Invention:
This invention comprises a class of tetrazolium-based prochelators for targeting and binding intracellular iron for selective cancer cell antiproliferation or other iron dysregulation. Various analogues within this class of chemistry can be tuned to the redox potential for selective targeting of cancer cell types. Following cellular uptake, the tetrazolium compounds of the present invention undergo reduction to produce metal-binding formazan species that are capable of in vivo binding of various metals. In this approach, the 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 resulting formazan compounds are stable in blood serum and present antiproliferative activities in the 10-30 µM range, as confirmed against a panel of various cancer cell lines.
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) may play important roles in these pathways and may be potential drug candidates for these pathological conditions. 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 (chelator).
This invention uses tetrazolium salts as pro-chelators, 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. A prochelation strategy uses disulfide switches to mask the tridentate binding unit of thiosemicarbazone and aroylhydrazone chelators. Upon cellular uptake, the reduction of the disulfide bond releases a thiolate chelator that coordinates iron with high affinity in mammalian cells. The treatment involves a prodrug strategy in which the pro-chelator forms accumulate in cancer cells and transform into the iron-binding chelator forms. Preliminary results have shown moderate anti-proliferative activity in two cancer cell lines.
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
