Targeting redox-active pyridinium cations to mitochondria to inhibit proliferation of drug-resistant cancer cells
Inventors
Zielonka, Jacek Michal • Sikora, Adam Bartlomiej • Kalyanaraman, Balaraman
Assignees
LODZ UNIVERSITY OF TECHNOLOGY • Medical College of Wisconsin
Publication Number
US-12358935-B2
Publication Date
2025-07-15
Expiration Date
2039-11-01
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Abstract
The present invention provides novel mito-pyridinium compounds, prodrugs and the uses thereof for the treatment of cancer, particularly drug resistant cancer.
Core Innovation
The invention provides novel mitochondria-targeted redox cycling agents, termed mito-pyridinium compounds and their prodrugs, designed to inhibit bioenergetic function and stimulate oxidative stress specifically in cancer cells, including colon and pancreatic cancers, particularly drug-resistant human cancer cells. These agents work by inducing superoxide production within mitochondria, leading to the inhibition of cancer cell proliferation and induction of cell death. The compounds carry two positive charges due to the conjugation of a pyridinium cation with a triphenylphosphonium (TPP+) moiety, enhancing both uptake and activity within mitochondria.
The background identifies the problem of colorectal cancer (CRC) being highly resistant to conventional chemotherapy, especially in metastatic states, resulting in poor prognosis and low survival rates. Drug resistance in CRC affects 90% of patients with metastatic disease, creating an unmet need for new therapeutic agents capable of overcoming this resistance.
The invention solves this problem by synthesizing novel redox-active pyridinium compounds linked to TPP+, which selectively accumulate in mitochondria of cancer cells. These compounds induce exceptionally high levels of superoxide generation compared to existing mitochondria-targeted agents, disrupt mitochondrial bioenergetics, oxidize mitochondrial peroxiredoxin-3, deplete cellular ATP, and thereby suppress proliferation and induce death of drug-resistant cancer cells. The compounds' efficacy depends on the nature of substituents on the pyridinium ring and the length of the alkyl linker connecting the pyridinium and TPP+ moieties.
Claims Coverage
There are seven main inventive features covering compounds, prodrugs, and methods for their use in cancer treatment and superoxide stimulation.
Compounds of formula I with specified substituents and linker length
Compounds defined by formula I or prodrugs thereof where n is an integer from 1-18 (preferably 4-10 or 8-10+), and substituents R1 to R5 are independently selected from specific groups such as —H, —OCH3, —CH3, —CF3, —C(O)NH2, —CN, —C(O)CH3, and —NO2, exemplified by various specific compounds (e.g., Mito-MeP-C10, Mito-NA-C10, Mito-CNP-C10, Mito-NP-C4 to C10).
Prodrug forms of the compounds
Prodrugs of the compounds of formula I, which are biologically inactive or less active precursors metabolized to active mito-pyridinium compounds in vivo, including specific prodrug structures.
Method of stimulating superoxide production within a cell
Contacting cancer cells, including colon or pancreatic and drug-resistant cancer cells, with the compound or prodrug in an amount effective to stimulate superoxide production.
Method of inhibiting cancer cell growth or proliferation
Contacting cancer cells or administering to subjects with cancer selected from colon, rectum, pancreas, prostate, lung and bronchus, breast, brain, liver, oral, bladder, stomach cancers, and leukemia, including drug-resistant forms, with effective amounts of the compounds or prodrugs to inhibit growth or proliferation.
Method of treating cancer in a subject
Administering a therapeutically effective amount of the compounds or prodrugs to treat cancer, including drug-resistant forms, optionally combined with radiation, chemotherapy, immunotherapy, or combinations thereof.
The claims cover novel mito-pyridinium compounds and their prodrugs defined by specific chemical structures, methods for inducing superoxide production, inhibiting cancer cell growth, and treating various cancers including drug-resistant types, with provisions for combination treatments.
Stated Advantages
The compounds selectively accumulate in mitochondria of cancer cells, enhancing effectiveness.
They induce unprecedented levels of superoxide production within cancer cells, surpassing other mitochondria-targeted agents.
Dual mechanism action by inhibiting mitochondrial respiration and redox cycling leads to potent anti-proliferative and cytotoxic effects on cancer cells.
Effective against drug-resistant cancer cells, including resistant colorectal and pancreatic cancers.
The use of prodrugs improves cellular uptake and increases intracellular levels of active compounds, enhancing potency.
Potential for combination therapy with standard chemotherapy, radiation, and immunotherapy without significant side effects at therapeutic doses.
Documented Applications
Treatment of colon cancer, including drug-resistant and metastatic colorectal cancer.
Treatment of pancreatic cancer, including drug-resistant pancreatic ductal adenocarcinoma.
Treatment of various other cancers including rectum, prostate, lung and bronchus, breast, brain, liver, oral, bladder, stomach cancers, and leukemia.
Use in combination with chemotherapy, radiation, immunotherapy, and standard-of-care drugs for enhanced therapeutic effect.
In vivo application demonstrated by inhibition of tumor growth in a syngraft mouse model using prodrug Mito-NPH.
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