Invention:
This invention comprises a class of tetrazolium-based prochelators for targeting and binding intracellular iron and thereby interfere in cancer cell proliferation or other iron dysregulation. The redox potential of various analogues within this class of compounds can be tuned for targeting of cancer cells. Following cellular uptake, the tetrazolium compounds of the present invention undergo reduction to produce formazan species that are capable of intracellular binding of various metals. In this approach, the initial prochelator compound forms an active metal-binding chelator under specific conditions in order to minimize indiscriminate depletion of essential metal ions and potential side effects. The tetrazolium prochelators are stable in blood serum and present antiproliferative activities at micromolar concentrations, as confirmed against a panel of various cancer cell lines. Multiple cell-based assays demonstrate that the compounds impact intracellular iron signaling and that the toxicity is associated, at least in part, to iron sequestration.
Background:
Iron is an essential element and is the most abundant transition metal in humans. The normal functions of human cells rely on iron due to its vital role in oxygen transport, energy generation, and DNA synthesis. Altered metabolism and homeostasis of transition metal ions (such as iron, copper, and zinc) are associated with several pathological conditions including cancer and neurodegeneration. Thus, metal-binding compounds (chelators) that affect metal availability in disease conditions may be potential drug candidates. Malignant cells have a higher demand for iron to sustain their rapid proliferation rates. As a result, targeting iron metabolism in cancer cells has become a promising strategy in cancer therapy. Iron chelation therapy is a treatment that removes iron in the organism by utilizing a small-molecule scavenger. This invention uses tetrazolium salts as prochelators, namely precursors to iron chelators that can limit intracellular iron availability and cause cell death. The invention relates to methods of making the tetrazolium salts and methods of treatment using the compounds.
Applications:
- Cancer treatment
- Neurodegeneration
- Iron overload treatment
Advantages:
- Targeting of iron metabolism
- Tune-able redox chemistry for cancer cell type
- Based on chemistry already widely used and accepted to assess cellular proliferation and viability
