Debunking Endogenous Ozone & Towards Tert-Butylated 3-Pyridinols and 5-Pyrimidinols

Abstract

Hydrocarbon autoxidation, a free radical chain reaction, is one of the most important chemical processes, and is ubiquitous in biological systems and industry. While it is vital to maintaining cellular homeostasis and plays central roles in the immune and inflammatory responses, it is also believed to play a role in the onset and development of diseases and degenerative disorders when not kept in check. In vivo, this process is generally initiated by the reduction of O2 to superoxide (O2•-), which can then afford various reactive oxygen species (ROS), such as HOO•, H2O2, HO•, and 1O2. Recently, it was suggested that antibodies, as part of the immune system, produce another ROS: ozone. The evidence for endogenous ozone formation was based largely on the isolation of the known cholesterol ozonolysis products in extracts of arterial plaque and brain tissue. Identification was accomplished by derivatization and subsequent HPLC-MS analysis. Herein, an alternative, more likely explanation for the appearance of these two compounds and their derivatized forms is given, via acid-catalyzed Hock cleavage of cholesterol 5-hydroperoxide. Radical-trapping chain-breaking antioxidants inhibit hydrocarbon autoxidation; in Nature and as additives in industrial materials, formulations, etc. Nature typically employs phenols in this context, and it is well documented that their potency is based largely on the lability of their phenolic O-H bond. While their reactivity can be improved by making the phenol more electron-rich by introducing electron-donating groups on the aromatic ring, this increases their air (oxygen) sensitivity, leading them to decompose in air and generate ROS themselves! To prevent this, nitrogen(s) can be introduced in the aromatic ring to make 3-pyridinols and 5-pyrimidinols; the most effective air-stable radical-trapping antioxidants reported to date. Unfortunately, introduction of nitrogen in the phenolic ring leads to a concomitant increase in the acidity of the O-H bond, leading to stronger interactions with H-bond accepting solvents. This interaction reduces the efficacy of these compounds as antioxidants in polar and heterogeneous media. Herein we describe our efforts to minimize the effect of this interaction, thereby maintaining the strong antioxidant activities of 3-pyridinols and 5-pyrimidinols, by introducing two tert-butyl moieties flanking the reactive hydroxyl group.