Mapping the binding site topology of amyloid protein aggregates using multivalent ligands

A key process in the development of neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases is the aggregation of proteins to produce fibrillary aggregates with a cross β-sheet structure, amyloid. The development of reagents that can bind these aggregates with high affinity and selectivity has potential for early disease diagnosis. By linking two benzothiazole aniline (BTA) head groups with different length polyethylene glycol (PEG) spacers, fluorescent probes that bind amyloid fibrils with low nanomolar affinity have been obtained. Dissociation constants measured for interaction with Aβ, α-synuclein and tau fibrils show that the length of the linker determines binding affinity and selectivity. These compounds were successfully used to image α-synuclein aggregates in vitro and in the post-mortem brain tissue of patients with Parkinson''s disease. The results demonstrate that multivalent ligands offer a powerful approach to obtain high affinity, selective reagents to bind the fibrillary aggregates that form in neurodegenerative disease.

Multivalent ligands offer a powerful approach to obtain high affinity reagents to bind the aggregates that form in neurodegenerative disease. Selectivity for different proteins was achieved by using different linkers to connect the head groups.     

Arylzinc alkoxides: [ArZnOCHPr(i)2]2 and Ar2Zn3(OCHPr(i)2)4 when Ar = C6H5, p-CF3C6H4, 2,4,6-Me3C6H2, and C6F5

From the reactions between diarylzinc compounds (Ar2Zn) and the alcohol (Pr(i)2CHOH) in toluene, the compounds [ArZn(OCHPr(i)2)]2 (Ar = C6H5, C6F5, p-CF3C6H4, and 2,4,6-Me3C6H2) have been isolated and shown to exist in equilibra with the trinuclear complexes Ar2Zn3(OCHPr(i)2)4 and Ar2Zn when Ar = C6H5, C6F5, and p-CF3C6H4. The trinuclear complexes have also been prepared from reactions of the Ar2Zn compounds with the alcohol, which reveals that the ease of Zn-C(aryl) bond cleavage is sensitive to the nature of the Ar group: C6H5 > 4-CF3C6H4 > C6F5. The molecular structures of Ar2Zn3(OCHPr(i)2)4 where Ar = p-CF3C6H4 and C6F5 and [ArZn(OCHPr(i)2)]2 where Ar = C6F5, p-CF3C6H4, and 2,4,6-Me3C6H2 are reported based on single-crystal X-ray diffraction studies. The X-ray structure of Zn(p-CF3C6H4)2 is also reported. The reactivity of these new compounds toward the polymerization of propylene oxide (PO) and the copolymerization of PO and CO2 have been investigated along with related reactions involving the partial hydrolysis of the Ar2Zn and R2Zn compounds, where R = t-Bu, n-Bu, and n-Oct. These results are compared with the previous studies employing Et2Zn as an organozinc precursor.     

Oxalate-bridged dinuclear M2 units: dimers of dimers, cyclotetramers, and extended sheets (m = Mo, W, Tc, Ru, and Rh)

The electronic structures of D(4h)-M(2)(O(2)CH)(4) and the oxalate-bridged complexes D(2h)-[(HCO(2))(3)M(2)](2)(mu-O(2)CCO(2)) and D(4h)-[(HCO(2))(2)M(2)](4)(mu-O(2)CCO(2))(4) have been investigated by a symmetry analysis of their MM and oxalate-based frontier orbitals, as well as by electronic structure calculations on the model formate complexes (M = Mo and W {d(4)-d(4)}, Tc, Ru {d(6)-d(6)}, and Rh {d(7)-d(7)}). Significant changes in the ordering, interactions, and electronic occupation of the molecular orbitals (MOs) arise through both the progression from d(4) to d(7) metals and the change from second to third row transition metals. For M = Mo and W, the highest-occupied orbitals are delta based, while the lowest-unoccupied orbitals are oxalate pi based; for M = Tc, the highest-occupied orbitals are an energetically tight delta-based set of MOs, while the lowest-unoccupied orbitals are MM-based pi. For both Ru and Rh, the highest-occupied MOs are the MM pi* and delta*, respectively, while the lowest-unoccupied MOs, in both instances, are MM-based sigma. With the exception of M = Ru, all of the complexes are closed shell. From the progression M(2) --> [M(2)](2) --> [M(2)](4), we can envision the nature of bandlike structures for a 2-dimensional square grid of formula [M(2)(mu-O(2)CCO(2))](infinity). Only for Mo and W oxalates should good electronic communication between MM centers generate a band of significant width to lead to metallic conductivity upon oxidation.     

Synthetic Diphenylacetylene-Based Retinoids Induce DNA Damage in Chinese Hamster Ovary Cells without Altering Viability

All-trans-retinoic acid (ATRA), the active metabolite of vitamin A, plays a pivotal role in cell differentiation, proliferation and embryonic development. It is an effective therapy for dermatological disorders and malignancies. ATRA is prone to isomerization and oxidation, which can affect its activity and selectivity. Novel diphenylacetylene-based ATRA analogues with increased stability can help to overcome these problems and may offer significant potential as therapeutics for a variety of cancers and neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we investigated the effects of these retinoids on cell viability and genotoxicity in the widely used model system of the rapidly proliferating Chinese hamster ovary cell line. DC360 is a fluorescent ATRA analogue and DC324 is a non-active derivative of DC360. EC23, DC525, DC540, DC645, and DC712 are promising analogues with increased bioactivity. The cytotoxic activity of the compounds was evaluated by ATP assay and DNA damage was tested by comet assay. No cytotoxicity was observed in the 10⁻⁶–10⁻⁵ M concentration range. All compounds induced DNA migration similar to ATRA, but DC324, DC360 and EC23 did so to a greater extent, particularly at higher concentrations. We believe that retinoid receptor-independent genotoxicity is a general characteristic of these compounds; however, further studies are needed to identify the molecular mechanisms and understand their complex biological functions.     

3,6-dioxypyridazine bridged tungsten-tungsten quadruple bonds. Comparisons of electron delocalisation with oxalate bridged compounds

The preparation and characterisation of the tungsten-tungsten quadruply bonded, 3,6-dioxypyridazine bridged complex [((t)BuCO(2))(3)W(2)](2)([micro sign]-H(2)C(4)N(2)O(2)) and its single electron oxidised radical cation are reported and, when compared with related bridged dimolybdenum complexes, reveal a different mechanism of electronic coupling from that seen in related oxalate bridged systems.     

Phospholipid lung surfactant and nanoparticle surface toxicity: Lessons from diesel soots and silicate dusts

Because of their small size, the specific surface areas of nanoparticulate materials (NP), described as particles having at least one dimension smaller than 100 nm, can be large compared with micrometer-sized respirable particles. This high specific surface area or nanostructural surface properties may affect NP toxicity in comparison with micrometer-sized respirable particles of the same overall composition. Respirable particles depositing on the deep lung surfaces of the respiratory bronchioles or alveoli will contact pulmonary surfactants in the surface hypophase. Diesel exhaust ultrafine particles and respirable silicate micrometer-sized insoluble particles can adsorb components of that surfactant onto the particle surfaces, conditioning the particles surfaces and affecting their in vitro expression of cytotoxicity or genotoxicity. Those effects can be particle surface composition-specific. Effects of particle surface conditioning by a primary component of phospholipid pulmonary surfactant, diacyl phosphatidyl choline, are reviewed for in vitro expression of genotoxicity by diesel exhaust particles and of cytotoxicity by respirable quartz and aluminosilicate kaolin clay particles. Those effects suggest methods and cautions for assaying and interpreting NP properties and biological activities.     

The σ2π4 Triple Bond between Molybdenum and Tungsten Atoms: Developing the Chemistry of an Inorganic Functional Group

Numerous analogies between organic and inorganic chemistry have emerged in recent years. The most prominent example is the isolobal relationship. Many reactions have shown that metal-metal double and triple bonds exhibit a pattern of reactivity similar to that of alkenes and alkynes. In compounds containing a σ²π⁴ triple bond between molybdenum and tungsten atoms, the M? M bond order can be increased from three to four by reductive elimination or decreased from three to two or one by oxidative addition. Complexes with M?M bonds can be used to prepare clusters or can serve as catalysts. In this review relationships between structure (electronic and stereochemical) and reactivity that are characteristic for modern inorganic chemistry are discussed.