Tri-Manganese(III) Salen-based Cryptands: A Metal Cooperative Antioxidant Strategy that Overcomes Ischemic Stroke Damage In vivo,Journal of the American Chemical Society

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Tri-Manganese(III) Salen-based Cryptands: A Metal Cooperative Antioxidant Strategy that Overcomes Ischemic Stroke Damage In vivo
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-05-10 , DOI: 10.1021/jacs.0c03805
Yingying Ning ₁ , Yan Huo ₂ , Haozong Xue ₁ , Yujing Du ₂ , Yuhang Yao ₁ , Adam C Sedgwick ₃ , Hengyu Lin ₁ , Cuicui Li ₂ , Shang-Da Jiang ₁ , Bing-Wu Wang ₁ , Song Gao _{1,

4} , Lei Kang ₂ , Jonathan L Sessler ₃ , Jun-Long Zhang ₁

Affiliation

Oxidative stress is one of the hallmarks of ischemic stroke. Catalase-based (CAT) biomimetic complexes are emerging as promising therapeutic candidates that are expected to act as neuroprotectants for ischemic stroke by decreasing the damaging effects from H2O2. Unfortunately, these molecules result in the unwanted produc-tion of the harmful hydroxyl radical, HO•. Here, we report a series of salen-based tri-manganese (Mn(III)) me-tallocryptands 1-3 that function as catalase biomimetics. These cage-like molecules contain a unique "active site" with three Mn centers in close proximity, an arrangement designed to facilitate metal cooperativity for the effective dismutation of H2O2 with minimal HO• production. In fact, significantly greater oxygen produc-tion is seen for 1-3 as compared to the monomeric Mn(Salen) complex, 1c. The most promising system, 1, was studied in further detail and found to confer a greater therapeutic benefit both in vitro and in vivo than the monomeric control system, 1c, as evident from inter alia studies involving a rat model of ischemic stroke dam-age and supporting histological analyses. We thus believe that metallocryptand 1 and its analogues represent a new and seemingly promising strategy for treating oxidative stress related disorders.

中文翻译：

基于三锰（III）Salen的Cryptands：一种克服体内缺血性中风损伤的金属协同抗氧化策略

氧化应激是缺血性中风的标志之一。基于过氧化氢酶 (CAT) 的仿生复合物正在成为有前景的治疗候选物，有望通过减少 H2O2 的破坏作用来充当缺血性中风的神经保护剂。不幸的是，这些分子会导致有害的羟基自由基 H2O• 的有害产生。在这里，我们报告了一系列基于 Salen 的三锰 (Mn(III)) 金属隐密物 1-3，它们起到过氧化氢酶仿生学的作用。这些笼状分子包含一个独特的“活性位点”，三个 Mn 中心紧邻，这种排列旨在促进金属协同作用，从而有效地歧化 H2O2，同时产生最少的 HO•。事实上，与单体 Mn(Salen) 配合物 1c 相比，1-3 的氧气产生量显着增加。对最有希望的系统 1 进行了更详细的研究，发现与单体对照系统 1c 相比，它在体外和体内都具有更大的治疗益处，尤其是在涉及缺血性中风损伤大鼠模型的研究中证明了这一点并支持组织学分析。因此，我们相信金属密码体 1 及其类似物代表了一种新的、看似有希望的治疗氧化应激相关疾病的策略。

更新日期：2020-05-10

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