Biomimetic Modeling of Superoxide Reductase

Abstract

Dioxygen is a thermnodynamically superior oxidam. with the ability to be reduced to water by a four-electron reduction. During this process, toxic reactive oxygen sPeciCis (ROS) are also generated. Nature uses metalloenzymes to combat this form of oxidative stress. Of particular interest to us is superoxide reductase (SOR). SOR is a non-heme thiolate-ligated metalloenzyme, consisting of a ferrous center ligated by four histidines and a cysteinate residue. It is responsible for superoxide detoxification in anaerobic and microaerophilic organisms by reducing superoxide to H202. A novel biomimetic model of the active site of SOR, [FelIcyclam.PrSY is described in Chapter 1. This complex reacts with superoxide under protic conditions at cryogenic temperatures to form (Fell1cyclam.prS(OOH)Y. This is a rare example of a high-spin FelIl~OOH species, and the first reported example of a high-spin non-heme Fel1l_O.OH containing a traIlS thiolate. The addition of acetic acid fonns the aceta~bound [FeIllcyclam-PrS(OAc)]+, a model of the Felli resting state of SOR. The addition of cobaltdcene regenerates the FelI species. completing the catalytic reduction of superoxide to hydrogen peroxide. • [FeD(NEl1)N.(tren)Cll'. a synthetic analogue of [FeDN.(iren)S""I'. is described (vide itifro). [FeD(NEa)N.(tren)C!t replaces the apical thiolale ligand found in [FeDN4(treD)SMe2t with a nitrogen. To our knowledge this is the.fIrst known aliphatic Fe-N5 complex. [FeD(NEa)N4(tren)ar is a six-roordinate FeU species, lacking an open site for substrate coordination. This and oilier changes in the structural and electronic factors induced by the removal of the thiolate moiety most likely plays a key role in impeding this Fell center from performing superoxide reduction. [FeuN4(tren)SMdt reacts with KOz under protic conditions, forming a metastabie FelllROOH species. [FeIIN4(tren)SMt2t also reacts with dioxygen to form [FemSMe2N4(tren)h~02+, an inert IJ.-Qxo dimer. In an effort to stabilize this Felli-DOH species and prevent JA.-oxo dimer formation, [FeDSMdN4(bdpa)t and [FeDSMe2N4(bdea)t are described. These species use alkylated derivatives of tren containing no protons within the primary coordination sphere of the FeU complex. The preliminary characterization and reactivity studies with these complexes are described in this dissertation.