N-substituted indenoisoquinolines and syntheses thereof
Inventors
Cushman, Mark S. • Morrell, Andrew E. • Nagarajan, Muthukaman • Pommier, Yves G. • Agama, Keli K. • Antony, Smitha • BECK, Daniel E.
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-9217010-B2
Publication Date
2015-12-22
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
N-substituted indenoisoquinoline compounds, particularly substituted 11H-indeno[1,2-c]isoquinoline compounds and their dimers linked by divalent linkers, are described along with pharmaceutical formulations comprising these compounds. Processes for preparing these compounds are also detailed, as well as methods for treating cancer in mammals by administering therapeutically effective amounts of these compounds or pharmaceutical compositions thereof.
The problem addressed by the invention lies in the challenges of effective cancer treatment, especially the need for chemotherapy agents that specifically target cancer cells or their proliferation mechanisms. Existing anticancer agents, such as camptothecin which inhibits topoisomerase I, are limited due to toxic side effects, molecular instability, and reversible inhibition allowing cancer cell recovery. Consequently, there remains a need for potent, stable inhibitors of topoisomerase I with effective anticancer activity against diverse human cancers, including slower growing solid tumors, where current treatments lack clinical efficacy.
The invention presents N-substituted indenoisoquinoline compounds that act as topoisomerase I poisons by stabilizing DNA-topoisomerase I cleavage complexes and inhibiting the DNA religation reaction. These compounds exhibit biological and pharmacological activities similar to camptothecins but are chemically more stable due to the absence of a lactone ring and may have unique DNA binding site selectivities. The invention further includes detailed synthetic processes for these compounds, including reactions involving benz[d]indeno[1,2-b]pyran-5,11-dione intermediates with various primary amines and polyamines, enabling preparation of both mono-indenoisoquinolines and bisindenoisoquinoline dimers.
Claims Coverage
The claims include independent claims directed to synthetic processes for preparing substituted indenoisoquinoline compounds, specifying reactants, reaction conditions, and substituents defining compound structures.
Process for preparing substituted indenoisoquinoline compounds
A process comprising reacting 2-carboxybenzaldehyde compounds with phthalide compounds to yield intermediates, followed by cyclization under acidic conditions or using coupling reagents to produce benz[d]indeno[1,2-b]pyran-5,11-dione derivatives, which are further reacted with primary amines or polyamines to form substituted indenoisoquinoline compounds or bisindenoisoquinoline dimers.
Selection of substituents and reaction conditions for compound synthesis
The process includes defining substituents Ra and Rd on the aromatic rings, selection of m (integer from 0 to about 6), and R6 substituents on the primary amines, with specific embodiments such as Ra as 3-nitro and Rd as 9-methoxy. Cyclizing steps employ one or more acids.
The claims focus on inventive synthetic processes for preparing N-substituted indenoisoquinoline compounds with defined substituents and reaction parameters, enabling production of compounds with potential anticancer activity and improved chemical stability.
Stated Advantages
The compounds may be chemically more stable than camptothecin due to the absence of a lactone ring.
The compounds exhibit potent anticancer activity through inhibition of topoisomerase I and stabilization of DNA-topoisomerase I cleavage complexes.
The compounds may have unique DNA binding site selectivities relative to camptothecin.
The compounds are effective against various types of human cancers, including potentially slower growing solid tumors.
Documented Applications
Treatment of cancer in mammals by administering therapeutically effective amounts of N-substituted indenoisoquinoline compounds or their pharmaceutical compositions.
Use as topoisomerase I poisons to inhibit DNA religation reaction catalyzed by topoisomerase I.
Antineoplastic agents with activity demonstrated by COMPARE screening and hollow fiber in vivo models for human cancer cell lines.
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