Li Defeng, Shen Shuting, Liu Chuanxu, Guo Tingyu, Liu Yuhuan, Pan Peng, Zhao Xiaoyi, Ma Yiwen, Li Lei, Huang Shitao, Shen Wenhao, Jiang Biao, Wang Wei, Yin Qianqian, Zhang Yongqiang
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, PR China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, PR China.
Eur J Med Chem. 2025 Sep 5;293:117714. doi: 10.1016/j.ejmech.2025.117714. Epub 2025 Apr 30.
Herein, the structural modification of noscapine via an elegant selenium scanning strategy has been demonstrated, which enables the production of three classes of novel seleno-containing noscapinoids, namely 6', 7', and 9'-seleno-substituted noscapines. Among them, 9'-seleno-substituted noscapines exhibited superior in vitro anti-proliferative activity, and 9'-cycloheptylselenomethyl-noscapine 17a16 with a large hydrophobic cycloheptyl group showed the most potent activity and good selectivity. Unlike most of the reported noscapinoids that induce G2/M phase arrest by targeting microtubules, 17a16 exhibited a distinct ability to induce S-phase arrest and displayed superior potency in inducing apoptosis, which attribute to the activation of two parallel checkpoint pathways orchestrating DNA damage response, including DNA-PKcs-dependent p53 stabilization and ATR-Chk1 axis activation. Dissecting the upstream mechanism revealed that 17a16 targets mitochondria and induces mitochondrial dysfunction. This study elucidates the interplay of mitochondrial stress, DNA damage response, p53 and ATR-Chk1 checkpoint activation in mediating the anticancer effects of 17a16. Furthermore, 17a16 treatment significantly suppressed tumor growth in p53-deficient JeKo-1 subcutaneous xenograft model in vivo, without inducing systemic toxicity. Overall, our findings highlight 17a16 as a promising lead compound in cancer therapy and demonstrate the potential of selenium scanning as a valuable strategy for anticancer drug discovery.
在此，通过一种精妙的硒扫描策略对那可丁进行了结构修饰，该策略能够产生三类新型含硒那可丁类化合物，即6'、7'和9'-硒取代那可丁。其中，9'-硒取代那可丁表现出卓越的体外抗增殖活性，带有大的疏水环庚基的9'-环庚基硒甲基那可丁17a16显示出最强的活性和良好的选择性。与大多数报道的通过靶向微管诱导G2/M期阻滞的那可丁类化合物不同，17a16表现出诱导S期阻滞的独特能力，并在诱导细胞凋亡方面表现出卓越的效力，这归因于两条协调DNA损伤反应的平行检查点途径的激活，包括DNA-PKcs依赖的p53稳定化和ATR-Chk1轴激活。对上游机制的剖析表明，17a16靶向线粒体并诱导线粒体功能障碍。本研究阐明了线粒体应激、DNA损伤反应、p53和ATR-Chk1检查点激活在介导17a16抗癌作用中的相互作用。此外，在体内p53缺陷的JeKo-1皮下异种移植模型中，17a16治疗显著抑制了肿瘤生长，且未诱导全身毒性。总体而言，我们的研究结果突出了17a16作为癌症治疗中有前景的先导化合物，并证明了硒扫描作为抗癌药物发现的一种有价值策略的潜力。
