Fluoroquinolone derivatives or sulfonamide moiety-containing compounds as inhibitors of tyrosyl-dnaphosphodiesterase (TDP1)
Inventors
Pommier, Yves • Marchand, Christophe • Selvam, Periyasamy • Dexheimer, Thomas • Maddali, Kasthuraiah
Assignees
US Department of Health and Human Services
Publication Number
US-8716295-B2
Publication Date
2014-05-06
Expiration Date
2031-10-27
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Abstract
A method for treating cancer in a subject, comprising administering to a subject having cancer a therapeutically effective amount of (i) a fluoroquinolone derivative that inhibits tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity or (ii) a sulfonamide moiety-containing compound that inhibits tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity, thereby treating the cancer in the subject. In certain embodiments, the fluoroquinolone derivative or sulfonamide moiety-containing compound is co-administered with a topoisomerase I (TopI) inhibitor.
Core Innovation
The invention discloses methods and pharmaceutical compositions for treating cancer by administering therapeutically effective amounts of fluoroquinolone derivatives or sulfonamide moiety-containing compounds that inhibit tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity. These compounds can be administered alone or co-administered with topoisomerase I (TopI) inhibitors such as camptothecin to enhance the anticancer effect. The fluoroquinolone derivatives particularly containing sulfadimidine or sulfadiazine moieties show potent nanomolar inhibition of Tdp1, a DNA repair enzyme that counteracts TopI inhibitors and promotes tumor resistance.
The problem addressed is that chemotherapy often fails due to resistance developed by cancer cells, limiting effective treatment and causing side effects at higher cytotoxic drug doses. Tdp1 repairs DNA lesions caused by TopI inhibitors, thereby reducing their anticancer activity. Hence, inhibiting Tdp1 presents a strategy to potentiate TopI inhibitors and overcome resistance, allowing lower doses and reducing side effects.
The invention further includes pharmaceutical formulations of these fluoroquinolone derivatives or sulfonamide moiety-containing compounds with TopI inhibitors. The compounds can induce selective cytotoxicity in cancer cells with less toxicity to normal cells, and methods to treat a wide variety of cancers including solid tumors, adenocarcinomas, and melanomas are disclosed. Synergistic effects of these inhibitors with TopI agents were demonstrated in experiments on human osteosarcoma cells.
Claims Coverage
The patent includes several independent claims directed at methods of treating cancer and pharmaceutical compositions involving fluoroquinolone derivatives inhibiting Tdp1, frequently combined with TopI inhibitors.
method for treating cancer using combined TopI inhibitors and fluoroquinolone Tdp1 inhibitors
Administering to a subject having cancer a therapeutically effective amount of a TopI inhibitor and a fluoroquinolone derivative inhibiting Tdp1 activity to treat cancer, specifically colon cancer or human osteosarcoma, wherein the TopI inhibitor is selected from camptothecin, irinotecan, topotecan, or saintopin, and the fluoroquinolone derivative has specific substituents detailed in defined chemical formulas.
method for treating cancer using fluoroquinolone derivative alone inhibiting Tdp1
Administering a therapeutically effective amount of a fluoroquinolone derivative that inhibits Tdp1 activity to treat cancer.
method for inhibiting Tdp1 activity in biological samples using fluoroquinolone derivatives
Inhibiting Tdp1 activity by contacting a biological sample with a fluoroquinolone derivative that inhibits Tdp1.
pharmaceutical composition comprising TopI inhibitor and fluoroquinolone derivative inhibiting Tdp1
Pharmaceutical compositions containing therapeutically effective amounts of a TopI inhibitor (selected from camptothecin, irinotecan, topotecan, or saintopin) and a fluoroquinolone derivative inhibiting Tdp1 activity with specified chemical structures.
The independent claims focus on the use of fluoroquinolone derivatives that inhibit Tdp1 activity either alone or in combination with TopI inhibitors to treat cancers such as colon cancer and osteosarcoma, and on pharmaceutical compositions containing these combinations, emphasizing chemical structural features of the fluoroquinolone derivatives.
Stated Advantages
Fluoroquinolone derivatives and sulfonamide moiety-containing compounds exhibit potent nanomolar inhibition of Tdp1, enhancing the efficacy of TopI inhibitors.
These compounds can synergize with TopI inhibitors to inhibit cancer cell growth, allowing potential dose reduction of cytotoxic drugs and minimizing side effects.
Selective cytotoxicity is induced in cancer cells with reduced or minimal toxicity to normal cells, improving therapeutic safety.
The compounds have balanced hydrophilicity and hydrophobicity aiding their bioavailability and tumor cell penetration, enhancing in vivo efficacy.
Documented Applications
Treatment of various cancers including colon cancer, human osteosarcoma, carcinomas, sarcomas, adenocarcinomas, melanomas, and a broad list of solid tumors.
Combination therapies using fluoroquinolone or sulfonamide moiety-containing Tdp1 inhibitors with TopI inhibitors such as camptothecin, irinotecan, topotecan, or saintopin to enhance anticancer effects.
Use in inhibiting cancer cell proliferation, invasiveness, metastasis, and inducing cytotoxicity selectively in cancer cells compared to normal cells.
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