Triarylmethane analogs and their use in treating cancers
Inventors
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-9358226-B2
Publication Date
2016-06-07
Expiration Date
2028-12-29
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Abstract
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are triphenyl methane analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, inflammatory, degenerative and vascular diseases, including various ocular diseases, and parasitic infections. Representative triphenyl methane analogs include triphenyl methane analogs of various dyes, hormones, sugars, peptides, oligonucleotides, amino acids, nucleotides, nucleosides, and polyols. The compounds are believed to function by inhibiting tNOX expression, the effects of ROS, and/or the production of HIF2. Thus, the compounds are novel therapeutic agents for a variety of cancers and other diseases.
Core Innovation
The invention discloses compounds, pharmaceutical compositions including these compounds, and methods of preparation and use thereof. The compounds are triarylmethane compounds, specifically triphenyl methane analogs formed by reacting diaryl ketones with aromatic or heteroaromatic compounds in the presence of a Lewis acid. These compounds have diverse structures including analogs of dyes, hormones, sugars, peptides, amino acids, and nucleotides. The prodrug forms, in which the iminium group is reduced, provide advantages such as higher lipophilicity and less irritation, with in vivo reoxidation restoring the active form.
The compounds function by mechanisms including inhibiting NAD(P)H oxidase (Nox) enzymes, particularly Nox1-5 and cancer-specific variants like tNox, inhibiting reactive oxygen species (ROS), promoting superoxide scavengers, and inducing G2/M cell cycle arrest. They are effective in selectively killing cancer cells, including metastasized tumor cells, while sparing healthy cells. They inhibit factors such as tNOX expression, ROS effects, and hypoxia inducible factor 2 (HIF2) production, which contribute to tumor growth and angiogenesis.
The problem addressed arises from the role of reactive oxygen species and NADPH oxidases in cancer progression and inflammatory, degenerative, and vascular diseases. Existing treatments for cancer often lack selectivity and have adverse effects due to non-specific cytotoxicity. There is a need for therapies that target reactive oxygen species and Nox enzymes, particularly in cancers and other diseases mediated by ROS, without harming normal cells. Additionally, there is a lack of effective, safe treatments for inflammatory and degenerative diseases involving ROS, as well as for parasitic infections such as malaria and leishmaniasis.
Claims Coverage
The patent contains four independent claims encompassing compound definitions and their therapeutic uses. The inventive features include the compound structures and therapeutic methods for treating cancers and parasitic infections.
Compound defined by specific triarylmethane structures
The invention includes compounds represented by defined chemical formulas describing triarylmethane analogs with specified substituents and linkages, including compounds like imipramine blue.
Method for treating reactive oxygen-driven cancers using defined compounds
A method of administering a therapeutically effective amount of the specified compound to a mammal to treat cancers driven by reactive oxygen species.
Method for treating parasitic infections using defined compounds
A method of administering a therapeutically effective amount of the specified compound to treat parasitic infections including malaria and trypanosomiasis in mammals.
Use of imipramine blue for treating diseases
Use of imipramine blue, a specific triarylmethane compound defined by formula, for treating cancers such as multiple myeloma and infectious parasitic diseases.
The claims cover the chemical compounds defined by triarylmethane formulas, and their therapeutic use in treating reactive oxygen-driven cancers and parasitic infections, highlighting methods of administration and specific compound embodiments such as imipramine blue.
Stated Advantages
Selective killing of cancer cells including metastatic cells, sparing healthy cells.
Potent inhibition of Nox enzymes and reactive oxygen species, targeting cancer and inflammatory disease pathways.
Reduced toxicity and side effects compared to conventional chemotherapeutic agents due to selective action.
Prodrugs with better cellular uptake and reduced irritation, enabling effective delivery and activation within tumors.
Potential for combination therapy with other anticancer agents for enhanced therapeutic effects.
Documented Applications
Treatment and prevention of a wide variety of cancers, including metastatic cancers such as melanoma, leukemia, lung, colon, breast, prostate, ovarian, CNS, renal cancers, and hematological malignancies like multiple myeloma and lymphoma.
Treatment of inflammatory, degenerative, and vascular diseases involving reactive oxygen species, including ocular diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, uveitis, and dry eye.
Treatment of parasitic infections including malaria, trypanosomiasis (sleeping sickness), and leishmaniasis with specific compound examples tested in models.
Use in combination therapies with known anticancer agents, proteasome inhibitors, kinase inhibitors, and other pharmacological agents.
Use for treatment of osteoporosis by modulating RANKL activity and osteoclastogenesis.
Potential neuroprotection by ameliorating inflammation and ROS-mediated neurodegeneration in diseases like Alzheimer's, Parkinson’s, multiple sclerosis, and stroke.
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