Fulvene and fulvalene analogs and their use in treating cancers
Inventors
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-8841276-B2
Publication Date
2014-09-23
Expiration Date
2028-05-02
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Abstract
Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are fulvene and/or fulvalene analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, as well as numerous inflammatory, degenerative and vascular diseases, including various ocular diseases. Representative fulvene and/or fulvalene analogs include fulvene and fulvalene analogs of various dyes, hormones, sugars, peptides, oligonucleotides, amino acids, nucleotides, nucleosides, and polyols. The compounds are believed to function, at least, by inhibiting Nox or ROS. In some embodiments, the Nox is one that is selectively expressed in cancer cells over normal cells, or one that is expressed in higher amounts in cancer cells over normal cells. Thus, the compounds are novel therapeutic agents for a variety of cancers and other diseases.
Core Innovation
The present invention discloses compounds which are fulvene and/or fulvalene analogs, as well as pharmaceutical compositions containing these compounds, and methods of their preparation and use. The compounds can be formed by reacting a cyclopentadienyl anion with ketone or aldehyde groups on intermediates or by attaching fulvene or fulvalene-containing carboxylic acids to hydroxyl, thiol, or amine-containing molecules such as sugars, nucleosides, amino acids, or peptides.
These compounds are believed to function primarily by inhibiting Nox enzymes or reactive oxygen species (ROS). They can selectively inhibit forms of Nox that are more prevalent or selectively expressed in cancer cells, such as Nox1-5 or tNox, especially Nox4, which is more expressed in cancer cells than normal cells. By inhibiting these enzymes or ROS, the compounds provide a novel therapeutic approach to selectively kill cancer cells, including metastatic and drug-resistant cancers, while sparing normal cells.
The problem being addressed is the need for cancer treatments that do not cause the adverse effects associated with non-selective conventional chemotherapeutics and the need for new treatments for inflammatory, degenerative, and vascular diseases linked to reactive oxygen species. The invention overcomes current limitations by targeting specific Nox enzymes implicated in cancer growth and other diseases by employing fulvene and fulvalene analogs which can inhibit ROS production and cancer cell proliferation selectively.
Claims Coverage
The patent contains three claims, including two compound claims and one pharmaceutical composition claim, covering unique chemical structures and compositions.
Compound of formula I
A compound characterized by a specific chemical formula comprising fulvene and/or fulvalene analogs with defined substitutions and structural features.
Compound of formula II
A compound structurally related to formula I, having particular functional groups and molecular structures as depicted in formula II.
Pharmaceutical composition comprising the compound
A pharmaceutical composition containing the compound of formula I or its pharmaceutically acceptable salt, formulated together with pharmaceutically acceptable carriers or excipients suitable for therapeutic administration.
The inventive features encompass the chemical structures of fulvene and fulvalene analog compounds and their inclusion in pharmaceutical compositions for therapeutic use as claimed.
Stated Advantages
Selective killing of cancer cells, including metastatic and drug-resistant types, without harming healthy cells.
Potent therapeutic effect against a wide variety of cancers and other diseases associated with reactive oxygen species.
Novel mechanism of action by selectively inhibiting Nox enzymes prevalent in cancer cells, minimizing side effects of conventional chemotherapy.
Potential therapeutic application extended to inflammatory, degenerative, and vascular diseases beyond cancer.
Documented Applications
Treatment and prevention of a wide variety of cancers, including melanoma, leukemia, non-small cell lung, colon, CNS, renal, ovarian, breast, and prostate cancers.
Treatment of drug-resistant and metastatic cancers.
Use in treating inflammatory disorders such as rheumatoid arthritis, asthma, psoriasis, lupus, scleroderma, and various heart and gastrointestinal diseases.
Treatment of ocular diseases including dry and wet age-related macular degeneration, diabetic retinopathy, glaucoma, ocular inflammation, and dry eye.
Treatment of osteoporosis by inhibiting RANKL induced osteoclast activation.
Potential treatment for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's Chorea, multiple sclerosis, and ischemic brain injury.
Applications in vascular disorders, including erectile dysfunction and migraines, where reactive oxygen species are involved.
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