Azonafide derived tumor and cancer targeting compounds
Inventors
Tarasova, Nadya I. • Dyba, Marcin • Michejda, Christopher J.
Assignees
US Department of Health and Human Services
Publication Number
US-8008316-B2
Publication Date
2011-08-30
Expiration Date
2027-09-12
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Abstract
An azonafide-based compound of Formula I, a composition comprising the compound, and a method of using the compound to deliver a cytotoxic azonafide derivative to a cell, as well as related compounds and methods for the use thereof to pre-pare an azonafide-based compound of Formula I.
Core Innovation
The invention provides azonafide-based compounds of Formula I, compositions comprising these compounds, and methods of using the compounds to deliver cytotoxic azonafide derivatives to cells. The invention also includes related compounds of Formula II and methods to prepare compounds of Formula I by linking peptides or peptidomimetics to compounds of Formula II. The compounds are designed to deliver cytotoxic molecules while potentially reducing systemic toxicity and targeting specific cells such as cancer cells.
The problem addressed by the invention is the systemic toxicity of drugs used in cancer chemotherapy, particularly azonafides, which, despite inhibiting tumor growth effectively, have dose-limiting toxicity. There is a continuing need for azonafide-based compounds with reduced toxicity that maintain anti-tumor efficacy. The invention seeks to provide compounds and methods that improve targeted delivery of cytotoxic agents to cancer cells and minimize side effects associated with systemic administration.
According to the invention, compounds of Formula I include a structure where a peptide and optionally a cell-targeting construct are linked to the azonafide core. The peptide is cleavable upon interaction with specific cellular receptors or proteases associated with cancer cells, thereby releasing the cytotoxic agent selectively at the tumor site. The compound is stable in general circulation but releases the active moiety upon specific cellular or enzymatic interaction, leading to reduced systemic toxicity. Preparations and linkers, including coupling moieties, peptides, and targeting ligands such as antibodies or peptides cleavable by tumor-associated proteases, form integral parts of the compound design to enable targeted delivery and activation.
Claims Coverage
The patent includes two independent claims, each directed to a class of azonafide-based compounds with specific structural features and related methods of use and preparation.
Azonafide-based compound with peptide and cell-targeting construct
A compound of Formula I that comprises an azonafide core linked through a moiety X, wherein X includes a peptide (A) of two or more amino acids optionally linked to a cell-targeting construct (B) by a coupling moiety (W). The compound structure allows for targeting and delivery of cytotoxic derivatives to cells, with defined ranges and functional groups for the substituents n, p, R1, R2, Z, m, and q.
Azonafide derivative compound for preparation of targeted compounds
A compound of Formula II that serves as a precursor for compounds of Formula I, characterized by a substituent R3 that can be hydrogen, an amine-containing moiety, or linked to a peptide and/or coupling moiety. This compound facilitates single-step or multi-step linkage to peptides and cell-targeting constructs to prepare active Formula I compounds.
Composition comprising the compound
A pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier suitable for administration to deliver cytotoxic azonafide derivatives.
Method of delivering cytotoxic azonafide derivative to cells
A method comprising administering a compound of Formula I to a cell, resulting in the release and delivery of cytotoxic azonafide derivatives upon cleavage of the peptide moiety, targeting specifically cancer or tumor cells either in vitro or in vivo.
Method of preparing Formula I compounds
A method that includes linking a peptide or peptidomimetic to a compound of Formula II, optionally attaching a cell-targeting construct before or after peptide attachment, utilizing coupling agents and functional groups to form compounds of Formula I.
The independent claims collectively cover the structure of azonafide-derived compounds linked to peptides and cell-targeting constructs for targeted delivery, precursor compounds enabling formation of these conjugates, related pharmaceutical compositions, therapeutic methods of delivering cytotoxic agents, and methods for synthesizing these compounds.
Stated Advantages
Reduced toxic side effects associated with systemic administration of azonafide compounds by using peptide and cell-targeting moieties that enable selective release of cytotoxic agents at target cells.
Stability of the compound in general circulation ensures that cytotoxic agents are preferentially released upon specific cellular or protease interactions associated with cancer cells.
Ability to target delivery to specific cancer cell types using cell-targeting constructs such as antibodies or ligands binding to cancer-associated receptors, enhancing therapeutic efficacy.
Compounds of Formula II facilitate preparation of targeted compounds by enabling straightforward attachment of peptides and targeting constructs, thereby simplifying synthesis.
Documented Applications
Delivery of cytotoxic azonafide derivatives to cells, preferably cancer or tumor cells, either in vitro or in vivo, to inhibit growth or proliferation.
Treatment or prevention of various cancers or tumors in mammals, including cancers of skin, lung, stomach, throat, salivary glands, colon, breast, prostate, pancreas, ovaries, uterus, endometrial tubes, leukemia, melanoma, renal cell carcinoma, multiple myeloma, and other azonafide-inhibitable cancers.
Use in research, treatment, or inhibition of cancer, employing the targeted delivery of cytotoxic agents to improve therapeutic outcomes while reducing systemic toxicity.
Pharmaceutical compositions comprising the compounds for oral, parenteral, or topical administration using conventional formulations and carriers suitable for delivering the compound effectively.
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