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·克拉克正在研究制备小分子的过程，这些小分子包含氚（和/或氘）原子标记和补充分析技术，以表征和探测这些材料。氚被广泛用作生物和化学研究中的放射性示踪元素，用这种稀有的氢同位素标记的分子在药物，农用化学品和其他种类的重要物质的开发过程中是有用的。预计资助研究的结果将允许以高精度将氚（/氘）掺入小分子中，从而可以精细地控制所选氢同位素的数量和位置。资助项目的更广泛的影响延伸到社会的好处，因为克拉克博士和他的研究团队成员从事各种教育和推广活动。这些努力中最重要的是一个整体的本科生职业发展和培训计划，该计划将本科生暑期研究经验与波多黎各卡伊大学和马奎特大学共同促进的制药业和学术研讨会相结合。该计划旨在为学生提供关键的培训，为他们在科学，技术，工程，氚是一种理想的示踪核素，因为它有足够长的半衰期，所以它是一种理想的示踪核素（12.3年），并有能力为化学和生物研究中的各种应用制备具有高比活度的氚化化合物。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。尽管含氚分子有许多重要的作用，但将精确量的氚选择性地掺入有机化合物中的有效合成方法数量有限。此外，表征和定量氚化小分子，特别是通过同位素取代而手性的对映体同位素异构体的光谱技术要么不发达，要么目前不存在。为了解决第一个挑战，一套铜催化的转移氚化和氢化反应正在研究中，允许区域和立体控制的氚原子标签纳入各种类型的烯烃和炔烃底物（包括：联烯，1，3-二烯，和烯炔）。这些转化的对映选择性变体的开发也在进行中，以允许获得凭借氚取代和/或凭借氘和氚取代而手性的对映同位素异构体。为了支持反应的发展，并在上面确定的第二个挑战，分子旋转共振（MRR）光谱被建立作为一种通用的分析技术，以量化对映体过量的对映体同位素物质，并确定其绝对构型。预计这项研究的结果将扩大选择性氚化小分子作为了解代谢物和/或药物制剂在生物系统中如何处理的有用工具的使用范围。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.