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

在化学系化学合成项目的支持下，马奎特大学的约瑟夫·克拉克正在研究结合氚（和/或氘）原子标记的小分子的制备过程，以及表征和探测这些材料的互补分析技术。氚作为一种放射性示踪元素在生物和化学研究中被广泛使用，用这种稀有的氢同位素标记的分子在药物、农用化学品和其他重要物质的开发中很有用。这项资助的研究结果预计将允许以高精确度将氚（/氘）结合到小分子中，从而可以很好地控制所选择的氢同位素的数量和位置。随着克拉克博士和他的研究团队成员参与各种教育和推广活动，资助项目的更广泛影响延伸到社会积累的利益。在这些努力中，最重要的是一个全面的本科生职业发展和培训计划，该计划将本科生夏季研究经验与波多黎各凯伊大学和马凯特大学共同促进的合作制药业和学术研讨会结合起来。该计划旨在为学生提供关键培训，为他们在科学、技术、工程和数学（STEM）领域取得成功做好准备，并强调吸引传统上在科学领域代表性不足的群体的个人参与。氚是一种理想的示踪核素，因为它的半衰期足够长（12.3年），并且能够制备具有高比活性的氚化化合物，在化学和生物研究中有多种应用。例如，氚标记的小分子通常用于放射性配体结合测定，也用于候选药物的吸收、分布、代谢和排泄（ADME）研究。尽管含氚分子具有许多重要的作用，但将精确数量的氚选择性地掺入有机化合物的有效合成方法数量有限。此外，表征和量化氚化小分子的光谱技术，特别是由于同位素取代而具有手性的对映体同位素，要么不发达，要么目前不存在。为了解决第一个挑战，研究人员正在研究一系列铜催化的转移氚化和加氢氚化反应，这些反应允许将氚原子标记结合到各种类型的烯烃和炔底物中（包括：烯、1,3-二烯和炔）。目前还在发展这些转化的对映选择性变体，以便获得由于氚取代和/或氘和氚取代而具有手性的对映同位素。为了支持反应发展，并针对上述第二个挑战，正在建立分子旋转共振光谱学，作为一种一般分析技术，以量化对映体同位素物质的过量对映体，并确定它们的绝对构型。预计这项研究的结果将扩大选择性氚化小分子作为理解生物系统中代谢物和/或药物制剂如何加工的有用工具的途径。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.