ROS-inducible DNA cross-linking agent as a new anticancer prodrug building block.
ROS-inducible DNA cross-linking agent as a new anticancer prodrug building block.
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DOI：
10.1002/chem.201200075
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发表时间：
2012-03-26
影响因子：
4.3
通讯作者：
Peng, Xiaohua
中科院分区：
文献类型：
--
作者：
Cao, Sheng;Wang, Yibin;Peng, Xiaohua
一些抗肿瘤药物通过诱导DNA链间交联（ICLs）与DNA发生反应，从而阻断DNA的转录和复制。[1]ICL诱导剂如氮芥、丝裂霉素C、顺铂和长春新碱已用于癌症治疗。[2]然而，这些药物的主要缺点是它们对癌细胞的选择性差。降低交联剂对正常细胞的毒性的一种新方法将是产生经历肿瘤特异性活化的前药。几个研究小组已经开发了可诱导的DNA交联剂或烷化剂。[3-6]然而，它们中很少有可以在肿瘤特异性条件下选择性地诱导DNA交联。癌细胞的独有特征之一是与活性氧（ROS）的量增加相关的高水平氧化应激。[7-10]因此，开发能够被癌细胞中高水平的ROS激活的新型交联剂将是有利的。在不同的ROS中，如过氧化氢（H2 O2），羟基自由基（· OH）和超氧阴离子自由基（O2·-），H2 O2具有关键作用，因为它是一种稳定的ROS，几乎可以从所有的氧自由基来源产生。[11]据报道，与正常细胞相比，癌细胞中H2 O2的水平增加。[7，12]这些因素使H2 O2成为开发对癌细胞具有高选择性的新ROS诱导型前药的治疗靶点的理想候选物。芳基硼酸酯特别适合于这种前药方法，因为H2 O2可以很容易地切割硼酸酯以释放醌甲基化物（QM）。[13]醌甲基化物是大量DNA交联和烷基化过程中的重要中间体。通过Rokita的小组，[4] Freccero的小组，[5] Zhou的小组[6]和其他人提出的简单修饰，[14] QM可以通过不同的引发策略诱导DNA ICLs，包括UV照射，氟离子，加热或氧化等。同时，Cohen的小组报道了通过用硼酸酯作为H2 O2敏感性触发剂保护锌结合基团（ZBG）的羟基来原位活化基质金属蛋白酶抑制剂。[15]基于硼酸盐的探针已经由Chang的小组、Lo的小组和其他人开发，用于选择性检测和成像细胞中的过氧化氢。[16]最近，我们的小组已经表明，氮芥的前药与芳基硼酸酯偶联可以被H2 O2触发，释放出可以杀死癌细胞的活性药物。[17]然而，治疗效用将需要更有效的触发剂，其可以与多种有效的效应物偶联以使前药的ROS诱导的细胞毒性最大化。我们预期芳基硼酸酯和联芳基硼酸酯衍生物1-3可以通过以下活化：
Some antitumor drugs react with DNA by inducing DNA interstrand cross-links (ICLs) which can block DNA transcription and replication.[1] ICL-inducing agents, such as nitrogen mustard, mitomycin C, cisplatin, and psoralens have been used in cancer therapy.[2] However, the major disadvantage of these agents is their poor selectivity for cancer cells. One novel approach to reduce the toxicity of cross-linking agents for normal cells would be the creation of prodrugs that undergo tumor-specific activation. Inducible DNA crosslinking or alkylating agents have been developed by several research groups.[3-6] However, few of them can induce DNA crosslinks selectively under tumor-specific conditions. One of the exclusive features of cancer cells is the high level of oxidative stress that is associated with the increased amounts of reactive oxygen species (ROS).[7-10] Therefore, it would be advantageous to develop novel cross-linking agents that can be activated by the high level of ROS in cancer cells.Among different ROS, such as hydrogen peroxide (H2O2), hydroxyl radical (• OH), and superoxide radical anions (O2•-), H2O2 has a pivotal role because it is a stable ROS and generated from nearly all sources of oxygen radicals.[11] Increased levels of H2O2 in cancer cells compared to normal cells have been reported.[7, 12] These factors make H2O2 an ideal candidate as a therapeutic target to develop new ROS-inducible prodrugs with high selectivity to cancer cells. Arylboronic esters are particularly suitable to this prodrug approach because H2O2 can readily cleave the boronic ester to release the quinone methide (QM).[13] Quinone methides are important intermediates in a large number of DNA crosslinking and alkylating processes. With simple modifications suggested by Rokita's group,[4] Freccero's group,[5] Zhou's group [6] and others,[14] QM can induce DNA ICLs through different strategies for initiation including UV irradiation, fluoride ion, heating, or oxidation et.. Meanwhile, Cohen's group reported the activation of Matrix Metalloproteinase inhibitor in situ by protecting the hydroxyl group of the zinc-binding group (ZBG) with boronic ester as the H2O2-sensitive trigger.[15] Boronate-based probes have been developed by Chang's group, Lo's group, and others for selective detection and imaging of hydrogen peroxide in cells.[16] Recently, our group has shown that a prodrug of nitrogen mustard coupled with an arylboronate can be triggered by H2O2 to release active drugs that can kill cancer cells.[17] However, therapeutic utility would require a more efficient trigger that can be coupled with multiple potent effectors to maximize the ROS-inducible cytotoxicity of prodrugs. We expect that the arylboronic ester and biarylboronic ester derivatives 1-3 can be activated by
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