Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere
Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere
复制标题
DOI：
10.1002/anie.201510675
复制
发表时间：
2016-03-07
影响因子：
16.6
通讯作者：
Williams, Craig M.
中科院分区：
文献类型：
--
作者：
Chalmers, Benjamin A.;Xing, Hui;Williams, Craig M.
为了满足日益增长的全球需求，制药和农用化学发现项目面临着相当大的压力，因此需要不断创新。传统的碳氢化合物支架长期以来一直有助于将新分子推向市场，但一个明显的遗漏是柏拉图式的固体立方体。然而，Eaton认为这种分子有可能作为苯的生物等异构体。在这里，我们报告验证伊顿的假设与五个分子的立方衍生物，用于临床或作为农用化学品。与苯类药物相比，两种cubane类似物显示出更高的生物活性，而另外两种类似物显示出相同的生物活性，而第五种类似物仅显示出部分功效。通过反映含有苯环的生物活性分子的数量，可以最好地了解这项研究的结果。在可能的情况下，用cubane支架替代可以使这些系统恢复活力，从而加快急需的候选先导物的鉴定。
Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand, and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.