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

职业：探索新的化学空间：生物相关应变分子的模块化合成

• 批准号: 2143925
• 负责人: Tian Qin
• 金额: $ 69万
• 依托单位: University of Texas Southwestern Medical Center
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143925&HistoricalAwards=false
• 关键词: CAREER; Exploring; Novel; Chemical; Space

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.

在化学系化学合成(SYN)计划的支持下，德克萨斯大学西南医学中心的田勤正致力于开发新的方法来获取应变小分子，以便在研究药物中潜在应用。这样的努力可以使药物发现的实践者能够探索扩大的化学空间，加速发现具有可口的类药物特性的药物分子。例如，双环[1.1.1]戊烷(BCP)是一种应变的碳氢分子，被确认为芳香族化合物的三维替代品，芳香族化合物通常存在于候选药物中，但往往导致不利的性能。为此，BCP提供了一种有吸引力的芳烃替代品。然而，由于缺乏容易获得的合成方法，该部分的更广泛的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合这一差距。该项目位于有机合成、理论化学、物理有机化学和药物化学的交界处。因此，它非常适合于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，将鼓励大学和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，德克萨斯大学西南医学中心的秦研究小组正在开发与药物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位取代物，由于其能够改善候选药物的物理化学性质而日益引起药物化学界的兴趣。虽然已经报道了几种制备多取代BCP的方法，但获得桥取代的BCP的途径一直受到限制。这项研究利用了一系列新型的BCPs试剂来促进这种应变环体系的合成和探索新的反应性。该项目同时调查了三个具体目标，以提供(I)获得复杂的多取代笼状双环分子，(2)系统地优化合成BCP的方法，以及(3)了解多取代BCP的性质。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.

桥取代的双环[1.1.1]戊烷双硼酸酯的可编程后期功能化。

• DOI: 10.1038/s41557-023-01342-7
• 发表时间: 2024
• 期刊: Nature chemistry
• 影响因子: 21.8
• 作者: Yang,Yangyang;Tsien,Jet;Dykstra,Ryan;Chen,Si-Jie;Wang,JamesB;Merchant,RohanR;Hughes,JonathanME;Peters,ByronK;Gutierrez,Osvaldo;Qin,Tian
• 通讯作者: Qin,Tian