New Directions in Bioisostere Research

新候选药物的开发依赖于一系列因素--不仅是有关分子的生物活性，还包括它的溶解性、它渗透细胞膜的能力以及它对人体新陈代谢的敏感性。含有苯环的化合物在许多药物中很常见，在所有这些领域都会出现问题。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)的化学基团来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‘生物等位体’，在这个项目中，我们寻求开发新的方法来获得‘双环戊烷’，这是一种功能基团，是苯环的生物等位体。在药物化学家以前的工作中，双环戊烷已被证明是药物化学环境中苯的有效替代品，因此该领域对该功能的使用有很高的兴趣。虽然对这些分子的一些方法是已知的，但所用的方法通常是相当苛刻的，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得这个重要的主题，主要基于自由基化学的当代使用，它在非常温和的条件下运行，因此能够容忍药物分子中发现的各种化学基团。我们的工作还将包括第一个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，我们将把项目时间的一部分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件商业化，这将加强我们的工作被更广泛的科学界的最终用户所接受。

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.