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Deuterated, "heavy", pyridine adopts a different crystalline form to pyridine with a natural distribution of isotopes. The effect might be exploited in creating novel, more effective, versions of pharmaceutical products, according to researchers in Germany, as well as opening up studies into crystal morphology. In principle, molecules that contain deuterium in place of hydrogen atoms are chemically identical. Adding a single neutron to the nuclei of ordinary hydrogen atoms should not alter the chemistry of the atom. In practice, however, there are differences in reaction rates between molecules with natural isotopic distribution and their heavy counterparts. This can have serious physiological effects. For instance, drinking heavy water will disrupt highly sensitive biochemical processes in the body and lead to metabolic failure. Now, a research team jointly led by Roland Boese at the University of Duisburg-Essen, Germany, and Simon Parsons of The University of Edinburgh, Scotland, have reported in the journal Angewandte Chemie another significant effect associated with the superficially simple molecule, pyridine. Boese worked on this research with Parsons and colleagues, Michael Kirchner, Dieter Bläser, and Annette Gehrke together with Stephen Crawford, Alice Dawson, and William David, Richard Ibberson, and William Marshall, of the ISIS Facility, at the Rutherford Appleton Laboratory, in Didcot, England, and Osamu Yamamuro of the Neutron Science Laboratory, at the University of Tokyo, Japan. Predicting the behaviour of gas-phase molecules is relatively straightforward thanks to twentieth century advances in theory. Solids, on the other hand, are yet to succumb to the full predictive prowess of ab initio calculations. Even a small molecule as apparently simple as pyridine, C5H5N has an unusually complicated crystal structure. The researchers explain that four independent molecules sit in its asymmetric unit and ab initio crystal structure prediction methods suggest that there are more than a dozen energetically favourable crystal structures. Clues regarding the polymorphism of pyridine could be teased out through experiments with deuteration, however. The team has now found that swapping all five hydrogen atoms of the aromatic nitrogen-containing compound, pyridine, with deuterium atoms, will force it to adopt a crystal form at -85 Celsius that is only available under high pressure with "natural" pyridine. Parsons and his colleagues determined the high-pressure non-deuterated pyridine crystal structure in parallel. The researchers have made a comparison of the two structures, the differences in which, they say, imply that pyridine adopts the same structure under high pressure as that adopted by heavy pyridine because it occupies a smaller volume than the standard structure of pyridine. Fundamentally, replacing the hydrogen atoms with deuterium atoms changes the strength of interactions between individual groups of atoms in neighbouring molecules, which means that some arrangements in the crystal structure are energetically more favourable than others depending on conditions of temperature and pressure. The research team suggests that despite the switch from hydrogen to deuterium in such a molecule being so apparently insignificant could have a major impact on fine-tuning molecules of medicinal interest. It might, for instance, lead to a new approach to improving the spectrum of properties available to pharmaceutical agents. Boese explains that tweaking the way a molecule interacts with neighbouring molecules, such as the active site of an enzyme or protein receptor drug target could be exploited to tweak the properties of some pharmaceutical agents. The pyridine ring is a common motif in pharmaceuticals and so subtle changes in the degree of deuteration might be used to alter the drug's activity by changing how well it fits into and interacts with its target. Boese believes that deuteration could be used to generate the next generation of drug variants that are more specific in their activity and so potentially have fewer side effects than their lightweight counterparts precursors. "Isotopic substitution is the smallest possible modification of a molecule, yet this can yield polymorphs for systems which are otherwise monomorphic," the researchers explain. They emphasise that, "Such examples of isotopic polymorphism [as in the case of pyridine] under varying conditions of temperature and pressure will form particularly sensitive test cases when dynamics are introduced into crystal structure prediction methodologies." Related links:
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