Nitric oxide-donating and reactive oxygen species-responsive prochelators based on 8-hydroxyquinoline as anticancer agents
Nitric oxide-donating and reactive oxygen species-responsive prochelators based on 8-hydroxyquinoline as anticancer agents
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基于 8-羟基喹啉的一氧化氮供体和活性氧响应型预螯合剂作为抗癌剂
DOI：
10.1016/j.ejmech.2021.113153
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发表时间：
2021
影响因子：
6.7
通讯作者：
Yin Jian
中科院分区：
文献类型：
--
作者：
Zhang Yuxia;Yang Jiaxin;Meng Tingting;Qin Yajuan;Li Tingyou;Fu Junjie;Yin Jian
基于8-羟基喹啉（8-HQ）的金属离子螯合剂已被广泛探索用于治疗许多疾病。当旨在被开发成有效的抗癌剂时，一个很大程度上未满足的问题是如何避免在正常细胞或组织中8-HQ对金属离子的非特异性螯合。在目前的工作中，采用两步策略来增强8-HQ的抗癌活性并提高其癌细胞特异性。考虑到一氧化氮（NO）的抗癌活性，首先将NO供体氧化呋咱连接到8-HQ上，构建HQ-NO缀合物。对这些缀合物的细胞毒性、金属结合能力和NO释放效率进行了筛选。用ROS响应性部分进一步修饰所选择的缀合物以提供前螯合剂。在所有目标化合物中，发现前药HQ-NO-11有效地抑制许多癌细胞的增殖，但不抑制正常细胞的增殖。HQ-NO-11的金属螯合和NO产生能力已被多种方法证实，并被证明是HQ-NO-11抗癌活性所必需的。体内研究表明，HQ-NO-11对SW 1990异种移植物生长的抑制作用比8-HQ更大。我们的研究结果展示了一个通用的方法来设计新的8-HQ衍生物，并阐明获得更可控的金属螯合剂。
Metal ion chelators based on 8-hydroxyquinoline (8-HQ) have been widely explored for the treatment of many diseases. When aimed at being developed into potent anticancer agent, a largely unmet issue is how to avoid nonspecific chelation of metal ions by 8-HQ in normal cells or tissues. In the current work, a two-step strategy was employed to both enhance the anticancer activity of 8-HQ and improve its cancer cell specificity. Considering the well-known anticancer activity of nitric oxide (NO), NO donor furoxan was first connected to 8-HQ to construct HQ-NO conjugates. These conjugates were screened for their cytotoxicity, metal-binding ability, and NO-releasing efficiency. Selected conjugates were further modified with a ROS-responsive moiety to afford prochelators. Among all the target compounds, prodrugHQ-NO-11was found to potently inhibit the proliferation of many cancer cells but not normal cells. The abilities of metal chelation and NO generation byHQ-NO-11were confirmed by various methods and were demonstrated to be essential for the anticancer activity ofHQ-NO-11.In vivostudies revealed thatHQ-NO-11inhibited the growth of SW1990 xenograft to a larger extent than 8-HQ. Our results showcase a general method for designing novel 8-HQ derivatives and shed light on obtaining more controllable metal chelators.