Potent and selective structure-based dibenzofuran inhibitors of transthyretin amyloidogenesis: kinetic stabilization of the native state

Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation.     

Linker influence on the stereochemical outcome of glycosylations utilizing solid support-bound glycosyl phosphates

[reaction: see text] Glycosyl phosphates can be readily accessed on a solid support via a three-step procedure from support-bound glycals. These resin-bound glycosyl phosphates were successfully used as glycosylating agents for coupling with a series of nucleophiles. The stereochemical outcome of disaccharide formation was dependent on the nature of the linker connecting the saccharide to the polymer. Interestingly, other glycosyl donors such as thioglycosides and trichloroacetimidates did not exhibit such a dependence, indicating a different reaction mechanism for glycosylation.     

Application of ESCA to polymer chemistry. XVI. Electron mean free paths as a function of kinetic energy in polymeric films determined by means of ESCA

Electron mean free paths as a function of kinetic energy have been measured by the substrate overlayer technique for in situ-polymerized films of poly(p-xylylene) and the monochloro- and monobromo-substituted derivatives. The results are compared with previous estimates of mean free paths available in the literature for organic materials. Comparison is also drawn with corresponding experimental data for typical metals and semiconductors, and it is shown that organic polymers fit into a consistent picture which may be rationalized on the basis of existing theory. For electrons of kinetic energy ～969 eV, ～1170 eV, 1202 eV, and 1403 eV, mean free paths of ～14 Å, ～22 Å, ～23 Å, and ～29 Å, respectively, are obtained for the poly(p-xylylene) polymer films studied in this work.     

On the trapping of positrons in cadmium in the temperature range from 80 to 330 K

The positron lifetime was measured in cadmium in the temperature range between 80 K and 500 K. For the first time a plateau was observed by this method in polycrystalline samples. The obtained data are well explained by depletion of shallow traps forT180 K and by self-trapping in the prevacancy region.     

Spin precession of Po in Ni detected by In-beam conversion electrons and the magnetic moment of the 15− isomer in204Po

The magnetic moment of the 11 ns, 15^? isomer in²⁰⁴Po and the internal magnetic field of Po in Ni were determined in an in-beam recoil implantation experiment. Time-differential perturbed angular distributions of conversion electrons were measured in an iron-free orange spectrometer. The magnetic hyperfine field of ¦H(PoNi)¦=555(22) kOe is in agreement with the systematic trend for the 6p elements. Theg-factorg(15^?) =0.41(2) is discussed, together with theB (E2, 15^?→13^?). within the shell model.     

Zur Luminiszenz von Cr(3)-Verbindungen

Whereas 2.4 is likely to be an upper limit for theDq/B-value of Cr(3)-complexes which show fluorescence the existence of a lower bound is rather unlikely. Experimental evidence suggests that the energy difference between the minima of the² E _g- and the⁴ T _2g-potential curves is one of the factors determining the relative intensities of phosphorescence and fluorescence.     

Molecular structures of phosphorus compounds: Part IX. Gas-phase structure of 2,2-dimethylpropylidynephosphine, (CH3)3C-CP

The geometric structure of 2,2-dimethylpropylidynephosphine, (CH₃)₃C-CP, in the gas phase has been determined by joint analysis of electron diffraction and microwave spectroscopy data. The following parameters (r_av values) were obtained: PC₁ = 1.536(2), C₁-C₂ = 1.473(4),C₂-C₃ (methyl) = 1.543(2), C₃-H = 1.080(3) Å, ∠C₁-C₂-C₃ = 109.0(2) and ∠H-C₃H = 108.8(5)°. Error limits are 2σ values.     

Push-pull effects and emission from ternary complexes of platinum(II), substituted terpyridines, and the strong-field cyanide ion

As part of an effort to develop new lumaphors involving late transition metal ions, this report describes the synthesis and characterization of the first platinum(II) derivatives containing 2,2':6',2'-terpyridine (trpy) and cyanide as co-ligands. According to existing models, including cyanide in the coordination sphere should raise the energies and minimize the influence of short-lived d-d excited states that otherwise compromise the excited-state lifetime. Both [Pt(trpy)(CN)]+ and the 4'-cyano-2,2':6',2'-terpyridine analogue [Pt(CN-T)(CN)]+ are emissive in dichloromethane solution, but the signals are weak. Part of the problem is that the d-pi* charge-transfer excited states also rise in energy, so that the emission actually originates from a (3)pi-pi* state with a relatively low radiative rate constant. However, another member of the series, the 4'-dimethylamino-2,2':6',2'-terpyridine (dma-T) derivative [Pt(dma-T)(CN)]+, proves to be a very promising platform with an emission quantum yield of phi= 0.26 and an excited-state lifetime of tau = 22 micros in room-temperature, deoxygenated dichloromethane solution. In the dma-T complex the electron-rich dimethylamino substituent provides the basis for an emissive, but largely ligand-based, charge-transfer excited state. The orbital parentage is such that the photoluminescence persists in donating solvents like dimethylformamide, which ordinarily quenches d-pi* excited states in complexes of this type.