# Mn(II) Complexes of Enlarged Scorpiand-Type Azamacrocycles as Mimetics of MnSOD Enzyme
## 1 Introduction  
Enzymes play a central role in life processes as biological catalysts. Most of the essential chemical processes in living organisms, from metabolism to replication, would not be possible without them speeding up and controlling the chemical reactions that support life. Among the thousands of roles they play, there is a group of enzymes that have evolved to protect organisms from the deleterious effect of certain reactive oxygen species (ROS) produced during the metabolism of molecular oxygen. Among these ROS, superoxide radical (O2\({}^{-}\)), a metabolic by-product generated after the one-electron reduction of molecular oxygen, is recognized as one of the most toxic ones [1].  
To maintain the endogenous O2\({}^{-}\) concentration in a low, beneficial range in the nanomolar level, living organisms are equipped with a family of enzymes known as superoxide dismutase (SOD) [2]. These oxidoreductaseness contain either Cu, Fe, Mn or Ni in their active site, and efficiently transform O2\({}^{-}\) into H2O2 and O2. Nevertheless, a malfunctioning of these protective mechanisms in living systems results in situations of redox imbalance, known in general as oxidative stress, that have been related to a plethoraof health issues, such as cardiovascular diseases, neurodegenerative disorders, inflammation, cancer, cerebral ischemia-reperfusion injury, and even transmissible spongiform encephalopathies [3, 4, 5, 6].  
The direct treatment of this conditions with the native enzymes is limited by a series of factors, among them: the lack of oral activity, immunogenicity, high costs of production, fast degradation, and low membrane permeability. For this reason, in recent decades there have been tremendous efforts to design and prepare low-molecular-weight molecules to mimic, at least in part, the activity of SOD enzymes to be tested as drugs for the different diseases related to oxidative stress. Enzyme mimics are cheaper to produce and might have a better pharmacokinetic profile. Different ligands and metals have been tested for this purpose, and there have been several reviews published covering the topic [7, 8, 9, 10].  
Among the ligands used to prepare SOD mimetics, comprising a Mn atom as the redox centre, it is worth mentioning the success of porphyrins [11], Salen derivatives [12] and azamacrocycles. A relevant example of the later is the compound M40403, prepared by [PERSON] et al. [13]. In the past decade, our research group has contributed to these efforts by developing several Mn\({}^{2+}\) complexes with polyazamacrocycles that showed high SOD activity, both in vitro and in vivo, and good pharmacokinetic characteristics [14, 15, 16]. Some of the ligands prepared belong to a particular family of polyamine macrocycles known as scorpiands, characterized by the presence of a pendant arm, attached to the macrocycle, which contains additional donor atoms [17, 18]. Interestingly, Cu\({}^{2+}\) complexes of these ligands show negligible SOD activity. This can be explained by the large thermodynamic stability of the pentacoordinated complex they form, which prevents the metal centre from interacting with the superoxide anion and cycle between Cu\({}^{2+}\)/Cu\({}^{+}\).  
To increase the structural library of these scorpiand-type molecules, we prepared the compounds L1-L3 shown in Figure 1, enlarged with a propylamine chain, and therefore possessing one additional nitrogen atom in the pendant arm. Furthermore, the compounds were functionalized with different aromatic units: 2-pyridine, 2-quinoline and 1-pyrene. These substituents, of decreasing polarity, should allow us to evaluate how the overall hydrophobicity of the manganese complex affects its SOD-mimetic activity.