Liang Weiqiu, Li Jiahao, Li Jianbin, Wu Chengda, Tu Zhiyu, Mu Bo-Shuai, Xu Yang, Song Longlong, Xu Mengxin, Cui Xi-Yang, Li Chao-Jun, Liu Zhibo
Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen 518172, China.
Innovation (Camb). 2025 Jan 22;6(4):100809. doi: 10.1016/j.xinn.2025.100809. eCollection 2025 Apr 7.
Late-stage functionalization is an attractive strategy that allows chemists to bypass lengthy synthetic processes, facilitating the rapid generation of drug analogs with potentially enhanced pharmacokinetic and pharmacological properties. This study describes a novel approach for cross-dehydrogenative oxyalkylation, leveraging a unique γ-ray-enabled photoredox process to generate oxyalkyl radicals, followed by a Minisci-type addition in an aqueous solution. The metal- and oxidant-free aqueous conditions, coupled with excellent functional group compatibility, establish this method as a versatile protocol for the late-stage oxyalkylation of unprotected, structurally complex drug molecules. Notably, this method demonstrated improved pharmacokinetics in hydroxymethylated fibroblast activation protein inhibitor (FAPI) molecules, highlighting its potential to accelerate drug discovery efforts.
后期官能团化是一种有吸引力的策略，它使化学家能够绕过冗长的合成过程，促进快速生成具有潜在增强药代动力学和药理学性质的药物类似物。本研究描述了一种用于交叉脱氢氧烷基化的新方法，利用独特的γ射线光氧化还原过程生成氧烷基自由基，随后在水溶液中进行米氏型加成反应。无金属和无氧化剂的水性条件，以及出色的官能团兼容性，使该方法成为未保护的、结构复杂的药物分子后期氧烷基化的通用方案。值得注意的是，该方法在羟甲基化的成纤维细胞活化蛋白抑制剂（FAPI）分子中表现出改善的药代动力学，突出了其加速药物研发工作的潜力。
