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

在化学系化学合成（SYN）项目的支持下，德克萨斯大学西南医学中心的田勤（Tian Qin）旨在开发新方法来获得应变小分子，以用于研究药物的潜在应用。这些努力可以使药物发现的从业者能够探索更广阔的化学空间，加速发现具有类似药物性质的药物分子。举例来说，双环[1.1.1]戊烷（BCP），一种应变烃分子，被鉴定为芳香族化合物的三维替代物，芳香族化合物通常存在于药物候选物中，但通常导致不利的性质。为此，BCP提供了芳烃的有吸引力的替代品。然而，该部分的更广泛的应用和官能化受到缺乏容易获得的合成方法的限制。秦博士的实验室正在开发一种新的合成策略来弥合这一差距。该项目处于有机合成、理论化学、物理有机化学和药物化学的接口。因此，它非常适合具有不同背景的各级有抱负的科学家的教育。利用建模和可视化技术的最新进展，在大学和K-12级别鼓励广泛参与科学，技术，工程和数学（STEM）教育。在这个项目中，UT西南医学中心的Qin研究团队正在开发药物相关的张力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电子等排替代物，由于其改善潜在候选药物的物理化学性质的能力，在药物化学界引起了越来越多的兴趣。尽管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。拟议的研究利用一系列新型BCP试剂来促进这种应变环系统的合成和探测新的反应性。三个具体目标是在该项目的同时调查，以提供（i）获得复杂的多取代笼双环分子，（2）系统优化合成方法的BCP，（3）多取代BCP的属性的知识。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.