Naphthoquinone containing gold carbene complexes and methods of uses thereof
Inventors
ARAMBULA, Jonathan • ARUMUGAM, Kuppuswamy • Sessler, Jonathan L. • BIELAWSKI, Christopher
Assignees
Wright State University • University of Texas System • Georgia Southern University
Publication Number
US-11332483-B2
Publication Date
2022-05-17
Expiration Date
2038-06-29
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Abstract
The present disclosure relates gold carbene naphthoquinone compounds and salts thereof. In some aspects, these compounds can be used to treat cancer including cancers which are resistant to one or more other chemotherapeutic agents such as cisplatin or platinum chemotherapeutic agents. Also provided herein are pharmaceutical compositions comprising the gold carbene naphthoquinone compounds.
Core Innovation
The invention provides gold carbene naphthoquinone compounds and their salts, which can act as dual-action therapeutic agents. These compounds contain two different biologically active centers, where the naphthoquinone complex is believed to function as a redox cycling agent that increases reactive oxygen species production, and the gold carbene portion inhibits thioredoxin reductase, thus reducing the cell's ability to modulate reactive oxygen species. Pharmaceutical compositions containing these compounds are also disclosed.
The core problem addressed is the development of resistance in cancer cell lines to commonly used metal-based chemotherapeutic agents, especially platinum compounds like cisplatin. In particular, cancers such as ovarian cancer develop resistance mechanisms often involving mutations in TP53, limiting the effectiveness of available therapies. Additionally, many current therapeutic agents target a single biological effector, resulting in limited efficacy due to the redundancy in biological pathways.
This invention aims to solve these challenges by creating therapeutic agents that impact multiple biological points within the same pathway. Specifically, by both elevating reactive oxygen species levels and reducing the cellular tolerance to such species, the disclosed compounds increase the likelihood of achieving effective therapeutic results in resistant cancers and certain parasitic infections. These agents are designed to be less susceptible to resistance from TP53 mutation and can be administered in various forms suitable for medical use.
Claims Coverage
There are two primary independent inventive features covered by the claims: a novel class of gold carbene naphthoquinone compounds with defined chemical structure, and pharmaceutical compositions including these compounds with an excipient.
Gold carbene naphthoquinone compound of defined formula
The invention covers a compound of the formula: - M1 is an Au or Ag ion; - R1, R2, R3, and R4 are each independently alkyl (C≤12), cycloalkyl (C≤12), aryl (C≤18), aralkyl (C≤18), or a substituted version of any of these groups, or —(CRaRb)C(O)Y1; where Y1 is selected from amino, hydroxy, alkoxy (C≤8), substituted alkoxy (C≤8), alkylamino (C≤8), substituted alkylamino (C≤8), dialkylamino (C≤8), or substituted dialkylamino (C≤8), and Ra and Rb are each independently the side chain of a canonical amino acid or various alkyl, cycloalkyl, aryl, heteroaryl, or aralkyl groups or their substituted versions; - R5 and R6 are each independently hydrogen, amino, cyano, halo, hydroxy, nitro, thio, or a defined set of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, alkoxy, alkylamino, dialkylamino, or a substituted version or —(OCH2CH2)xZ1 (with further definition for x and Z1); - m and n are each independently 1, 2, 3, or 4; - X1 is Cl−, Br−, I−, PF6−, BF4−, OTf−, SbF6−, AgCl2−, ClO4−, NO3−, or H3CC(O)O−. This structural definition allows for extensive substitution, covering a wide range of potential compounds within the described formula.
Pharmaceutical composition comprising the gold carbene naphthoquinone compound
The inventive feature includes a pharmaceutical composition comprising: - (A) a compound defined in the claim (the gold carbene naphthoquinone compound); - (B) an excipient. The composition is suitable for use as a pharmaceutical product, providing the active compound in combination with a pharmaceutically acceptable excipient.
The claims broadly cover a structurally defined class of gold carbene naphthoquinone compounds and their inclusion in pharmaceutical compositions with excipients, supporting a range of therapeutic uses.
Stated Advantages
The compounds may be more efficacious, less toxic, longer acting, more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile than compounds known in the prior art.
The compounds are designed to achieve multiple biological effects, both increasing reactive oxygen species and reducing the threshold of reactive oxygen species tolerance, to improve therapeutic effectiveness.
The compounds are less susceptible to resistance due to their ability to bypass dependence on the TP53 enzyme.
Documented Applications
Treatment of cancer, including platinum resistant cancers such as platinum resistant ovarian, lung, mesothelioma, bladder, head and neck, cervical, or esophageal cancer.
Induction of immunogenic cell death in cancer cells.
Treatment of infections with parasites, including those associated with tropical diseases or intracellular parasites.
Applications where the inhibition of thioredoxin reductase is beneficial.
Applications where increased production of reactive oxygen species is therapeutically advantageous.
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