CAREER: Exploring Novel Chemical Space: Modular Synthesis of Biologically Relevant Strained Molecules

在化学合成（SYN）项目的支持下，德克萨斯大学西南医学中心的田勤致力于开发新的方法来获取紧张的小分子，以用于研究药物的潜在应用。这样的努力可以使药物发现的实践者探索更广阔的化学空间，加速发现具有令人愉快的药物性质的药物分子。例如，双环[1.1.1]戊烷（BCP）是一种烃类分子，被认为是芳烃的三维替代品，芳烃常见于候选药物中，但往往会导致不利的性质。为此，BCP提供了一种有吸引力的芳香剂替代品。然而，由于缺乏易于获得的合成方法，该片段的广泛应用和功能化受到限制。秦博士的实验室正在开发一种新的合成策略来弥补这一差距。本项目是有机合成、理论化学、物理有机化学、药物化学的交叉学科。因此，它非常适合教育具有不同背景的各级有抱负的科学家。利用建模和可视化技术的最新进展，鼓励在大学和K-12阶段广泛参与科学、技术、工程和数学（STEM）教育。在这个项目中，UT西南医学中心的秦研究团队正在开发与药学相关的应变双环分子的合成方法。双环[1.1.1]戊烷（BCP）基序作为芳香环的生物等构替代物，能够改善潜在候选药物的理化性质，因此在药物化学界引起了越来越多的兴趣。虽然已经报道了几种制备多取代bcp的方法，但获得桥取代bcp的途径有限。本研究利用一系列新的bcp试剂来促进该应变环体系的合成和探索新的反应性。该项目同时研究三个具体目标，以提供(i)获得复杂的多取代笼状双环分子，(2)系统优化bcp的合成方法，以及(3)了解多取代bcp的性质。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 the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Tian Qin of University of Texas Southwestern Medical Center is aiming to develop new methods to access strained small molecules for potential application in investigational drugs. Such endeavors could empower practitioners of drug discovery to explore an expanded chemical space, accelerating the discovery of drug molecules with palatable drug-like properties. By way of example, bicyclo[1.1.1]pentane (BCP), a strained hydrocarbon molecule, is identified as a three-dimensional surrogate for aromatics, which are commonly found in drug candidates but often contribute to unfavorable properties. To this end, BCP provides an attractive alternative to aromatics. However, the broader application and functionalization of this moiety is limited by a lack of readily accessible synthetic approaches. Dr. Qin's laboratory is developing a novel synthetic strategy to bridge this gap. This project lies at the interface of organic synthesis, theoretical chemistry, physical organic chemistry, and medicinal chemistry. It is thus well-suited for the education of aspiring scientists at all levels with diverse backgrounds. Broad participation in science, technology, engineering, and mathematics (STEM) education will be encouraged at the collegiate and K-12 levels, taking advantage of recent advances in modeling and visualization technologies.In this project, the Qin research team of UT Southwestern Medical Center is developing synthetic methods for pharmaceutically relevant strained bicyclic molecules. The bicyclo[1.1.1]pentane (BCP) motif has increasingly garnered interest in the medicinal chemistry community, due to its ability to improve the physicochemical properties of prospective drug candidates, as a bioisosteric replacement of aromatic rings. Although several methodologies have been reported to prepare multi-substituted BCPs, access to bridge-substituted BCPs has been limited. The proposed research leverages a series of novel BCPs reagents to facilitate the synthesis and probe new reactivities of this strained ring system. Three specific aims are under concurrent investigation in this project to provide (i) access to complex multi-substituted caged bicyclic molecules, (2) systematic optimization of synthetic approaches to BCPs, and (3) knowledge of the properties of multi-substituted BCPs.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.