Mito-honokiol compounds and methods of synthesis and use thereof
Inventors
Kalyanaraman, Balaraman • Zielonka, Jacek Michal • Cheng, Gang • Hardy, Micael J. • Ouari, Olivier • You, Ming
Assignees
Aix Marseille Universite • Medical College of Wisconsin
Publication Number
US-11897910-B2
Publication Date
2024-02-13
Expiration Date
2036-06-10
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Abstract
The present invention provides mito-honokiol or mito-magnolol compounds, pharmaceutical compositions thereof, and methods of using the mito-honokiol or mito-magnolol compounds in the treatment of cancer.
Core Innovation
The invention provides novel mito-honokiol and mito-magnolol compounds, which are mitochondria-targeted derivatives of honokiol and magnolol linked via long alkyl chains to a triphenylphosphonium (TPP) moiety. These modifications significantly increase the compounds’ ability to selectively inhibit cancer proliferation and progression. The compounds include both mono-substituted and bis-substituted forms and are capable of exerting potent anticancer effects at much lower concentrations compared to their parent compounds.
The problem addressed by the invention arises from the limited efficacy and significant side effects associated with previous honokiol modifications and mitochondrial OXPHOS inhibitors. Cancer cells frequently become resistant to standard therapies, in part through metabolic reprogramming that increases their reliance on mitochondrial respiration (OXPHOS). Existing inhibitors such as rotenone or cyanide exhibit low therapeutic indices and are non-specific, while drugs like metformin are limited by weak mitochondrial targeting.
This invention solves the problem by employing TPP-mediated mitochondrial targeting to enhance the delivery of honokiol and magnolol analogs directly into tumor cell mitochondria, exploiting the increased negative mitochondrial membrane potential characteristic of cancer cells. The resulting compounds display 100- to 1,000-fold increased antiproliferative activity over their non-targeted counterparts, lack the toxicity of conventional OXPHOS inhibitors, and efficiently inhibit tumor cell growth, metastasis, and therapeutic resistance, as demonstrated in multiple in vitro and in vivo cancer models.
Claims Coverage
There are three independent inventive features claimed, primarily covering novel compounds, methods of use, and methods to inhibit metastasis.
Mito-magnolol compound with specific structural features
The invention claims a mito-magnolol compound characterized by: - Specific structures as shown in the claims, including mono- and bis-substituted forms where n is an integer from 1–18 (with preferred ranges specified). - The compound features L1 and/or L2 as organic linkers attached to the triphenylphosphonium moiety. - Variations where L2 can be H or other specified linkers, and the presence of alkyl side chains of specific lengths. - Compounds include selected examples with n as 9 or 10 and those with both L1 and L2 having n as an integer from 1–12.
Method of reducing or inhibiting tumor growth with mito-magnolol compounds
The invention claims a method which involves: - Administering a therapeutically effective amount of a pharmaceutical composition comprising at least one mito-magnolol compound as claimed to a subject. - The method is specifically for reducing or inhibiting tumor growth in cancers including melanoma, lung cancer, colon cancer, and pancreatic cancer. - The scope includes application to metastatic tumors and methods combined with antiglycolytic agents or other standard-of-care drugs, as well as surgery, radiation therapy, or chemotherapy.
Method of inhibiting or reducing metastasis with mito-magnolol compounds
The invention claims a method which includes: - Administering an effective amount of a pharmaceutical composition containing the mito-magnolol compound to a patient to inhibit or reduce metastasis of cancer. - Applicable to cancer types such as melanoma, colon cancer, lung cancer, and pancreatic cancer. - The method covers inhibition or reduction of metastasis in lymph nodes or distal organs.
The claims comprehensively cover the novel mito-magnolol compounds, their use in treating and inhibiting tumor growth and metastasis (including specific cancer types), and their combination with other therapies and antiglycolytic agents.
Stated Advantages
The compounds are 100–1,000 times more potent in inhibiting tumor cell proliferation than their parent, non-mitochondria-targeted analogs.
Mitochondria-targeted analogs lack the toxicity and off-target effects associated with conventional mitochondrial OXPHOS inhibitors, providing a high therapeutic index.
The compounds demonstrate selective inhibition of tumor, but not normal, cells, resulting in minimal toxic effects on healthy tissues.
The invention provides effective inhibition of tumor formation and metastasis, including in chemoresistant and metastatic cancers.
The compounds sensitize tumors to existing therapies and can be used synergistically with antiglycolytic agents and standard-of-care treatments.
They can prevent, inhibit, or delay the onset of drug resistance in various cancers by targeting adaptive metabolic shifts in tumor cells.
The synthesis approach allows for straightforward modification and large-scale preparation of active compounds.
Documented Applications
Treatment of cancers such as melanoma, lung cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, ovarian cancer, thyroid cancer, non-Hodgkin’s lymphoma, and leukemia.
Inhibition or reduction of tumor metastasis, including metastasis to lymph nodes and distal organs (such as brain, liver, stomach, pancreas).
Use in overcoming resistance to chemotherapies, including resistance to kinase inhibitors, checkpoint inhibitors, and standard anti-cancer drugs.
Method for protecting healthy (non-cancerous and neuronal) cells during cancer therapy.
Combination therapy with antiglycolytic agents (e.g., 2-deoxyglucose), chemotherapeutics, radiation, or surgery.
Use in stimulating T cell response or augmenting the effect of anti-cancer immunotherapies (e.g., PD-1/PD-L1 inhibitors).
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