University of Pittsburgh researchers have discovered a novel approach to produce prodrugs capable of selectively targeting cancer cells. Using borylated allylic esters and acetals as protecting groups, and associated production strategies, it is possible to synthesize inert prodrugs to be selectively activated in cancer cells and in the tumor microenvironment. This novel approach could allow clinicians to selectively target cancers reducing the risk of adverse effects associated with off–target mechanisms, improving patient outcomes and quality of life.
Boryl allyloxy groups can be used to develop novel cancer prodrugs. The reactive boronate is cleaved only in the presence of peroxide resulting in a selective cytotoxin release in cancer cells. This novel approach could result in more targeted chemotherapy with fewer adverse effects.
Description
Cytotoxic chemotherapy is a systemic treatment used to treat cancer in hundreds of thousands of patients in the US each year. However, adverse effects, including damage to tissue such as hair, bone marrow, and mucosa, as well as major organ damage, can occur causing long–term medical complications in patients and limiting treatment dose. These adverse effects are a consequence of the cytotoxic agents targeting non-cancerous cells instead of the intended cancer target. To over-come this clinical challenge, much research now focuses on the development of prodrugs – inert agents that can be systemically administered and selectively activated in the unique chemical envi-ronment of cancer cells. Novel prodrugs have been synthesized which are converted to a cytotoxic agent in the presence of high levels of endogenous peroxide levels routinely found in cancer cells and hypoxic environments, and could lead to a new selective treatment for cancer.
Applications
• Cancer
• Targeted drug delivery
Advantages
A boronate group was strategically added in the finally stages of chemical synthesis of a known cytotoxic compound analog. This strategy ensured no interaction of the boronate group with common reaction conditions, which is highly advantageous during the multi-step synthesis process. In cancer cells the boronate group is readily removed by elevated concentrations of endogenous per-oxide releasing the therapeutic agent and selectively targeting cancer cells. In the absence of peroxide, i.e., non-cancerous cells, the prodrug remains inactive reducing the risk of off–target effects.
Invention Readiness
Pederin is a naturally occurring cytotoxic molecule. An analog of pederin (aPED) with a reactive boronate protecting group at position C7 was synthesized using an 11-step linear process to produce BAO-aPED. In lab-based biological conditions, the boronate group was cleaved releasing aPED with 98% efficiency within 20 minutes. Testing BAO-aPED against several cancerous and non-cancerous cell lines including kidney and renal carcinoma cell lines, the prodrug was up to 100–fold more toxic to cancerous cells than non-cancerous cell lines. Further studies showed that high sensitivity of cancer cells to the prodrug correlated to endogenous peroxide cells. BAO groups could be used to develop a variety of prodrugs to selectively target cancer cells with high concentrations of perox-ide.
IP Status
https://patents.google.com/patent/US11738088B2
