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Dr. Christian Wolf's Chemisty Research Advances Understanding of Chiral Compounds

By Megan Weintraub

When you look at your reflection in the mirror, you expect to see yourself as others do. This, however, is not possible. Instead, a mole on your left cheek will appear on the right side of the image while a right-hand part of your hair will actually show up on the left side. The same is true on the molecular level for many chemicals that exist in the form of mirror images, called enantiomers. This phenomenon is called chirality and it plays a major role throughout nature. While the enantiomers look almost perfectly identical, they can actually have quite different biological activities and pharmacological profiles. Chirality is often referred to as “handedness” because enantiomers behave like your right and left hand.

Dr. Christian Wolf, an associate professor in Georgetown’s Department of Chemistry, researches asymmetric synthesis and analysis of chiral compounds, stereodynamic properties of chiral compounds, transition metal catalysis, and drug discovery. Dr. Wolf is motivated to explore these research areas by the omnipresence in nature and general significance of molecular chirality. This field was highly influenced by the proliferation of Thalidomide, a chiral drug prescribed to pregnant women in Europe in the 1950s and 1960s to treat morning sickness.

While Thalidomide is effective at reducing morning sickness, it is also teratogenic, a term used to describe mechanisms that produce devastating birth defects. Roughly 8,000-12,000 babies born to mothers who took Thalidomide exhibited severe development abnormalities. After the drug was pulled from the shelves, scientists realized that it contained two enantiomers that demonstrate the phenomenon of “handedness”: one enantiomer indeed treats the morning sickness, while the other causes severe birth defects.

“Occasionally, we see that one enantiomer is transformed to the other one—its mirror image,” explains Dr. Wolf. “This chemical reaction, called interconversion of enantiomers, can take place inside or outside of the body. In the case of Thalidomide, a mixture of both enantiomers was prescribed to pregnant woman in Europe. One could argue that the birth defects could have been avoided if only the non-teratogenic enantiomer had been used. However, we know today that this is not the case because the enantiomers of Thalidomide rapidly interconvert under physiological conditions.”

Although the enantiomers of chiral drugs do not always have dramatically different effects, the Thalidomide tragedy clearly illustrates the significance of Dr. Wolf’s research. For example, a chiral drug could contain two non-toxic enantiomers with different levels of pharmaceutical efficacy. If the patient is exposed to the less effective enantiomer, he or she would require more of the drug to combat the same symptoms that a smaller dose of the “correct” enantiomer would have cured. For that reason, the synthesis of pure enantiomers is extremely important, and pharmaceutical makers now follow updated rules mandated by the U.S. Food and Drug Administration to develop drugs that contain only one enantiomer.

“If we produce a compound that is 99 percent of one enantiomer and 1 percent of another enantiomer, that’s not good enough,” explains Dr. Wolf. “That 1 percent could be devastating to the patient. We must make sure that we are aware of any enantiomeric impurities.”

Enantioselective analysis, the second area of Dr. Wolf’s research on chirality, is equally important and goes hand-in-hand with asymmetric synthesis. Dr. Wolf’s research group has therefore designed new sensors that can be used for fast and accurate detection of enantiomers.

“There is an ever-increasing demand for fast and accurate methods that allow one to determine the ratio of two enantiomers in an unknown mixture,” he says.

This work is particularly interesting to the pharmaceutical industry, because Dr. Wolf’s sensing methodology is suitable for high-throughput screening of the enantiomeric composition of many chiral drug candidates.

The third aspect of Dr. Wolf’s research on chirality focuses on stereodynamics, a subject about which he recently published a book, Dynamic Stereochemistry of Chiral Compounds. Stereodynamics is the change of the three-dimensional structure of chemicals over time. A profound understanding of the stereodynamic behavior of chiral compounds provides knowledge necessary to develop asymmetric reactions and to assess potential problems with chiral drugs, such as the interconversion of the enantiomers of Thalidomide.

“As scientists, we have a huge incentive to isolate these enantiomers and to make drugs that contain just the one we’re looking for,” remarks Dr. Wolf. “By studying interconversion processes, we hope to prevent another catastrophe like the Thalidomide case.”

Dr. Wolf’s important work with chiral compounds is somewhat metaphorical for his approach to research and teaching, which he views as “closely intertwined and synergistic.”

“We set up such artificial barriers within our scholarly work,” explains Dr. Wolf. “It’s important to be able to look past these to see the whole picture. For example, during discussions in class or in the laboratory, my students often ask excellent questions that nurture our research. The learning process definitely goes both ways and integrates teacher and student.”

Dr. Wolf moved into the academic setting at Georgetown from the pharmaceutical sector in 2000 in order to gain flexibility in the scope and independence of his research. During his time here, he has seen many improvements in the quality of resources and the level of support that the school has invested in the sciences, a direction he sees as truly promising.

“Georgetown is really setting the stage to become a leader in the sciences,” he explains. “We have always had excellent teachers; now the infrastructure is state-of-the art as well. It is very exciting to see how nicely we can engage our students in cutting-edge chemistry, thus providing a truly outstanding education that prepares them for their future careers.”

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