Tri-Manganese(III) Salen-Based Cryptands: A Metal Cooperative Antioxidant Strategy that Overcomes Ischemic Stroke Damage .

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 HO. Unfortunately, these molecules result in the unwanted production of the harmful hydroxyl radical, HO. Here, we report a series of salen-based tri-manganese (Mn(III)) metallocryptands (-) 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 HO with minimal HO production. In fact, significantly greater oxygen production is seen for - as compared to the monomeric Mn(Salen) complex, . The most promising system, , was studied in further detail and found to confer a greater therapeutic benefit both and than the monomeric control system, , as evident from studies involving a rat model of ischemic stroke damage and supporting histological analyses. We thus believe that metallocryptand and its analogues represent a new and seemingly promising strategy for treating oxidative stress related disorders.