Dual Diomarkers Triggered Prodrugs for Precise Treatment of Melanoma: Design,Synthesis and Activities
Dual Diomarkers Triggered Prodrugs for Precise Treatment of Melanoma: Design,Synthesis and Activities
复制标题
用于精准治疗黑色素瘤的双 Diomarkers 触发前药：设计、合成和活性
DOI：
10.1007/s40242-022-2121-y
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发表时间：
2022
影响因子：
3.1
通讯作者：
Huang Jing
中科院分区：
文献类型：
--
作者：
Ruan Yawen;Huang Peiling;Yan Jiangyu;Li Guorui;Huang Jing
靶向前药策略是利用肿瘤细胞内的内源性生物标志物作为激活剂释放活性药物，已在基础研究和临床治疗中得到广泛应用。然而，许多前药由于"脱靶激活"而遭受安全性问题。双或多生物标志物触发的前药可能为克服"脱靶效应"提供有效的策略。黑色素瘤细胞具有高水平的活性氧（ROS）和酪氨酸酶（TYR），这使得它们与其他肿瘤细胞和正常细胞显著不同。在这里，我们报告了一系列喹唑啉酮-芳基硼酸/酯基前药，它们可以被ROS和TYR级联激活，并选择性地杀死黑色素瘤细胞。构效关系（SAR）分析表明，它们的细胞毒性与靶向性密切相关，双激活效应子在它们对黑色素瘤细胞的选择性中起重要作用。在这些候选化合物中，化合物4b对B16显示出最高的毒性，导致黑色素瘤细胞中氧化还原系统的失衡，引起线粒体DNA损伤，进而促进黑色素瘤细胞死亡。
Targeted prodrug strategy, which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug, has been well established either in the fundamental research or the clinical treatment. However, many prodrugs suffer from safety concern due to "off-target activation". Dual or multiple biomarkers triggered prodrug may provide an effective strategy to overcoming the "off-target effect". Melanoma cells have both high levels of reactive oxygen species(ROS) and tyrosinase(TYR), which makes them significantly different from other tumor cells and normal cells. Here we reported a series of quinazolinone-aryl boronic acid/ester-based prodrugs, which can be activated by the cascade of ROS and TYR and selectively kill melanoma cells. The structure-activity relationship(SAR) analysis revealed that mitochondria-targeting property was vital for their cytotoxicity and the dual activated effector played a significant role in their selectivity towards melanoma cells. Among these candidates, compound 4b showed the highest toxicity to B16, leading to an imbalance of the redox system in melanoma cells, causing mitochondrial DNA damage, and then promoting melanoma cells death.