Iron Chelation Strategies in Cancer Drug Design: Prooxidant Complexes, Enzymatic Activation, and Photosensitizing

Abstract

The study of iron and its metabolism is a critical endeavor in the pursuit of improving human health. It is a vital component of hemoglobin, which is responsible for oxygen transport in red blood cells, and myoglobin, which helps in oxygen storage in muscles. Iron is also necessary for enzymes involved in energy production, DNA synthesis, and immune system function. Imbalances in iron metabolism, whether too little or too much iron, can have profound health consequences, affecting everything from cognitive function to immune responses.Iron deficiency is one of the most common nutritional deficiencies worldwide and can lead to anemia, a condition characterized by a reduced number of red blood cells or hemoglobin, resulting in fatigue, weakness, and impaired oxygen delivery to tissues. On the other hand, iron overload can also have detrimental effects, contributing to oxidative stress and organ damage. Conditions such as hereditary hemochromatosis, where the body absorbs too much iron, can lead to liver disease, heart problems, and diabetes due to iron deposition in tissues. Iron metabolism is closely linked to tumor growth and progression. Cancer cells require an abundant supply of iron to support their rapid proliferation and survival. Iron is essential for the function of enzymes involved in DNA synthesis and cell division, processes that are heightened in cancer cells. Furthermore, the microenvironment surrounding tumors, often characterized by low oxygen levels (hypoxia), can stimulate mechanisms that increase iron availability, thus facilitating tumor growth. Excess iron can also promote the production of reactive oxygen species (ROS), leading to DNA damage and genomic instability, which can enhance cancer progression. Iron chelation therapy has been an increasingly viable strategy for treating cancer with multiple iron chelators in clinal trials. Chapter one of this work details the relationship between iron and cancer and explores the historical development of small molecule iron chelators used as potential cancer therapies. Chapter two discusses the development of prooxidant iron chelators. Generation of ROS is an emerging strategy in cancer therapy with the discovery of ferroptosis. Many ligands for redox-active complexes with may promote the generation of ROS and kill cancer cells through a combination of iron deprivation and oxidative damage. We developed a series of prochelators that were shown to induce ROS production in cancer cells in contrast to our group’s previously reported ligands. We also showed that the preformed iron complex of our lead compound, (PH4-S)2, displayed cytotoxicity in addition to the ROS generation suggesting the oxidative damage also plays a role in the mechanism of action. Chapter three details the design and synthesis of a novel prochelation approach inspired by FDA-approved ProTides. These phosphoramidate-based prochelators were shown to be stable toward glutathione, only activating the presence of an esterase. This allowed for the release of a salicylate-based thiosemicarbazone intracellularly. Chapter four describes our synthetic work toward the creation of an iron-binding photoacoustic/photosensitizer using naturally derived pheophorbide a, a chlorophyll degradation product. Our approach was to modify two existing ester moieties on the macrocycle with iron binding groups which would allow for the potential imaging of intracellular iron. Finally, chapter five discusses the future direction of each of these projects.