FLUOROQUINOLONE DERIVATIVES OR SULFONAMIDE MOIETY-CONTAINING COMPOUNDS AS INHIBITORS OF TYROSYL-DNAPHOSPHODIESTERASE (TDP1)

• US 20120172371A1
• Filed: 10/27/2011
• Published: 07/05/2012
• Est. Priority Date: 10/27/2010
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: National Institutes of Health (NIH) (Government of the United States of America), US Department of Health and Human Services (Government of the United States of America)
• Inventors: Pommier, Yves, Marchand, Christophe, Selvam, Periyasamy, Dexheimer, Thomas, Maddali, Kasthuraiah
• Granted Patent: US 8,716,295 B2
• Time in Patent Office: Days
• US Class Current: 514/252.18
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 9/99 Enzyme inactivation by chemical treatment
• CPC Class Codes: C12Y 301/04 Phosphoric diester hydrolases (3.1.4)

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.

Claims

1. A method for treating cancer in a subject, comprising administering to a subject having cancer a therapeutically effective amount of a topoisomerase I (TopI) inhibitor and 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.

4. The method of claim 1, wherein the Tdp1 inhibitor is the fluoroquinolone derivative, and the fluoroquinolone derivative comprises:

5. The method of claim 4, wherein R₄ is

6. The method of claim 5, wherein each R⁵ is methyl.

7. The method of claim 4, wherein:

R₁ is cyclopropyl, R₂ is methoxy, R₃ is methyl, and R₄ is

8. The method of claim 1, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety in the sulfonamide moiety-containing compound is a sulfadimidine moiety or a sulfadiazine moiety.

10. The method of claim 1, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety in the sulfonamide moiety-containing compound is coupled to a nitrogen-containing fused heterocyclic moiety.

12. The method of claim 10, wherein the nitrogen-containing fused heterocyclic moiety is selected from isatin, benzimidazole, isoindole, indole, isoindazole, isoindoline, indoline or purine.

14. The method of claim 1, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety-containing compound, or a pharmaceutically acceptable salt or ester thereof, has a structure represented by formula II:

16. The method of claim 1, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfadimidine moiety-containing compound, or a pharmaceutically acceptable salt or ester thereof, may have a structure represented by formula IV:

18. The method of claim 14, wherein R¹⁰ comprises a substituted or unsubstituted benzimidazole.

20. The method of claim 1, wherein the TopI inhibitor comprises a camptothecin.

21. The method of claim 1, wherein the cancer is colon cancer or human osteocarcinoma.

2. 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.

9. The method of claim 2, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety in the sulfonamide moiety-containing compound is a sulfadimidine moiety or a sulfadiazine moiety.

11. The method of claim 2, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety in the sulfonamide moiety-containing compound is coupled to a nitrogen-containing fused heterocyclic moiety.

13. The method of claim 11, wherein the nitrogen-containing fused heterocyclic moiety is selected from isatin, benzimidazole, isoindole, indole, isoindazole, isoindoline, indoline or purine.

15. The method of claim 2, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfonamide moiety-containing compound, or a pharmaceutically acceptable salt or ester thereof, has a structure represented by formula II:

17. The method of claim 2, wherein the Tdp1 inhibitor is the sulfonamide moiety-containing compound, and the sulfadimidine moiety-containing compound, or a pharmaceutically acceptable salt or ester thereof, may have a structure represented by formula IV:

19. The method of claim 15, wherein R¹⁰ comprises a substituted or unsubstituted benzimidazole.

3. A method for inhibiting tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity in a biological sample with Tdp1 activity, comprising contacting the biological sample with (i) a fluoroquinolone derivative that inhibits Tdp1 activity or (ii) a sulfonamide moiety-containing compound that inhibits tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity, thereby inhibiting Tdp1 activity.

22. A pharmaceutical composition, comprising a therapeutically effective amount of a TopI inhibitor and a therapeutically effective amount of (i) a fluoroquinolone derivative that inhibits Tdp1 activity, or (ii) a sulfonamide moiety-containing compound that inhibits tyrosyl-DNA-phosphodiesterase 1 (Tdp1) activity.