|Ph.D Thesis||Department of Chemistry|
|Supervisors:||Prof. Gross Zeev|
|Prof. Aviram Michael|
|Full Thesis text|
The imbalance between the desired production of reactive oxygen/nitrogen species (ROS/RNS) and the capability of biological systems to detoxify excess amounts thereof, a situation called oxidative stress, is involved in the development and progression of many diseases. Oxidation of the cholesterol carriers, low and high density lipoproteins (LDL and HDL, respectively), is a major cause for the development of atherosclerosis, as it increases the pro-atherogenicity of LDL and reduces the anti-atherogenicity of HDL. Consumption of dietary antioxidants is hence advised for preventing the risk of atherosclerosis. Transition-metal complexes of corroles may serve as ROS/RNS decomposition catalysts, as opposed to the sacrificial mode of action of natural antioxidants, and are hence appealing alternatives for the treatment of oxidative stress driven diseases.
In this thesis we have discovered that complexes of the bis-sulfonated amphipolar corrole preferably associate to lipoproteins on the expense of all other serum components, thus pointing towards atherosclerosis as an appropriate target for treatment by these corroles. We further found that the iron(III) complex of the bis-sulfonated corrole (1-Fe) binds with very high affinity and selectivity to HDL, and serves as a shield that protects HDL against oxidation and consequential loss of anti-atherogenic properties. On the other hand, the manganese(III) complex of the same corrole 1-Mn increased lipoprotein oxidation, and the non-redox active gallium(III) complex 1-Ga had no effect.
A new detection method we have developed allowed for direct determination of intracellular amounts of 1-Fe. This cellular fraction of the compound served well for protecting macrophage cells against both basal and induced oxidative stress. Despite the negative results regarding lipoprotein oxidation in non-biological media, 1-Mn displayed cellular protection at the same level as 1-Fe. Interestingly, 1-Ga was highly toxic toward the cells. An unexpected discovery is that 1-Fe inhibited cellular cholesterol biosynthesis in macrophages. This is a highly important property, considering that statins, the most prescribed pharmaceuticals for reducing the risk of atherosclerosis, reduce blood cholesterol levels by delaying cellular cholesterol biosynthesis.
Treatment of mice (genetically engineered to develop atherosclerosis) with the various corroles showed that 1-Fe is highly beneficial, 1-Mn is moderately effective, and 1-Ga is non-efficient for reducing atherosclerosis development. The effectiveness of 1-Fe was displayed both in young asymptomatic mice and in aged mice with advanced atherosclerosis. The discoveries of this work pave the way for ongoing regulated preclinical studies that are needed for advancing metallocorroles towards potential drugs for treating cardiovascular diseases.