Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators.
Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators.
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DOI：
10.1039/c4mt00153b
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Tomat E
中科院分区：
文献类型：
--
作者：
Akam EA;Chang TM;Astashkin AV;Tomat E
与正常细胞相比，铁清除剂（螯合剂）针对癌细胞对铁的需求增加，为抗癌药物设计提供了治疗机会。由于螯合剂在特定的细胞内条件下释放，预螯合方法有望避免全身铁耗竭。在本文描述的策略中，二硫键用作抗增殖缩氨基硫脲前螯合剂的结合单元内的氧化还原定向开关，其在还原为硫醇盐螯合剂后被激活用于铁配位。在谷胱甘肽氧化还原缓冲液中，这种还原事件发生在生理浓度和半电池电位下。与同时发生的还原和激活相一致，较高的细胞内硫醇浓度会增加培养癌细胞对前螯合剂毒性的敏感性。使用钙黄绿素作为顺磁性离子的荧光探针的细胞测定证实了二硫键开关的减少和细胞内铁螯合。通过 EPR 光谱测量在完整的 Jurkat 细胞中鉴定出由此产生的低自旋 Fe(III) 复合物，该测量还记录了暴露于原螯合剂后活性核糖核苷酸还原酶浓度的降低。细胞活力和基于荧光的测定表明，铁络合物具有低细胞毒性，并且不参与细胞内氧化还原化学，表明这种抗增殖螯合策略不依赖于活性氧的产生。
Iron scavengers (chelators) offer therapeutic opportunities in anticancer drug design by targeting the increased demand for iron in cancer cells as compared to normal cells. Prochelation approaches are expected to avoid systemic iron depletion as chelators are liberated under specific intracellular conditions. In the strategy described herein, a disulfide linkage is employed as a redox-directed switch within the binding unit of an antiproliferative thiosemicarbazone prochelator, which is activated for iron coordination following reduction to the thiolate chelator. In glutathione redox buffer, this reduction event occurs at physiological concentrations and half-cell potentials. Consistent with concurrent reduction and activation, higher intracellular thiol concentrations increase cell susceptibility to prochelator toxicity in cultured cancer cells. The reduction of the disulfide switch and intracellular iron chelation are confirmed in cell-based assays using calcein as a fluorescent probe for paramagnetic ions. The resulting low-spin Fe(III) complex is identified in intact Jurkat cells by EPR spectroscopy measurements, which also document a decreased concentration of active ribonucleotide reductase following exposure to the prochelator. Cell viability and fluorescence-based assays show that the iron complex presents low cytotoxicity and does not participate in intracellular redox chemistry, indicating that this antiproliferative chelation strategy does not rely on the generation of reactive oxygen species.
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影响因子：
3
作者：
Daniels, Tracy R.;Bernabeu, Ezequiel;Rodriguez, Jose A.;Patel, Shabnum;Kozman, Maggie;Chiappetta, Diego A.;Holler, Eggehard;Ljubimova, Julia Y.;Helguera, Gustavo;Penichet, Manuel L.
通讯作者：
Penichet, Manuel L.
影响因子：
4.4
作者：
McCue, JM;Link, KL;Freed, BM
通讯作者：
Freed, BM
影响因子：
2.9
作者：
Epsztejn, S;Kakhlon, O;Cabantchik, ZI
通讯作者：
Cabantchik, ZI
影响因子：
4.6
作者：
Jackson, HL;Shoner, SC;Kovacs, JA
通讯作者：
Kovacs, JA
影响因子：
7.4
作者：
Hoke, EM;Maylock, CA;Shacter, E
通讯作者：
Shacter, E