Salen-manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents: structure-activity relationship studies
Salen-manganese complexes as catalytic scavengers of hydrogen peroxide and cytoprotective agents: structure-activity relationship studies
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DOI：
10.1021/jm020207y
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发表时间：
2002-09-26
影响因子：
7.3
通讯作者：
Malfroyt, B
中科院分区：
文献类型：
--
作者：
Doctrow, SR;Huffman, K;Malfroyt, B
合成的活性氧自由基(ROS)催化清除剂具有广泛的临床应用前景。在以前的文献中，两个Salen-锰络合物EUK-8和EUK-134具有超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活性，并可防止ROS相关的组织损伤。本研究描述了两个系列的Salen-锰络合物，比较了催化清除ROS的性能和细胞保护活性。这些化合物清除过氧化氢的能力差异很大，这一活性最受Salen环烷氧基取代和芳香桥修饰的影响。相反，所有化合物都显示出类似的超氧化物歧化酶活性。最活跃的烷氧基取代过氧化氢酶模拟物保护培养细胞免受过氧化氢的影响，其中一部分在啮齿动物中风模型中也具有神经保护作用。因此，原型EUK-8的结构修饰产生了具有增强的过氧化氢酶活性的化合物，进而产生了生物有效性。这支持萨伦-锰络合物代表一类超氧化物歧化酶的概念，特别是过氧化氢酶模拟物，可能对治疗ROS相关疾病有用。
Synthetic catalytic scavengers of reactive oxygen species (ROS) may have broad clinical applicability. In previous papers, two salen-manganese complexes, EUK-8 and EUK-134, had superoxide dismutase (SOD) and catalase activities and prevented ROS-associated tissue injury. This study describes two series of salen-manganese complexes, comparing catalytic ROS scavenging properties and cytoprotective activities. The compounds vary widely in ability to scavenge hydrogen peroxide, with this activity most influenced by salen ring alkoxy subsitution and aromatic bridge modifications. In contrast, all compounds show comparable SOD activities. The most active alkoxy-substituted catalase mimetics protected cultured cells from hydrogen peroxide, and a subset of these were also neuroprotective in a rodent stroke model. Thus, structural modification of the prototype EUK-8 yields compounds with enhanced catalase activity and, in turn, biological effectiveness. This supports the concept that salen-manganese complexes represent a class of SOD and, in particular, catalase mimetics potentially useful against ROS-associated diseases.