmosphere.     

New carbon materials: biological applications of functionalized nanodiamond materials

Nanoscale diamond particles have become an interesting material. Due to their inertness, small size and surface structure, they are well-suited for biological applications, such as labelling and drug delivery. Here we discuss the surface structure and functionalisation of diamond nanoparticles. Non-covalent as well as covalent grafting of bioactive moieties is possible, and first applications of fluorescent diamond nanoparticles are described.     

Hydroaminomethylation with novel rhodium-carbene complexes: an efficient catalytic approach to pharmaceuticals

Starting from [{Rh(cod)Cl}(2)] and 1,3-dimesitylimidazole-2-ylidenes the novel [RhCl(cod)(carbene)] complexes 1-5 have been synthesized, characterized, and tested in the hydroaminomethylation of aromatic olefins. The influence of different ligands and reaction parameters on the catalytic activity was investigated in detail applying 1,1-diphenylethylene and piperidine as a model system. The scope and limitations of the novel catalysts is shown in the preparation of 16 biologically active 1-amino-3,3-diarylpropenes. In general, high chemo- and regioselectivity as well as good yields of the desired products were achieved.     

Sound Insulation of Porous Plates

Because of the still increasing noise pollution the numerical simulation of acoustic problems becomes more and more important. One essential aspect is the numerical treatment of noise insulation of solid walls. The main noise source is the bending vibration of separating components. In general, they consist of porous material, e.g., concrete or bricks. To take into account the porous structure as well as the damping effect of the porosity of these components a poroelastic plate theory is developed. The Finite Element implementation of this plate theory shows the importance of taking porous materials into account. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Optically Active Cyclophane Receptors for Mono‐ and Disaccharides: The Role of Bidentate Ionic Hydrogen Bonding in Carbohydrate Recognition

A new family of optically active cyclophane receptors for the complexation of mono‐ and disaccharides in competitive protic solvent mixtures is described. Macrocycles (−)‐(R,R,R,R)‐ 1 – 4 feature preorganized binding cavities formed by four 1,1′‐binaphthalene‐2,2′‐diyl phosphate moieties bridged in the 3,3′‐positions by acetylenic or phenylacetylenic spacers. The four phosphodiester groups converge towards the binding cavity and provide efficient bidentate ionic H‐bond acceptor sites (Fig. 2). Benzyloxy groups in the 7,7′‐positions of the 1,1′‐binaphthalene moieties ensure solubility of the nanometer‐sized receptors and prevent undesirable aggregation. The construction of the macrocyclic framework of the four cyclophanes takes advantage of Pd⁰‐catalyzed aryl—acetylene cross‐coupling by the Sonogashira protocol, and oxidative acetylenic homo‐coupling methodology (Schemes 2 and 8 – 10). Several cleft‐type receptors featuring one 1,1′‐binaphthalene‐2,2′‐diyl phosphate moiety were also prepared (Schemes 1, 6, and 7). An undesired side reaction encountered during the synthesis of the target compounds was the formation of naptho[b]furan rings from 3‐ethynylnaphthalene‐2‐ol derivatives, proceeding via 5‐endo‐dig cyclization (Schemes 3 – 5). Computer‐assisted molecular modeling indicated that the macrocycles prefer nonplanar puckered, cyclobutane‐type conformations (Figs. 7 and 8). According to these calculations, receptor (−)‐(R,R,R,R)‐ 1 has, on average, a square binding site, which is complementary in size to one monosaccharide. The three other cyclophanes (−)‐(R,R,R,R)‐ 2 – 4 feature, on average, wider rectangular cavities, providing a good fit to one disaccharide, while being too large for the complexation of one monosaccharide. This substrate selectivity was fully confirmed in ¹H‐NMR binding titrations. The chiroptical properties of the cyclophanes and their nonmacrocyclic precursors were investigated by circular dichroism (CD) spectroscopy. The CD spectra of the acyclic precursors showed a large dependence from the number of 1,1′‐binaphthalene moieties (Fig. 9), and those of the cyclophanes were remarkably influenced by the nature of the functional groups lining the macrocyclic cavity (Fig. 11). Profound differences were also observed between the CD spectra of linear and macrocyclic tetrakis(1,1′‐binaphthalene) scaffolds, which feature very different molecular shapes (Fig. 10). In ¹H‐NMR binding titrations with mono‐ and disaccharides (Fig. 13), concentration ranges were chosen to favor 1 : 1 host−guest binding. This stoichiometry was experimentally established by the curve‐fitting analysis of the titration data and by Job plots. The titration data demonstrate conclusively that the strength of carbohydrate recognition is enhanced with an increasing number of bidentate ionic host−guest H‐bonds (Table 1) in the complex formed. As a result of the formation of these highly stable H‐bonds, carbohydrate complexation in competitive protic solvent mixtures becomes more favorable. Thus, cleft‐type receptors (−)‐(R)‐ 7 and (−)‐(R)‐ 38 with one phosphodiester moiety form weak 1 : 1 complexes only in CD₃CN. In contrast, macrocycle (−)‐(R,R,R,R)‐ 1 with four phosphodiester groups undergoes stable inclusion complexation with monosaccharides in CD₃CN containing 2% CD₃OD. With their larger number of H‐bonding sites, disaccharide substrates bind even more strongly to the four phosphodiester groups lining the cavity of (−)‐(R,R,R,R)‐ 2 and complexation becomes efficient in CD₃CN containing 12% CD₃OD. Finally, the introduction of two additional methyl ester residues further enhances the receptor capacity of (−)‐(R,R,R,R)‐ 3 , and efficient disaccharide complexation occurs already in CD₃CN containing 20% CD₃OD.     

Tetrakis(phenylamidinium)‐Substituted Resorcin[4]arene Receptors for the Complexation of Dicarboxylates and Phosphates in Protic Solvents

Three bowl‐type cavitand receptors ( 1 – 3 ), consisting of a resorcin[4]arene core with four convergent phenylamidinium groups, were prepared in gram quantities by efficient synthetic routes (Schemes 1 and 2) for the recognition of organic anions in CD₃OD and D₂O. The key steps in the syntheses are the Suzuki cross‐coupling reactions between the tetraiodo cavitands 12 , 13 , and 23 , respectively, with the m‐cyanophenylboronic ester 14 and subsequent conversion of the nitrile to amidinium groups by the Garigipati reaction. Compounds 1 and 2 displayed limited solubility in protic solvents, and evidence for stoichiometric host‐guest association between 2 and AMP ( 28 ) could only be obtained by FAB‐MS analysis of a complex precipitated from MeOH (Fig. 2). In contrast, receptor 3 with four triethyleneglycol monomethyl ether side chains was readily soluble in the protic environments, and complexation of isophthalates and nucleotides 25 – 37 was extensively studied by ¹H‐NMR titrations and Job's method of continuous variation. In CD₃OD and pure D₂O, isophthalates 25 and 26 formed stable 1 : 2 host‐guest complexes (Table 1 and Fig. 3), whereas upon addition of borate (pH 9.2) or Tris/HCl buffer (pH 8.3) to the D₂O solution, the tendency for higher‐order complexation vanishes. Stable 1 : 1 complexes formed in the buffered solutions (Fig. 4) with 5‐methoxyisophthalate being selectively bound over the 5‐NO₂ derivative. Complexation‐induced upfield shifts of specific isophthalate ¹H‐NMR resonances (Fig. 5) suggest a preferred inclusion of the methoxyphenyl ring into the receptor cavity. Cavitand 3 forms stable 1 : 1 host‐guest complexes with nucleotides in Tris/HCl‐buffered D₂O. Association constants increase strongly with increasing guest charge in the series cAMP<AMP<ADP<ATP (Table 2). Association strength is strongly reduced in the presence of high salt (NaCl) concentration (Table 3). Receptor 3 shows a slight preference for the complexation of AMP (Fig. 7) and analogs dAMP or ε‐AMP (Table 4) over nucleotides containing G (guanine), C (cytosine), T (thymine), or U (uracil) as bases. According to the ¹H‐NMR analysis, only the nucleobase adenine and derivatives thereof possess the necessary stereoelectronic complementarity for inclusion into the bowl‐type cavity. The major forces stabilizing the complexes of 3 with isophthalates and nucleotides result from ion pairing and ionic H‐bonding between the charged groups of host and guest, and from the desolvation of these groups upon complexation. Apolar interactions and hydrophobic desolvation do not seem to make a large contribution to the measured binding free enthalpies.