期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 22, 页码 10219-10227出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c03805
关键词
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资金
- National Key Basic Research Support Foundation of China [2015CB856301]
- National Scientific Foundation of China (NSFC) [21571007, 21621061, 21778002, 21861162008]
- National Natural Science Foundation of China [81871385]
- National Institutes of Health [CA 68682]
- Robert A. Welch Foundation [F-1018]
- PKU medicine-X Youth Program [PKU2020LCXQ007]
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 production of the harmful hydroxyl radical, HO center dot. Here, we report a series of salen-based tri-manganese (Mn(III)) metallocryptands (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 center dot production. In fact, significantly greater oxygen production 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 damage 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.
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