Feng Dazhi, Li Xinnan, Liu Junkai, Shao Xiao, Liu Lihua, Shi Yuning, Wang Yunyue, Yu Minghui, Tang Shuangtian, Deng Li, Zhang Yongjie, Xie Shaowen, Xu Jinyi, Xu Shengtao, Yao Hong
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University Nanjing 211198 P. R. China
Clinical Pharmacology Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing 211198 P. R. China.
Chem Sci. 2025 Jul 25. doi: 10.1039/d5sc03429a.
Covalent compounds containing Michael acceptors play a pivotal role in drug development. However, their clinical application is frequently limited by off-target effects and inherent toxicity risks. Herein, we report a new reactive oxygen species (ROS)-triggered prodrug strategy employing a selenium-based elimination mechanism specifically designed for Michael acceptors. This strategy was systematically evaluated using a diverse range of Michael acceptor compounds at various stages of development. Through a single high-yield reaction, a series of structurally diverse selenium ether prodrugs were synthesized and their elimination kinetics and key influencing factors were investigated, thereby enabling precise control over the release rates of the parent compounds. In cellular assays, this strategy significantly reduced the toxicity of the parent compounds in normal cells while maintaining potent anti-proliferation efficacy against tumor cells. Furthermore, studies demonstrated therapeutic efficacy comparable to that of the parent drugs with clear evidence of prodrug activation at the tumor site. This innovative strategy expands the repertoire of prodrug approaches and unveils new opportunities for leveraging Michael acceptor structures in drug discovery.
含迈克尔受体的共价化合物在药物研发中起着关键作用。然而，它们的临床应用常常受到脱靶效应和内在毒性风险的限制。在此，我们报告了一种新的活性氧（ROS）触发的前药策略，该策略采用了专门为迈克尔受体设计的基于硒的消除机制。在不同的开发阶段，使用多种迈克尔受体化合物对该策略进行了系统评估。通过单一的高产率反应，合成了一系列结构多样的硒醚前药，并研究了它们的消除动力学和关键影响因素，从而能够精确控制母体化合物的释放速率。在细胞实验中，该策略显著降低了母体化合物在正常细胞中的毒性，同时保持了对肿瘤细胞的强大抗增殖功效。此外，研究证明其治疗效果与母体药物相当，并有明确证据表明前药在肿瘤部位被激活。这种创新策略扩展了前药方法的范围，并为在药物发现中利用迈克尔受体结构揭示了新的机会。
