当前位置:科学网首页 > 小柯机器人 >详情
[3.1.1]螺桨烷合成间取代芳烃生物异构体
作者:小柯机器人 发布时间:2022/9/18 14:45:18

英国牛津大学Anderson, Edward A.团队报道了[3.1.1]螺桨烷合成间取代芳烃生物异构体。相关研究成果发表在2022年9月15日出版的《自然》。

小环笼状碳氢化合物是药物设计中常见的对位取代苯环的常见生物同构体(分子替代物)。这些笼状结构的用途来源于其与母体芳香化合物相比的优越药代动力学特性,包括改善溶解度和降低代谢敏感性。一个主要例子是双环[1.1.1]戊烷基元,这主要是通过应变碳氢化合物[1.1.1]螺桨烷与自由基或阴离子之间的桥头键的开环来合成的。相比之下,由于合成准确再现取代基向量的饱和同构体的挑战,缺乏模拟间取代芳烃的支架。

该文中,研究表明,桥头取代基精确映射到间取代苯几何形状的碳氢化合物可方便地从[3.1.1]庚烷中获取。研究发现[3.1.1]庚烷可以在多克尺度上合成,并容易进行一系列基于自由基的转化,以生成医学上相关的碳原子和杂原子取代的BCHEP,包括药物类似物。对这些类似物的ADME性质的比较显示,相对于其母体含芳烃的药物,代谢稳定性增强,验证了这种间芳烃类似物在药物设计中作为富含sp3基序的潜力。

总之,研究结果表明,BCHEP可以使用多种方法在有用的规模上制备,为药物发现计划的实施提供了间取代苯环的新替代物。

附:英文原文

Title: Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Author: Frank, Nils, Nugent, Jeremy, Shire, Bethany R., Pickford, Helena D., Rabe, Patrick, Sterling, Alistair J., Zarganes-Tzitzikas, Tryfon, Grimes, Thomas, Thompson, Amber L., Smith, Russell C., Schofield, Christopher J., Brennan, Paul E., Duarte, Fernanda, Anderson, Edward A.

Issue&Volume: 2022-09-15

Abstract: Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. In contrast, scaffolds mimicking meta-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally-relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of ADME properties of these analogues revealed enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a novel surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

DOI: 10.1038/s41586-022-05290-z

Source: https://www.nature.com/articles/s41586-022-05290-z

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:42.778
官方网址:http://www.nature.com/