New Directions in Bioisostere Research

生物等排体研究的新方向

• 批准号: EP/S013172/1
• 负责人: Edward Anderson
• 金额: $ 72.98万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS013172%2F1
• 关键词: New; Directions; Bioisostere; Research

The development of new drug candidates relies on a number of factors - not only the bioactivity of the molecule in question, but also properties such as its solubility, its ability to permeate cell membranes, and its susceptibility to metabolism by the body. Compounds containing benzene rings, as are common in many pharmaceuticals, can display problems in all these areas. One solution is to replace such problematic motifs with a chemical group that has the same size (and positions its substituents in the same way), but avoids these pharmacology issues. These groups are termed 'bioisosteres', and in this project, we seek to develop new approaches to 'bicyclopentanes', a functional group that is a bioisostere for benzene rings. In previous work by medicinal chemists, the bicyclopentane has proven to be an efficient substitute for benzene in medicinal chemistry settings, and as such there is a high level of interest in this field in the use of this functionality. While some approaches to these molecules are known, the methods used are generally rather harsh, and limited in scope. In this project, we will develop a number of new methodologies to access this important motif, mainly based around contemporary uses of free radical chemistry, which operate under very mild conditions and therefore are able to tolerate the kinds of chemical groups that are found in drug molecules. Our work will also include first-of-kind examples of asymmetric bicyclopentane synthesis, and demonstrations of the technology by application to real-life drug molecules. Finally, we will spend a proportion of the project time on developing scalable routes for bicyclopentane synthesis, with a view to commercialisation of some of the most useful building blocks, which will enhance the uptake of our work by end-users in the wider scientific community.

新候选药物的开发依赖于许多因素-不仅是所讨论分子的生物活性，而且还包括其溶解度，渗透细胞膜的能力以及对身体代谢的易感性等特性。含有苯环的化合物，就像许多药物中常见的那样，会在所有这些领域出现问题。一种解决方案是用具有相同大小（并以相同方式定位其取代基）的化学基团取代这些有问题的基序，但避免了这些药理学问题。这些基团被称为“生物同工异构体”，在这个项目中，我们寻求开发“双环戊烷”的新方法，双环戊烷是苯环的生物同工异构体。在药物化学家以前的工作中，双环戊烷已被证明在药物化学环境中是苯的有效替代品，因此在这一领域使用这种功能具有很高的兴趣。虽然已知一些研究这些分子的方法，但所使用的方法通常相当苛刻，而且范围有限。在这个项目中，我们将开发一些新的方法来获取这个重要的基序，主要基于自由基化学的当代应用，自由基化学在非常温和的条件下起作用，因此能够耐受药物分子中发现的各种化学基团。我们的工作还将包括首次不对称双环戊烷合成的例子，以及将该技术应用于现实生活中的药物分子的演示。最后，我们将把项目的一部分时间用于开发可扩展的双环戊烷合成路线，以期将一些最有用的构建模块商业化，这将增强最终用户在更广泛的科学界对我们工作的吸收。

项目成果

Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes.

• DOI: 10.1021/jacs.3c13080
• 发表时间: 2024-01-10
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Dasgupta A;Bhattacharjee S;Tong Z;Guin A;McNamee RE;Christensen KE;Biju AT;Anderson EA
• 通讯作者: Anderson EA

Structure-activity relationship study of cytotoxic neolignan derivatives using multivariate analysis and computation-aided drug design.

使用多变量分析和计算辅助药物设计研究细胞毒性新木脂素衍生物的结构-活性关系。

• DOI: 10.1016/j.bmcl.2020.127349
• 发表时间: 2020
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: De Sousa FS

Rationalizing the diverse reactivity of [1.1.1]propellane through sigma-pi-delocalization

通过 sigma-pi-离域化合理化[1.1.1]丙烷的多种反应性

• DOI: 10.26434/chemrxiv.9733628
• 发表时间: 2020
• 作者: Duarte F

Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis.

• DOI: 10.1039/d3md00081h
• 发表时间: 2023-07-20
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1

Synthesis of All-carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada CrossCoupling

铁催化 Kumada 交叉偶联合成全碳二取代双环[1.1.1]戊烷

• DOI: 10.26434/chemrxiv.12009390
• 发表时间: 2020
• 作者: Anderson E