Noteworthy Chemistry

March 12, 2012

Virtual screening turns up a botulinum neurotoxin inhibitor. Botulinum neurotoxins (BoNTs) secreted by the bacterium Clostridium botulinum are among the most poisonous natural compounds. Of the seven neurotoxin serotypes, the most common are BoNT/A, BoNT/B, and BoNT/E. Nonpeptide inhibitors have been reported for serotypes A and B, but not for E. G. Kumar, R. Agarwal, and S. Swaminathan* at Brookhaven National Laboratory (Upton, NY) describe the first BoNT/E nonpeptide inhibitor.

The authors screened 1990 compounds, a diverse, representative set of 140,000 compounds in the NCI Compound Database that have the appropriate pharmacophore characteristics. They docked the compounds in the active site of BoNT/E with the help of AutoDock software. After this computational screening, they obtained 18 promising candidates and tested them against BoNT/E. Two compounds emerged from this analysis: one that contains two metal atoms—dismissed because of a lack of “drugability”—and another that contains the fluorene ring system (1).

Further testing of compound 1 showed that it has a low Ki value of 1.29 ± 0.26 μM. As suggested by molecular docking studies, this compound tends to occupy the S1’ and S2’ subsites of BoNT/E. The carbonyl group of the benzoic acid moiety coordinates with a zinc atom in the receptor, and the hydroxyl group interacts with a glutamic acid residue. The fluorene ring of the inhibitor is located in a hydrophobic pocket created by one phenylalanine and two tyrosine residues. The authors are developing a structure–activity relationship model for compound 1 and its derivatives. (Chem. Commun. 2012, 48, 2412–2414; JosÉ C. Barros)

Which protecting group should you use for a primary alcohol, and how should you attach it? S. T. Hayes and co-workers at Pfizer (Sandwich, UK) needed to selectively protect a primary alcohol in a chiral diol as part of a commercial route to (S,S)-reboxetine succinate, a candidate drug for fibromyalgia. They initially selected the trimethylsilyl group, but it gave poor regioselectivity, moderate yields, and a lack of robustness upon scale-up.

The authors screened several alternatives and identified acetate as a suitable alternative. Classical chemical acetylation also exhibited poor regioselectivity, but a biocatalytic acetylation gave excellent results. A commercially available immobilized enzyme, Novozyme 335 (Candida antarctica lipase B), was used as the biocatalyst and gave >98% regioselectivity and >99% yield in situ. The immobilized enzyme was filtered off, and the solution was used in the next step of the synthesis. The enzyme could be reused for several cycles without loss of activity. (Org. Process Res. Dev. 2011, 15, 1305–1314; Will Watson)

This ligand makes lithium hydride soluble in hydrocarbons. The use of LiH, the lightest metal hydride with 12.7% hydrogen content, as a hydrolithiation reagent is limited by its unusually high stability. Previous efforts to produce more active forms of LiH yielded mixed metal complexes, such as LiAlH4, and lithium alkoxide–LiH mixtures. The challenge is to prepare LiH-containing reagents compatible with hydrocarbon solvents.

A. Stasch at Monash University (Melbourne, Australia) prepared a LiH cluster compound (3) by using the phosphinoamine ligand DipNHPPh2 (1; Dip is 2,6-diisopropylphenyl). Treating 1 with 2 equiv n-BuLi forms intermediate complex [(DipNPPh2)2Li4-n-Bu2] (2) that is soluble in n-hexane. Using excess n-BuLi prevents the formation of insoluble oligomeric or polymeric complexes.

Intermediate 2 is treated with 2 equiv PhSiH3 to give [{(DipNPPh2)Li}4(LiH)4] (3) in crystalline form with an estimated yield of 90%. The authors used single-crystal X-ray diffraction to characterize 3 in the solid state as a Li8 cluster with a distorted cubic (LiH)4 center. The cluster unit has overall D2 symmetry, consistent with its solution state symmetry as confirmed by NMR studies.

Benzene- and toluene-soluble complex 3 is a promising hydrolithiation reagent, as shown by its reaction with benzophenone in benzene at room temperature. The authors isolated the product, [{(Ph2CHO)Li}6], in 88% yield on a 0.25-g scale. (Angew. Chem., Int. Ed. 2012, 51, 1930–1933; Xin Su)

Surfactants are promising supporting co-electrolytes in nonaqueous electropolymerization. Because conjugated polymers have limited solubility in conventional solvents, electropolymerization has advantages over chemical oxidation for directly depositing films onto surfaces. The electropolymerization of monomers with high oxidation potentials, however, frequently produces overoxidized (i.e., nonconjugated) polymer films with poor electrical conductivity.

H. T. Santoso and co-workers in the B. A. Cola laboratory at Georgia Tech (Atlanta) investigated the use of anionic surfactants as supporting electrolytes in a nonaqueous medium for polythiophene electropolymerization. They showed that sonication helps solubilize anionic surfactants in a BF3·Et2O electrolyte to increase the conductivity of the medium and lower the thiophene monomer’s oxidation potential.

The electrical conductivity of polythiophene films increases by as much as 300% when they are synthesized in the presence of anionic surfactants. This improvement is achieved without changing the modulus or the tensile strength of the films. The authors attribute this result to the dual role of surfactants as dopants and templates for molecular ordering.

This technique can be used to synthesize hybrid structures that combine conjugated polymers with carbon nanotubes. The surfactants stabilize the CNTs and act as a supporting soft-template electrolyte for polymer growth. The method may also be a potential strategy for developing anticorrosion coatings with high electrical conductivity on metal and alloy surfaces. (ACS Appl. Mater. Interfaces 2012, 4, Article ASAP DOI: 10.1021/am201823g; Gary A. Baker)

Iridium complexes show reversible piezochromic effects. Organoiridium complexes have high phosphorescence efficiency and optical stability. They are promising materials for high-tech applications such as organic light-emitting diodes, chemical sensors, and biological probes.

Piezochromism is an optical effect associated with a chromophore’s color change that is induced by applying mechanical force. Until now, it has been not observed in iridium-based phosphor systems. Z.-M. Su, Y. Liao, and coauthors at Northeast Normal University (Changchun, China) and Capital Normal University (Beijing) report an example of a piezochromic effect in cationic iridium salt systems.

Powders of phosphor 1 emit blue light when excited with UV radiation. Grinding it in a ceramic mortar changes the emission color to blue-green. A similar piezochromic effect is observed in phosphor 2: Its emission changes from green to yellow upon grinding.

The authors believe that the piezochromism stems from a mechanically induced crystalline-to-amorphous phase transformation. Heating the ground sample to an appropriate temperature fully recovers its original emission color. The phosphorescence can be switched by grinding and heating. (Chem. Commun. 2012, 48, 2000–2002; Ben Zhong Tang)

Use electrospun mats to tailor wound-healing. L.-M. Zhang and colleagues at Sun Yat-sen University (Guangzhou, China) and Guangdong Medical College (Dongguan, China) developed electrospun nanofibers made from the proteins collagen and zein for wound healing. They prepared a series of co-electrospun mats with various protein blend ratios from 70 vol% aq HOAc.

Incorporating zein improves the electrospinnability of collagen. Higher weight fractions of zein produce higher average fiber diameters, which give higher tensile strengths and lower extensibility, most likely because nanofiber stiffness also increases. Zein’s apolar nature results in a more hydrophobic surface with increasing zein fraction. The rate of electrospun mat degradation also decreases with higher zein content.

The authors show that balancing stiffness and wettability is necessary to achieve optimum cell attachment and viability. They encapsulated berberine, an antimicrobial drug, in the collagen–zein electrospun mat. The nanofibers remained smooth, and the effect on fiber diameter and antimicrobial efficacy was minimal. The rate and degree of wound-healing with co-electrospun 1:1 collagen–zein mats were improved over the cotton gauze control. (ACS Appl. Mater. Interfaces 2012, 4, 1050–1057; LaShanda Korley)

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