Imidazoles are crucial structural components in a variety of small-molecule inhibitors designed to target different kinases in anticancer treatment. However, the effectiveness of such inhibitors is often hampered by nonspecific effects and the development of resistance. Photopharmacology provides a compelling solution by enabling external control over drug activity with spatiotemporal precision. Herein, we introduce a novel strategy for caging bioactive triarylimidazole-based drug molecules. This approach involves introducing a dialkylamino group as a photoremovable group on the carbon atom of the imidazole ring, which intrinsically modulates the core structure from planar imidazole to tetrahedral 2H-imidazole, enabling the caged compound to be selectively uncaged upon visible light exposure. We applied this innovative caging technique to SB431542, a triarylimidazole-based small-molecule inhibitor that targets the pivotal TGF-β signaling pathway, the dysregulation of which is linked to several human diseases, including cancer. Our results demonstrated the selective inhibition of human breast cancer cell migration in vitro upon light activation, highlighting the potential of our approach to transform triarylimidazole-based drug molecules into visible light–activatable drugs, thereby facilitating spatiotemporal regulation of their pharmacological activity.

中文翻译：

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笼养生物活性三芳基咪唑：一种制造可见光激活药物的方法


咪唑是各种小分子抑制剂的重要结构成分，这些小分子抑制剂旨在抗癌治疗中针对不同激酶。然而，此类抑制剂的有效性常常受到非特异性作用和耐药性发展的阻碍。光药理学通过以时空精度对药物活性进行外部控制，提供了一种引人注目的解决方案。在此，我们介绍了一种用于捕获基于三芳基咪唑的生物活性药物分子的新策略。该方法涉及在咪唑环的碳原子上引入二烷基氨基作为光可去除基团，其本质上将核心结构从平面咪唑调节为四面体2H-咪唑，使得笼状化合物在可见光照射下选择性地释放。我们将这种创新的笼锁技术应用于 SB431542，这是一种基于三芳基咪唑的小分子抑制剂，针对关键的 TGF-β 信号通路，该信号通路的失调与包括癌症在内的多种人类疾病有关。我们的结果证明了光激活对体外人乳腺癌细胞迁移的选择性抑制，突显了我们的方法将基于三芳基咪唑的药物分子转化为可见光激活药物的潜力，从而促进其药理活性的时空调节。