近日，英国牛津大学Russell, Angela J.团队报道了芳基稠合双环[3.1.1]庚烷的合成及其作为萘基生物异构体的验证。相关论文发表在2026年5月6日出版的《自然-化学》杂志上。

尽管萘环骨架在药物和先导化合物中含量较高，但其平面性、富sp²杂化特征以及对细胞色素P450介导代谢的易感性常常限制了其成药性。

研究组报道了一种可衍生化的芳基稠合双环[3.1.1]庚烷（BCHep）作为萘及其他稠合双环（杂）芳烃（包括研究不足的β-萘基单元）的富sp³杂化生物等排替代体。通过可见光能量转移实现的分子内交叉[2+2]光环加成反应，可高效合成BCHep骨架，并进一步衍生化得到一系列不同结构。

研究组表明，将基于BCHep的萘等排体引入AhR拮抗剂ezutromid中，能够在保持关键几何出矢量方向的同时，降低sp²杂化碳原子的占比。重要的是，这些类似物仍保留生物活性，并且对CYP1A介导的代谢表现出更高的代谢稳定性。固态结构、细胞实验及微粒体研究证实，BCHep替代可减少反应性代谢物的生成，验证了芳基稠合BCHep作为间位取代芳烃和2-萘酚类化合物的真正生物等排替代体的可行性。

附：英文原文

Title: Synthesis of aryl-fused bicyclo[3.1.1]heptanes and validation as naphthyl bioisosteres

Author: Kerckhoffs, Aidan, Tregear, Maud, Hernndez-Llad, Pol, Runfola, Massimiliano, Shearsmith, Holly, Frank, Nils, Panosetti, Marc, Squire, Sarah E., Moir, Lee, Christensen, Kirsten E., Duarte, Fernanda, Davies, Kay E., Russell, Angela J.

Issue&Volume: 2026-05-06

Abstract: Although naphthalene motifs are frequently encountered in drugs and lead compounds, their flat, sp2-rich nature and susceptibility to cytochrome P450-mediated metabolism often limit their developability. Here we report the study of derivatizable aryl-fused bicyclo[3.1.1]heptanes (BCHeps) as sp3-rich bioisosteric replacements for naphthalene and other fused bicyclic (hetero)aromatics, including underrepresented β-naphthyl units. The BCHeps were efficiently accessed via an intramolecular crossed [2+2] photocycloaddition enabled by visible light energy transfer and subsequently diversified to provide a range of different scaffolds. Here we show that the incorporation of BCHep-based naphthyl isosteres into the AhR antagonist ezutromid preserves key geometric exit vectors while reducing the fraction of sp2 carbon atoms. Importantly, these analogues retain biological activity and display improved metabolic stability towards CYP1A-mediated metabolism. Solid-state structures, cellular assays and microsomal studies confirm that BCHep substitution mitigates reactive metabolite formation, validating aryl-fused BCHeps as true bioisosteric replacements for meta-substituted arenes and 2-naphthalenes.

DOI: 10.1038/s41557-026-02129-2

Source: https://www.nature.com/articles/s41557-026-02129-2