Noteworthy Chemistry

February 11, 2013

Monitor β amyloid aggregation with an improved fluorescent probe. The ability to sensitively detect and quantify β amyloid (Aβ) fibrils and to screen amyloid inhibitors is important for diagnosis and therapy design. A research team led by X. Qu at the Chinese Academy of Sciences (Changchun) developed a cationic perylenetetracarboxylic acid derivative (1) and demonstrated that it can be used to discriminate between native and fibrillar forms of Aβ.

The authors’ assay is based on the change in fluorescence caused by the aggregation of 1. The compound is highly emissive in aqueous solution, but it becomes almost nonfluorescent in the aggregated state. Solutions of compound 1 fluoresce in the presence of native Aβ, but the fluorescence is quenched gradually as the protein forms aggregates. This phenomenon allows Aβ fibril formation to be monitored kinetically and can be used to screen Aβ inhibitors.

Compound 1 is more sensitive to Aβ oligomers than conventional Aβ fluorescence probes such as thioflavin T, making it a promising tool for diagnosing neurodegenerative pathogenesis such as Alzheimer’s disease. (Small 2013, 9, 52–55; Ben Zhong Tang)

Calculate the hydrazoic acid concentration in reactor headspace. During the development of a first-generation allylic azide displacement reaction with Me3SiN3, F. GonzÁlez-Bobes, N. Kopp, and co-workers at Bristol-Myers Squibb (New Brunswick, NJ) developed a process control strategy based on assessing the vapor–liquid equilibrium in the reactor headspace. They used a previously published figure for the Henry’s law constant for the partition coefficients of hydrazoic acid (HN3) between the aqueous and gaseous phases.

The Henry’s law constant can be adjusted for pH and temperature. To maintain the vapor concentrations of HN3 below the US National Institute for Occupational Safety and Health’s threshold limit value of 0.1 ppm, it is necessary to operate at low azide ion concentrations or in high-pH media. (Org. Process Res. Dev. 2012, 16, 2051–2057; Will Watson)

A macrocyclic azo compound has multichromic properties. The photoswitchable azobenzene scaffold has been incorporated in many functional molecules, systems, and materials. L. Schweighauser and H. A. Wegner* at the University of Basel (Switzerland) found a way to use the azobenzene moiety for more sophisticated switching functions. They synthesized a cyclotetraazocarbazole derivative that has photo-, temperature-, and pH-dependent chromic properties.

The authors began the synthesis with unsubstituted carbazole (1). Alkylating the molecule with a solubilizing dodecyl group and regioselectively adding two nitro groups produced intermediate 2 in 63% yield. Reductively coupling 2 with LiAlH4 in THF gave <1% cyclotetramer 3; linear polymerization was the more favorable reaction.

When the authors irradiated a CHCl3 solution of 3 with UV light for 20 min, the azo groups photodegraded, causing the solution to gradually change from yellow to dark green and eventually to colorless. A similar change occurred with linear dimer 4, but fragment 5 did not undergo a visible color change. No color change occurred in nonchlorinated solvents such as THF. The authors believe that electron transfer from singlet excited carbazole to CHCl3 causes photochromism in 3.

Azo compounds 3 and 4 reversibly change color when acid or base is added. The color can be further modulated by adjusting the solution temperature; this process is reversible for at least 10 heating–cooling cycles.

The authors used the multichromic characteristics of 3 and 4 to design a molecular logic gate with absorption at 570 nm as the output. The three inputs, UV irradiation, acidity, and temperature translate to the logical function (UV OR H+) AND (NOT temp). (Chem. Commun. 2013, 49, Advance Article DOI: 10.1039/C2CC37956B; Xin Su)

Use tetrafluoroboric acid to fluorinate β-keto esters. Many synthetic bioactive compounds, such as pharmaceuticals and agrochemicals, contain fluorine atoms. Most methods for introducing fluorine rely on electrophilic reagents derived from molecular fluorine. C. J. Moody and co-workers at the University of Nottingham (UK) developed a nucleophilic fluorination of β-keto ester derivatives that uses readily available HBF4.

The key to the authors’ method is using a reactive electrophilic substrate to overcome the inertness of the nucleophilic BF4 anion. The authors chose easily accessible diazo carbonyl compounds. Treating the diazo carbonyl with inorganic fluorides in the presence of rhodium or copper catalysts does not give fluorinated β-keto esters. But acid-mediated processes that use HF–pyridine, BF3·Et2O, or HBF4·Et2O form the desired products.

Using HF–pyridine results in a Wolff rearrangement side reaction, and BF3·Et2O gives only moderate yields. HBF4·Et2O is the best fluorination reagent; it can be regarded as a combination of Brønsted acids BF3 and HF. To ensure safety, the reaction is run at room temperature or under flow conditions with short residence times. The yields are comparable: 82–84% when the R substituent is phenyl.

The authors expanded the reaction to heteroaryl and alkyl β-keto esters. In the latter case, however, β,β-difluoro-α-hydroxy ester byproducts were detected. Fluorinated β-keto esters can be made into 3-fluorocoumarins, 4-fluoropyrazoles, and 5-fluoropyrimidin-4-ols—all “privileged” structures in medicinal chemistry. (Chem. Commun. 2012, 48, 12077–12079; José C. Barros)

Make robust, low-permeability bionanocomposites. L. A. Berglund and colleagues at the Royal Institute of Technology (Stockholm) developed a route to mechanically robust, high-barrier xyloglucan biopolymer–montmorillonite clay nanocomposites. They used the strong adsorption of water-soluble xyloglucan onto as much as 20 wt% montmorillonite to create a nacre-like arrangement in the composites.

Forming the xyloglucan–montmorillonite composites via solvent casting produces platelets that are highly oriented (74%) in the in-plane direction. The dispersed montmorillonite is exfoliated at low filler content (1–2.5 wt%); it is intercalated at higher weight fractions. This bioinspired strategy produces high–tensile strength, high-modulus materials with relatively low montmorillonite content because of effective stress transfer (mediated by strong interfacial adhesion) and dispersion.

The transparent nanocomposites also exhibit high thermal stability and reduced oxygen permeability, which are key properties for potential applications in barrier packaging and durable coatings. (Biomacromolecules 2013, 14, 84–91; LaShanda Korley)

This molecule may lead to treatments for a variety of cancers. When the myeloid cell leukemia 1 (Mcl-1) protein is overexpressed, it allows cancer cells to avoid programmed cell death (apoptosis) and proliferate out of control. This amplification of Mcl-1 is the most common aberration seen in human cancers. Inhibiting the protein could lead to treatments for a variety of cancers, but no effective Mcl-1 inhibitors have been discovered.

S. W. Fesik and colleagues at Vanderbilt University School of Medicine (Nashville) tackled this challenge by using a combination of fragment-based methods and structured-based design. Screening a large fragment library identified two series of hits (1 and 2).

After optimization, compound 3 had the best properties from series 1, and compound 4 was the best from series 2. The researchers used structure–activity relationship studies to merge 3 and 4 into a new molecule that conserved properties needed to inhibit Mcl-1. The studies resulted in compound 5, which is >2 orders of magnitude more potent than 3 or 4.

Additional optimization is needed, but compound 5 is a promising starting point for finding cancer treatments. (J. Med. Chem. 2013, 56, 15–30; Chaya Pooput)

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