Bioorthogonal cleavage reactions have been developed as an intriguing strategy to enhance the safety of chemotherapeutics. Aiming to reduce the toxicity and improve the targeted release properties of the colchicine binding site inhibitors (CBSIs) based on previous work, a series of biologically inert prodrugs were further designed and synthesized through a bioorthogonal prodrug strategy. The therapeutic effects of prodrugs could be “turned-on” once combined with palladium resins. Particularly, prodrug 2b was 68.3-fold less cytotoxic compared to the parent compound, while its cytotoxicity was recovered in situ in the presence of palladium resins. Mechanism studies confirmed that 2b inhibited cell growth in the same manner as CBSIs. More importantly, in vivo efficacy studies demonstrated the efficient activation of 2b by palladium resins, resulting in significant inhibition of tumor growth (63.2%). These results suggest that prodrug 2b with improved safety and targeted release property catalyzed by a Pd-mediated bioorthogonal cleavage reaction deserves further investigation.

中文翻译：

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钯介导的生物正交系统，用于含 N-苄基苯甲酰胺的微管蛋白聚合抑制剂的前药活化，用于治疗实体瘤


生物正交切割反应已被开发为一种提高化疗药物安全性的有趣策略。为了降低秋水仙碱结合位点抑制剂 （CBSIs） 的毒性并提高靶向释放特性，通过生物正交前药策略进一步设计和合成了一系列生物惰性前药。一旦与钯树脂结合，前药的治疗效果就可以“开启”。特别是，与母体化合物相比，前药 2b 的细胞毒性降低了 68.3 倍，而其细胞毒性在钯树脂存在下原位恢复。机制研究证实 2b 抑制细胞生长的方式与 CBSI 相同。更重要的是，体内药效研究表明钯树脂可有效激活 2b，从而显着抑制肿瘤生长 （63.2%）。这些结果表明，由 Pd 介导的生物正交切割反应催化的具有更高安全性和靶向释放特性的前药 2b 值得进一步研究。