טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentHaber Adi
SubjectInteractions of Corroles with Macromolecules
DepartmentDepartment of Chemistry
Supervisor Professor Zeev Gross
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


Abstract

The corrole is a member of the porphyrinoid family, whose naturally occurring derivatives are key components in vital biological processes. Synthetic porphyrins are of great importance in numerous applications in chemistry, biology, material science and medicine. Leading examples regarding the last aspect include the involvement in anti-cancer treatments, as well as in the combat against reactive oxygen and nitrogen species (ROS and RNS). Our general goal is to identify applications where corroles are superior.


Previous research has revealed that amphiphilic corroles are able to induce damage to cultured cancerous cells when bound to a carrier protein. Any extension to in vivo research has to take into account the possible association of corroles with serum proteins, which may act as mediators for specific uptake to cancerous cells. This research focused on serum transferrin, the protein responsible for transporting iron. Transferrin was chosen because it penetrates into cells by a specific receptor, which shows high density on rapidly dividing cells and the endothelial cells of the blood-brain barrier but not on resting cells.

For the amphiphilic corroles investigated in this study we found that several corrole molecules (2-7) bind to the protein, with one of these binding sites of the highest affinity. The dissociation constant of the strong binding site is 10-6-10-7 M for the gallium complex and in the magnitude of 10-9 M for the metal free corrole. Importantly, this dissociation constant is relevant for corrole binding under physiological conditions, as the concentration of transferrin in serum is 2.5-4∙10-5 M.


ROS and RNS are produced in the body during normal metabolism. A raise above the physiological need leads to oxidative stress, which is considered to cause the development of Parkinson's disease, atherosclerosis and more. Atherosclerosis is generated because of oxidative modification of low density lipoproteins (LDL) by ROS. The oxidized form of LDL enters macrophage cells in a non-controlled fashion, leading to accumulation of large quantities of cholesterol in the cells, and gradually to the formation of the atherosclerotic lesion.

The iron(III) and manganese(III) corroles were excellent catalysts for decomposition of H2O2 and HOONO. We have now explored the in vitro effect of these metallocorroles on LDL to evaluate their potential as atherosclerosis inhibitors. The iron corrole gave excellent results, reducing the formation of oxidation products and preventing cholesterol accumulation in macrophage cells. This complex is currently tested for its in vivo effect.