Search

Oxidative stress from the increase of reactive oxygen species in cells is a common part of the normal aging process and is accelerated in patients with Alzheimer's disease (AD). Herein, we report the evaluation of three benzothiazole amphiphiles (BAMs) that exhibit improved biocompatibility without loss of biological activity against amyloid-β induced cell damage compared to a previously reported hexa(ethylene glycol) derivative of benzothiazole aniline (BTA-EG6). The reduced toxicity of these BAM agents compared to BTA-EG6 corresponded with their reduced propensity to induce membrane lysis. In addition, all of the new BAMs were capable of protecting differentiated SH-SY5Y neuroblastoma cells from toxicity and concomitant oxidative stress induced by AD-related aggregated Aβ (1-42) peptides. Binding and microscopy studies support that these BAM agents target Aβ and inhibit the interactions of catalase with Aβ in cells, which, in turn, can account for an observed inhibition of Aβ-induced increases in hydrogen peroxide in cells treated with these compounds. These results support that this family of benzothiazole amphiphiles may have therapeutic potential for treating cellular damage associated with AD and other Aβ-related neurologic diseases.

The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Herein, we report the design and evaluation of a new class of benzothiazole amphiphiles that exhibit a dose-dependent response leading to an increase in dendritic spine density in primary hippocampal neurons. Cell exposure studies reveal that the increase in spine density can persist for days in the presence of these compounds, but returns to normal spine density levels within 24 h when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity. Time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Biochemical studies support that promotion of spine formation by these compounds is accompanied by Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism for dendritic spine loss induced by Alzheimer-related aggregated amyloid-β peptides in primary neurons. Evaluation of this new group of spinogenic agents reveals that they also exhibit relatively low toxicity at concentrations displaying activity. Collectively, these results suggest that small molecules that promote spine formation could be potentially useful for ameliorating cognitive deficiencies associated with spine loss in neurodegenerative diseases such as Alzheimer disease, and may also find use as general cognitive enhancers.

Abstract: Eniminiumionen, die aus den entsprechenden Carbonylverbindungen (Enonen und Enalen) hergestellt wurden, konnten durch Energietransfer in ihren Triplett‐Zustand angeregt werden. Die Intermediate unterzogen sich bei einer Anregungswellenlänge von λ=433 nm oder λ=457 nm in guten Ausbeuten (50–78 %) einer intra‐ oder intermolekularen [2+2]‐Photocycloaddition. Für die Reaktion wurden Iridium‐ oder Rutheniumkatalysatoren (2.5 Mol‐%) mit einer ausreichend hohen Triplett‐Energie verwendet. Ausgehend von einem chiralen sekundären Amin wurde ein Eniminiumion synthetisiert, das mit hoher Enantioselektivität (88 % ee) in einer intermolekularen [2+2]‐Photocycloaddition umgesetzt werden konnte. [ABSTRACT FROM AUTHOR]

Here we present a structural design aimed at the control of phosphorescence emission as the result of changes in molecular rotation in a crystalline material. The proposed strategy includes the use of aurophilic interactions, both as a crystal engineering tool and as a sensitive emission probe, and the use of a dumbbell-shaped architecture intended to create a low packing density region that permits the rotation of a central phenylene. Molecular rotor 1, with a central 1,4-diethynylphenylene rotator linked to two gold(I) triphenylphosphane complexes, was prepared and its structure confirmed by single-crystal X-ray diffraction, which revealed chains mediated by dimeric aurophilic interactions. We showed that green-emitting crystals exhibit reversible luminescent color changes between 298 and 193 K, which correlate with changes in rotational motion determined by variable-temperature solid-state ²H NMR spin-echo experiments. Fast two-fold rotation with a frequency of ca. 4.00 MHz (τ = 0.25 μs) at 298 K becomes essentially static below 193 K as emission steadily changes from green to yellow in this temperature interval. A correlation between phosphorescence lifetimes and rotational frequencies is interpreted in terms of conformational changes arising from rotation of the central phenylene, which causes a change in electronic communication between the gold-linked rotors, as suggested by DFT studies. These results and control experiments with analogue 2, possessing a hindered tetramethylphenylene that is unable to rotate in the crystal, suggest that the molecular rotation can be a useful tool for controlling luminescence in the crystalline state. [ABSTRACT FROM AUTHOR]

The stereospecific photochemistry of ten N-aryl-substituted cis- or trans-Δ2-1,2,3-triazolines to form the corresponding cis- or trans-aziridines was investigated both in solution and in the solid-state. We found that photochemical reactions in the solid state are more stereospecific than in solution for the 8 crystalline Δ2-1,2,3-triazolines. Additionally, triplet sensitization for some triazolines results in triplet biradicals, which provide the more thermodynamically favored trans-aziridine regardless of the starting triazoline stereochemistry. Product analyses as a function of temperature and solvent polarity suggest that the electronic excitation of the Δ2-1,2,3-triazolines results in the formation of a 1,3-biradical intermediate. [ABSTRACT FROM AUTHOR]

Safety culture is often divided into three domains, which include personal, environmental, and behavioral factors. In order to improve the behavioral components of the safety culture in the research group of the authors (the Garcia-Garibay group, or GG research group), we implemented three safety practices intended to sensitize group members on the importance of best practices that depend on simple actions taken by individual researchers. These best practices include (1) a rotating twice-daily safety inspection to enhance an appreciation for the value of safety regulations that may be considered less significant and are frequently overlooked, (2) frequent safety discussions followed by quizzes to give researchers an opportunity to assess their safety knowledge on a range of topics, and (3) the use of an overnight reaction form that is posted on lab entryways as a safety communication best practice to ensure that other researchers in the laboratory and emergency responders are aware of the potential hazards associated with ongoing chemical reactions that do not require continual monitoring. To determine the impact of these measures we analyzed the UCLA Office of Environment, Health and Safety (EH&S) laboratory safety inspection records from the GG research group and compared the findings with those of all other experimental research groups in the Department of Chemistry and Biochemistry at UCLA from the period of 2011 to 2013. We propose that in the absence of any other (either punitive or rewarding) actions, an accelerated improvement in the reduction of the number of inspection findings in the GG research group can be associated with behavioral components of a safety culture addressed by those measures. [ABSTRACT FROM AUTHOR]