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

职业：反应开发和推进小分子选择性标记和放射性标记的光谱分析

• 批准号: 2237610
• 负责人: Joseph Clark
• 金额: $ 65万
• 依托单位: Marquette University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2237610&HistoricalAwards=false
• 关键词: CAREER; Reaction; Development; Advancing; Spectroscopic

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.

在化学系化学合成项目的支持下，马凯特大学的 Joseph Clark 正在研究掺有氚（和/或氘）原子标记的小分子的制备工艺以及用于表征和探测这些材料的补充分析技术。氚在生物和化学研究中广泛用作放射性示踪元素，用这种稀有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过程中非常有用。预计该资助研究的结果将允许将氚（/氘）高精度地掺入小分子中，从而可以精细控制所选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外展活动，该资助项目的更广泛影响延伸到为社会带来的利益。其中最重要的是全面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凯伊大学和马凯特大学联合主办的制药业合作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) 领域的成功职业做好准备，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。氚是一种理想的选择示踪核素，因为其半衰期足够长（12.3 年），并且能够制备具有高比活度的氚化化合物，用于化学和生物研究的各种应用。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作用，但用于选择性地将精确数量的氚掺入有机化合物中的有效合成方法数量有限。此外，用于表征和量化氚化小分子，尤其是通过同位素取代而具有手性的对映同位素异构体的光谱技术要么不发达，要么目前还不存在。为了解决第一个挑战，正在研究一套铜催化的转移氚化和氢化氚化反应，这些反应允许将氚原子标记以区域和立体控制的方式掺入到各种类型的烯烃和炔烃底物中（包括：丙二烯、1、 3-二烯和烯炔）。还正在开发这些转化的对映选择性变体，以允许获得通过氚取代和/或通过氘和氚取代而呈手性的对映同位素异构体。为了支持反应的发展，并针对上述第二个挑战，分子旋转共振（MRR）光谱学正在被建立为一种通用分析技术，用于量化对映同位素材料的对映体过量并确定其绝对构型。预计这项研究的结果将扩大选择性氚化小分子的使用范围，作为了解代谢物和/或药剂在生物系统中如何加工的有用工具。该奖项反映了 NSF 的法定使命，并被认为值得通过评估获得支持利用基金会的智力优势和更广泛的影响审查标准。