N-substituted indenoisoquinolines and syntheses thereof
Inventors
Cushman, Mark S. • Morrell, Andrew E. • Nagarajan, Muthukaman • Pommier, Yves G. • Agama, Keli K. • Antony, Smitha
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-8053443-B2
Publication Date
2011-11-08
Expiration Date
2026-11-13
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Abstract
N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for treating cancer in mammals using the described N-substituted indenoisoquinoline compounds or pharmaceutical formulations thereof.
Core Innovation
The invention describes N-substituted indenoisoquinoline compounds, specifically substituted 11H-indeno[1,2-c]isoquinoline compounds and their dimers formed with a divalent linker. The invention provides pharmaceutical compositions of these compounds and processes for their preparation. Methods for treating cancer in mammals using therapeutically effective amounts of these compounds or pharmaceutical formulations thereof are also described.
The problem addressed by the invention relates to the ongoing challenges in cancer treatment, particularly the need for compounds that effectively target cancer cells or cellular mechanisms involved in cancer proliferation. Existing chemotherapeutic agents often have limited clinical efficacy, especially against slower growing solid tumors. Known inhibitors of topoisomerase I like camptothecin have toxicity issues, instability, and reversible inhibition that reduce effectiveness. Therefore, there is a need for potent, chemically stable topoisomerase I inhibitors with improved DNA binding characteristics for cancer treatment.
The invention provides novel N-substituted indenoisoquinoline compounds that act as inhibitors of topoisomerase I by stabilizing DNA-topoisomerase I cleavage complexes and inhibiting the DNA religation reaction after cleavage. These compounds may be chemically more stable than camptothecin and demonstrate unique DNA binding site selectivities. The compounds have demonstrated antineoplastic activity in various human cancer cell lines and may be useful for treating cancers characterized by abnormally fast cell growth or proliferation, particularly those responsive to enzyme inhibition such as topoisomerase I inhibition.
Claims Coverage
The patent includes two independent claims related to novel N-substituted indenoisoquinoline compounds and their dimers, with inventive features in their chemical structure and functionality as cancer treatments.
Novel chemical structure of N-substituted indenoisoquinoline compounds
The compounds have a formula featuring substitutions including R6 groups selected from a wide range of functional groups such as haloalkyl, heteroaryl, amino derivatives, and others, with variable integer m defining side chain length. The compounds include monovalent and divalent substituents on Ra and Rd positions, enabling diverse chemical modifications.
Bisindenoisoquinoline dimers linked by specific divalent linkers
The dimers comprise two indenoisoquinoline units connected by a divalent linker X composed of radicals such as —(CR1R2)—, —(NR1)—, and —O—, with restrictions such as no consecutive —O—O— groups. Linker structures include general formulae with defined integer ranges for chain length and substituent types, potentially forming heterocycles.
Pharmaceutical compositions and methods for cancer treatment
Compositions comprising the compounds or their dimers are provided in therapeutically effective amounts for treating cancer in patients. Methods include administration routes and effective dosage ranges, exploiting the compounds’ activity as inhibitors of topoisomerase I and their chemical stability compared to existing agents like camptothecin.
The claims cover the novel chemical entities of N-substituted indenoisoquinolines and their dimers with specified substituents and linkers, emphasizing their utility as topoisomerase I inhibitors in cancer therapy. The inventive features focus on molecular substitutions, dimerization with distinct linkers, and therapeutic applications in oncology.
Stated Advantages
The compounds may be chemically more stable than camptothecin due to the absence of the lactone ring.
These compounds exhibit potent inhibition of topoisomerase I with potentially longer in vitro and in vivo activity than conventional treatments.
Compounds show unique DNA binding site selectivities relative to camptothecin.
Demonstrated antineoplastic activity across diverse human cancer cell lines, including slower growing solid tumors.
Documented Applications
Treatment of cancer in mammals using N-substituted indenoisoquinoline compounds or pharmaceutical formulations thereof.
Use as inhibitors of topoisomerase I, acting as topoisomerase I poisons to stabilize DNA cleavage complexes and inhibit DNA religation.
Pharmaceutical compositions for cancer therapy including parenteral and oral administration routes.
Screening and evaluation against human cancer cell line panels (COMPARE screening) to identify cytotoxic activity.
In vivo anticancer activity evaluation using hollow fiber assays in animal models to assess reduction in viable tumor cell mass.
Methods for synthesizing the compounds for use in therapeutic applications.
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