טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentOkun Zoya
SubjectMetallocorroles for Therapeutic and Related Applications
DepartmentDepartment of Chemistry
Supervisor Professor Zeev Gross
Full Thesis textFull thesis text - English Version


Abstract

Oxidative stress, the situation occurring due to an imperfect balance between the required and excessive amounts of reactive oxygen and nitrogen species (ROS and RNS respectively), is nowadays well recognized as a key contributor to numerous diseases. This is the rational behind the extensive search for synthetic antioxidants and further exploration of the antioxidant potential of natural products.

One of the research goals of this study was to examine metallocorroles as catalysts for the decomposition of ROS and RNS in cellular models of diabetes and neurodegenerative diseases, by investigating if and how well they may protect cells from toxin-induced oxidative damage. The results revealed that the ability to decompose peroxynitrite (PN) is not limited to chemical systems, but that water-soluble corrole complexes act as potent antioxidants in cellular models as well. Corroles were cytoprotective against damage induced by PN, hydrogen peroxide and 6-hydroxydopamine.In all these cases, the metallocorroles were more potent than the analogous porphyrins. Next, we focused on studies to increase the catalytic anti-oxidative performances of water-soluble manganese(III) corroles via the establishment of a structure-activity relationship. Towards this goal, we have prepared a series of compounds similar to the most efficient manganese(III) corrole regarding catalytic decomposition of PN and superoxide radical. The new complexes, corroles bearing positively-charged substituents that differ only in the C10 meso substituent, were examined regarding PN decomposition rates and the prevention of nitration by it, as well as for the ability to decompose superoxide radical. The results provided new insight regarding the mechanism by which manganese(III) corroles act as catalytic antioxidants, and disclosed the superiority of the C10-anysil-substituted complex in all examined aspects.

Another aspect presented in this thesis is cellular uptake and organ accumulation of the water-soluble corroles. The results revealed that corroles penetrate cellular membranes and accumulate in the cytoplasm, but remain excluded from the nucleus. Regarding the distribution among body organs, the intraperitoneally injected fluorescent gallium(III) derivative was found to accumulate in tissues sections of the kidney, liver, lung, heart, and pancreas. It also reached the brain blood vessels, but did not cross the blood brain barrier (BBB). These findings are of prime importance for future in vivo studies on disease models, as they point toward a large utility of this kind of corrole chelates for treating cancer, neurodegenerative diseases characterized by “leaking BBB”, cardiovascular diseases, and diabetes.