A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.
A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.
复制标题
一种基于三唑骨架的硼酸盐预螯合剂，用于过氧化物触发的三齿金属结合。
DOI：
10.1016/j.ica.2012.06.011
复制
发表时间：
2012
影响因子：
2.8
通讯作者：
Franz,KatherineJ
中科院分区：
文献类型：
--
作者：
Kielar,Filip;Wang,Qin;Boyle,PaulD;Franz,KatherineJ
铁螯合剂有可能使一系列疾病中与氧化应激相关的损伤最小化;然而，这种潜力被与全身性铁过载无关的条件下的不分青红皂白的金属结合或铁耗竭的风险抵消。地拉罗司是临床上用于铁过载的螯合剂，但也对培养物中的细胞具有细胞毒性。为了测试地拉罗司的前药版本是否可以最大限度地减少其细胞毒性，但保留其对铁诱导的氧化损伤的保护特性，我们合成了一种前螯合剂，其含有自分解的硼酸酯掩蔽基团，该基团在暴露于过氧化氢时被去除以释放双羟基苯基三唑配体地拉罗司。本文报道了一种三唑类自分解前螯合剂TIP（4-（5-（2-（（4-硼苄基）氧基）苯基）-3-（2-羟基苯基）-1H-1，2，4-三唑-1-基）苯甲酸）的合成和表征。TIP不与Fe 3+配位，并且仅显示出对Cu 2+或Zn 2+的弱亲和力，这与地拉罗司形成鲜明对比，地拉罗司强烈结合所有三种金属离子。TIP在体外与过氧化氢反应后有效转化为地拉罗司。在细胞培养中，TIP保护视网膜色素上皮细胞免于过氧化氢诱导的死亡;然而，TIP本身在未应激的细胞中比地拉罗司更具细胞毒性。这些结果意味着地拉罗司的细胞毒性可能不完全来自其铁抑制特性。
Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis-hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5-(2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe3+and shows only weak affinity for Cu2+or Zn2+, in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties.