State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Ling Ling Road, Shanghai 200032, PR China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China.
Bioorg Med Chem Lett. 2022 May 15;64:128683. doi: 10.1016/j.bmcl.2022.128683. Epub 2022 Mar 17.
Photoinduced drug release can reduce systemic side effects by releasing active drugs with high spatiotemporal accuracy, representing a promising strategy for precise cancer therapy. Here we designed and synthesized a novel photocaged B-Raf inhibitor 2, which, upon UV irradiation, could release a potent B-Raf inhibitor 1. Accordingly, once activated by the UV light, compound 2 could potently inhibit the proliferation of melanoma cells bearing B-Raf mutant while sparing melanoma cells expressing wild-type B-Raf, and could dose-dependently suppress the activation of the MAPK signaling pathway. Notably, the UV-mediated active component release and the resulting antiproliferative effects of compound 2 could be recapitulated when exposed to the sunlight, greatly enhancing its practicality. This photocaged B-Raf inhibitor 2 might serve as a novel therapeutic agent toward precise melanoma treatment.
光诱导药物释放可以通过高时空精度释放活性药物来减少全身副作用，代表了一种精确癌症治疗的有前途的策略。在这里，我们设计并合成了一种新型的光笼蔽 B-Raf 抑制剂 2，它在紫外光照射下可以释放出一种有效的 B-Raf 抑制剂 1。因此，化合物 2 一旦被紫外光激活，就可以强烈抑制携带 B-Raf 突变的黑色素瘤细胞的增殖，而对表达野生型 B-Raf 的黑色素瘤细胞则没有影响，并且可以剂量依赖性地抑制 MAPK 信号通路的激活。值得注意的是，当暴露在阳光下时，化合物 2 的光介导的活性成分释放及其产生的抗增殖作用可以重现，大大提高了其实用性。这种光笼蔽的 B-Raf 抑制剂 2 可能成为一种针对精确黑色素瘤治疗的新型治疗剂。
