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.

新药候选者的发展依赖于许多因素 - 不仅是所讨论的分子的生物活性，而且还取决于其溶解度，渗透细胞膜的能力以及对人体代谢的易感性。在许多药品中常见的情况下，含有苯环的化合物在所有这些区域都会显示出问题。一种解决方案是用具有相同尺寸的化学基团替代此类有问题的基序（并以相同的方式定位其取代基），但避免了这些药理学问题。这些群体被称为“生物培养官”，在这个项目中，我们试图开发新的方法来“自行车”，这是一个功能群体，是苯甲环的生物酶。在药物化学家的先前工作中，这位自行车烷已被证明是药物化学环境中苯的有效替代品，因此，对该领域的使用对使用该功能有很高的兴趣。尽管已知这些分子的某些方法，但所使用的方法通常相当苛刻，并且范围有限。在这个项目中，我们将开发许多新方法来访问这一重要基序，主要是基于当代自由基化学的使用，这些化学在非常温和的条件下运行，因此能够忍受在药物分子中发现的化学基团的种类。我们的工作还将包括非对称性两种自然合成的首个例子，以及通过应用于现实生活中的药物分子来证明该技术的示例。最后，我们将花费一定比例的项目时间来开发可扩展的自行车构成综合途径，以期商业化一些最有用的构件，这将增强更广泛科学界的最终用户对我们的作品的吸收。

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

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

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