Broadening the Toolbox in Drug Development and Analysis - Pharmaceutical Technology

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Broadening the Toolbox in Drug Development and Analysis
Some recent advances involve strategies for accelerating reaction discovery, approaches for inducing chirality and stereochemical analysis, and applications in nanotechnology for protein elucidation.

Pharmaceutical Technology
Volume 36, Issue 1, pp. 52-56

Chiral chemistry

Inducing chirality. Researchers at Case Western Reserve University developed a "top-down" approach to introduce chirality into a nonchiral molecule by using a macroscopic blunt force to impose and induce chirality. "The key is that we used a macroscopic force to create chirality down to the molecular level," said Charles Rosenblatt, professor of physics at Case Western Reserve University in Cleveland, Ohio, in a December 2011, press release and senior author of a recent paper on the research (3).

Formulation development forum: nanosized dendrimers
Specifically, the researchers imposed a macroscopic helical twist on an achiral nematic liquid crystal by controlling the azimuthal alignment directions at the two substrates (3). On application of an electric field, the director rotates in the substrate plane. This electroclinic effect, which requires the presence of chirality, is strongest at the two substrates and increases with increasing imposed twist distortion (3).

The researchers treated two glass slides so that cigar-shaped liquid crystal molecules would align along a particular direction. They then created a thin cell with the slides, but rotated the two alignment directions by approximately a 20-degree angle, according to the university release. The 20-degree difference caused the molecules' orientation to undergo a right-handed helical rotation, or a so-called imposed "chiral twist." Because of the higher energy needed to maintain the naturally left-handed molecules in the crystal, some of the left-handed molecules in the crystal became right-handed, with this shift being the induced chirality. To test for chirality, the researchers applied an electrical field perpendicular to the molecules. If there were no chirality, there would be nothing to see. If there were chirality, the helical twist would rotate in proportion to the amount of right-handed excess. The result was a model involving a trade-off among bulk elastic energy, surface anchoring energy, and deracemization entropy that suggested the large equilibrium director rotation induced a deracemization of chiral conformations in the molecules or "top-down" chiral induction (3).

Stereochemical analysis . Researchers at Carnegie Mellon University successfully used nuclear magnetic resonance (NMR) to analyze the stereochemical structure of gold nanoparticles, a potentially important advance in drug development. Determining a nanoparticle's chirality is a key step toward developing them as chiral catalysts.

The researchers reported on the chirality in gold nanoclusters by NMR spectroscopic probing of the surface ligands. The Au38 (SR)24 and Au25 (SR)18 (where, R = CH2CH2Ph) were used as representative models for chiral and nonchiral nanoclusters, respectively (4). The researchers compared the NMR signal from the hydrogen atoms in the nonchiral gold nanoparticle with the NMR signal from the hydrogen atoms in the chiral gold nanoparticle. The NMR method overcame the limitations of circular dichoism spectroscopy in determining the chirality of gold nanoparticles in a racemic mixture. The nanoparticles' chiral core induced the methylene group's two hydrogen atoms to give off different frequencies, a phenomenon known as diastereotopicity.

The researchers compared the NMR signal from the hydrogen atoms in the nonchiral gold nanoparticle with the NMR signal from the hydrogen atoms in the chiral gold nanoparticle. The nonchiral nanoparticle's NMR spectrum did not reveal any differences, but the chiral nanoparticle's NMR spectrum revealed two different hydrogen signals, providing a simple and efficient way of telling whether the particle is chiral or not, even for a 50/50 mixture of isomers, according to a Dec. 7, 2011, Carnegie Mellon University release. The researchers concluded that NMR spectroscopy can be a useful tool for investigating chirality in gold nanoclusters. Since the diastereotopicity induced on the methylene protons by chiral nanoclusters is independent of the enantiomeric composition of the chiral particles, NMR can probe the chirality of the nanoclusters even in the case of a racemic mixture while circular dichroism spectroscopy is not useful for racemic mixtures (4).


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