CAREER: Reaction Development and Advancing Spectroscopic Analysis for Selective Labeling and Radiolabeling of Small Molecules

About This Grant

With support of the Chemical Synthesis Program in the Division of Chemistry, Joseph Clark of Marquette University is studying processes for the preparation of small molecules incorporating tritium (and/or deuterium) atomic labels and complementary analytical techniques to characterize and probe these materials. Tritium is widely used as a radioactive tracer element in biological and chemical research and molecules labeled with this rare isotope of hydrogen are useful during the development of pharmaceuticals, agrochemicals, and other kinds of important substances. The findings of the funded research are anticipated to permit the incorporation of tritium (/deuterium) into small molecules with a high level of precision, such that the quantity and location of the hydrogen isotope of choice can be finely controlled. The broader impacts of the funded project extend to the benefits accrued to society as Dr. Clark and his research team members engage in a variety of educational and outreach activities. Foremost among these efforts is a holistic undergraduate career development and training program that combines undergraduate summer research experiences with a collaborative pharmaceutical industry and academic workshop jointly facilitated by the University of Puerto Rico Cayey and Marquette University. The program is designed to provide students with critical training to prepare them for successful careers in science, technology, engineering, and mathematics (STEM) and it places an emphasis on attracting participation from individuals belonging to groups traditionally underrepresented in science. Tritium is an ideal tracer nuclide because of its sufficiently long half-life (12.3 years) and the ability to prepare tritiated compounds with high specific activity for a variety of applications in chemical and biological research. For example, tritium-labeled small molecules are often used in radioligand binding assays and also for absorption, distribution, metabolism, and excretion (ADME) studies of drug candidates. Despite the many important roles for tritium-containing molecules, there are a limited number of effective synthetic methods for the selective incorporation of precise quantities of tritium into organic compounds. Furthermore, spectroscopic techniques to characterize and quantify tritiated small molecules, especially enantioisotopomers that are chiral by virtue of isotopic substitution, are either underdeveloped or do not currently exist. To address the first challenge, a suite of copper-catalyzed transfer tritiation and hydrotritiation reactions are being investigated that permit the regio- and stereo-controlled incorporation of tritium-atom labels into various types of alkene and alkyne substrates (including: allenes, 1,3-dienes, and enynes). The development of enantioselective variants of these transformations is also being pursued to allow for access to enantioisotopomers that are chiral by virtue of tritium substitution and/or by virtue of deuterium and tritium substitution. To support reaction development, and in regard to the second challenge identified above, molecular rotational resonance (MRR) spectroscopy is being established as a general analytical technique to quantify enantiomeric excess of enantioisotopomeric materials and to determine their absolute configurations. It is anticipated that the findings from this research will expand access to selectively tritiated small molecules as useful tools for understanding how metabolites and/or pharmaceutical agents are processed in biological systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.