Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells.
Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells.
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DOI：
10.1016/j.bmc.2014.10.029
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发表时间：
2014-12-15
影响因子：
3.5
通讯作者：
Merino EJ
中科院分区：
文献类型：
--
作者：
Vadukoot AK;AbdulSalam SF;Wunderlich M;Pullen ED;Landero-Figueroa J;Mulloy JC;Merino EJ
一些癌症，如急性髓性白血病 (AML)，利用活性氧来内源性激活细胞增殖和血管生成信号级联。因此，许多癌症表现出活性氧（如过氧化氢）浓度的增加。为了将这一发现转化为治疗策略，我们设计了具有两个关键分子药效团的新型过氧化氢激活剂。第一个药效团是过氧化物受体，第二个是侧胺。受体是对过氧化氢氧化敏感的N-(2,5-二羟基苯基)乙酰胺。我们假设通过调整侧链胺可以实现 AML 和正常细胞之间的选择性。通过合成和测试 14 种侧胺不同的化合物，鉴定出一种药物 (14)，其针对 AML 癌细胞的活性为 2 μM，而针对健康 CD34+ 血液干细胞的活性则低 11 倍。有趣的是，分析表明，氧化后，侧胺与受体环化，喷出水，得到能够与亲核试剂反应的双环化合物。初步机制研究表明，添加两种癌基因（NrasG12D 和 MLL-AF9）制成的 AML 细胞会增加 ROS 状态，最初是一种抗氧化剂，因为消耗过氧化氢来激活前药，并且细胞通过上调亲电子防御来做出反应，如 KEAP1 的蛋白质印迹所示。因此，利用这种化学方法，我们获得了一种简单、有效、选择性 ROS 激活的抗 AML 药物。
Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl)acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 μM activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent.
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影响因子：
7.4
作者：
Reuter, Simone;Gupta, Subash C.;Chaturvedi, Madan M.;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.
影响因子：
20.3
作者：
Sallmyr, Annahita;Fan, Jinshui;Rassool, Feyruz
通讯作者：
Rassool, Feyruz
影响因子：
4.2
作者：
Peng X;Gandhi V
通讯作者：
Gandhi V
活性氧 (ROS) 诱导 DNA 交联剂及其对癌细胞和正常淋巴细胞的影响
影响因子：
7.3
作者：
Chen, Wenbing;Balakrishnan, Kumudha;Peng, Xiaohua
通讯作者：
Peng, Xiaohua
影响因子：
3.4
作者：
Li, Guorui;Bell, Tiffany;Merino, Edward J.
通讯作者：
Merino, Edward J.