Aza-A-ring indenoisoquinoline topoisomerase I poisons
Inventors
Cushman, Mark S. • BECK, Daniel E. • Pommier, Yves
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-10759795-B2
Publication Date
2020-09-01
Expiration Date
2037-03-15
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Abstract
The invention described herein pertains to four series of aza-A-ring indenoisoquinolines, which are inhibitors of topoisomerase IB (Top1), and the processes for preparing said aza-A-ring indenoisoquinolines. Also described are methods for treating cancer in mammals using the described aza-A-ring indenoisoquinoline compounds or pharmaceutical formulations thereof.
Core Innovation
The invention relates to four series of aza-A-ring indenoisoquinoline compounds which function as inhibitors of topoisomerase IB (Top1). This includes their synthesis methods and the use of these compounds or their pharmaceutical formulations for treating cancer in mammals.
Topoisomerase IB catalyzes DNA relaxation essential for replication and transcription in vertebrate cells, producing transient covalent Top1-DNA cleavage complexes. Certain cancer chemotherapeutics, called Top1 poisons, stabilize these complexes, preventing their reversal and causing DNA double-strand breaks which induce apoptosis.
Existing Top1 poisons based on natural camptothecin have limitations including poor water solubility, instability, rapid diffusion, dose-limiting toxicities, drug resistance, and removal by drug efflux pumps, leading to unmet clinical needs for improved treatments. Indenoisoquinoline derivatives have been developed to overcome many of these drawbacks.
Claims Coverage
The claims include a primary compound formula encompassing various substituents and compositions, pharmaceutical compositions containing such compounds, and methods for treating cancer using these compounds alone or in combination.
Compound structure encompassing aza-A-ring indenoisoquinolines with specific substituents
A compound of formula (I) characterized by R1 as various alkyl, alkenyl, heteroalkyl, heteroalkenyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, or arylalkenyl groups optionally substituted, substituents R2 to R5 independently selected from hydrogen, halo, azido, cyano, nitro, hydroxy, amino, thio, or derivatives thereof, or two adjacent substituents forming an optionally substituted heterocycle; with ring atoms A, B, C, and D being either nitrogen or carbon atoms.
Compound selection with specific substituent patterns and nitrogen placement
Compounds wherein R1 is a C1-C12 alkyl, alkenyl, heteroalkyl, heteroalkenyl, or heterocyclyl optionally substituted with various substituents; variations where R1 is —(CH2)nR with n=2,3,4 and R as 1-imidazolyl, 1,2,4-triazol-2-yl, 1-morpholinyl, —N(CH3)2, amino, or —CH2CH(OH)CH2OH; and ring nitrogen located at positions A, B, C or D singly, with R2 to R5 as hydrogen or particular substitutions forming a heterocycle.
Pharmaceutical compositions containing the claimed compounds
Compositions comprising one or more of the described compounds or their pharmaceutically acceptable salts, together with diluents, excipients, or carriers, suitable for administration as medicaments.
Methods for treating cancer
Methods involving administering a therapeutically effective amount of one or more of the claimed compounds, alone or in combination with other compounds of the same or different mode of action, for treating cancer in patients in need thereof.
The claims cover a wide range of aza-A-ring indenoisoquinoline compounds with specific substituent and nitrogen atom configurations, pharmaceutical compositions containing these compounds, and their use in cancer treatment methods, either individually or combined with other therapeutics.
Stated Advantages
Aza-A-ring indenoisoquinolines overcome many drawbacks associated with camptothecin-based Top1 poisons, including issues with stability, solubility, drug resistance, and toxicity.
The synthetic approach allows for preparation of multiple azaindenoisoquinolines with differing lactam nitrogen side chains from a common intermediate, enabling structural diversity.
The compounds demonstrate Top1 poisoning activity and display inhibitory activities against DNA repair enzymes TDP1 and TDP2, which may enhance therapeutic efficacy.
Documented Applications
Treatment of cancer in mammals using aza-A-ring indenoisoquinoline compounds or pharmaceutical formulations thereof.
Use of the compounds in pharmaceutical compositions for administration as medicaments for cancer treatment.
Combination therapies involving administration of the compounds alongside other compounds of the same or different mechanism of action for cancer treatment.
Use of the compounds in cancer cell growth inhibitory applications as evidenced by tested cytotoxicity against various cancer cell lines.
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