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作为基生物异构剂的古巴体的一般使用

Mario P Wiesenfeldt¹, James A Rossi-Ashton¹, Ian B Perry¹

¹Merck Center for Catalysis at Princeton University, Princeton, NJ, USA.

|April 4, 2023

概括

研究人员开发了新方法来合成1,3和1,2非替代的古巴基石. 这使得古巴可以作为药物设计中所有替代模式的多功能生物.

科学领域:

医学化学
有机合成
药物发现

背景情况:

将环替换为sp3混合生物异构体可以增强药物的药理动力学并维持生物活性.
由于高的C-H键强度, 古巴这样的硬,紧张的框架提供了代谢稳定性,并且紧密地模仿了的几何结构.
由于合成挑战和交叉合不兼容,目前的限制限制了cubane的使用.

研究的目的:

为1,3-和1,2-非替代的古巴原料开发高效的合成途径.
建立与古巴脚手架相容的强大的交叉合协议.
在候选药物中全面使用古巴作为所有替代模式的生物.

主要方法:

使用循环丁前体合成1,3-异位古巴.
用光解C-H碳化来获取1,2-非替代的古巴基质.
铜催化交叉合反应的发展 (C-N,C-C(sp³),C-C(sp²,C-CF₃) 利用特定的铜反应性.

主要成果:

确定了通往关键1,3和1,2非替代的古巴中间产品的方便途径.
新的交叉合方法成功地应用于古巴脚手架,克服了以前的局限性.
现在可以轻松地将所有古巴同位素加工成潜在的药物候选物.

结论:

开发的合成策略和交叉合协议显著扩大了古巴在药物化学中的实用性.
现在可以有效地使用cubane作为ortho,meta和para-substituted的生物.
通过理想的环替代,这种进步有助于设计具有改善药物动力学的候选药物.

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