Methods and Compositions for Treating Cancer

• US 20090264421A1
• Filed: 03/18/2009
• Published: 10/22/2009
• Est. Priority Date: 10/05/2007
• Status: Abandoned Application

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Inventors: Xu, Ruifang, Isham, Crescent R., Bible, Keith C., Tibodeau, Jennifer D.
• Application Number:
  US12/406,444
• Publication Number:
  US 20090264421A1
• Time in Patent Office: Days
• US Class Current: 514/222.800
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 513/08 Bridged systems

Abstract

Compositions and methods for treating cancer, including hematologic cancers such as multiple myeloma, are disclosed. In some embodiments, chaetocin, chaetomin, or gliotoxin can be used to treat or ameliorate one or more symptoms or disorders associated with multiple myeloma.

Claims

1. A composition comprising a compound according to Formula I:

or a pharmaceutically acceptable salt or derivative thereof,

wherein R, R′

, R₂, and R₂′

, independently, can be selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heteroalkyl, heterocyclyl, halo, pseudohalo, carboxy, haloalkyl, hydroxyalkyl, alkaryl, aralkyl, aminocarbonyl, aminoalkyl, alkylcarbonyl, arylcarbonyl, alkoxy, alkylthio, aryloxy, and arylthio;

or

wherein R and R₂, and/or R′ and

R₂′

, independently, together to which the atoms to which they are attached, form a fused heterocyclic ring system which is optionally substituted with one or more alkyl, cycloalkyl, alkoxy, aryl, hydroxy, heteroaryl, heteroalkyl, heterocyclyl, halo, pseudohalo, carboxy, haloalkyl, hydroxyalkyl, alkaryl, aralkyl, aminocarbonyl, aminoalkyl, alkylcarbonyl, arylcarbonyl, alkoxy, alkylthio, aryloxy, or arylthio groups, or another optionally substituted aryl, heterocyclyl, or cycloalkyl fused ring system,

provided that R and R′

are not substituted with the same group when R₂ and R₂′

are both H, and provided that if R and R₂ form a fused ring heterocyclic ring system, then R′ and

R₂′

do not also form a fused ring heterocyclic system, and if R and R₂ form a fused ring heterocyclic ring system and R′

is methyl, then R₂′

is not hydroxyalkyl or alkyl.

2. The composition according to claim 1, wherein R and R′

are selected independently from hydrogen, halo, pseudohalo, hydroxyl, alkyl having from 1 to 8 carbon atoms, aralkyl, where the alkyl group has from 1 to 8 carbon atoms, alkaryl, where the alkyl group has from 1 to 8 carbon atoms, hydroxyalkyl, where the alkyl group has from 1 to 8 carbon atoms, alkylcarbonyl, where the alkyl group has from 1 to 8 carbon atoms, and arylcarbonyl.

3. The composition according to claim 1, wherein R and R′

are independently selected from H, methyl, ethyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl.

4. The composition according to claim 1, wherein R₂ and R₂′

are independently selected from hydrogen, halo, pseudohalo, alkyl having from 1 to 8 carbon atoms, and hydroxyalkyl, where the alkyl group has from 1 to 8 carbon atoms.

5. The composition according to claim 1, wherein R and R′

are H.

7. A method of treating or ameliorating one or more symptoms associated with cancer in a mammal, comprising administering a composition according to claim 1 or claim 6, or a composition comprising chaetocin, chaetomin, or gliotoxin, or a pharmaceutically acceptable salt or derivative thereof, to said mammal.

8. The method of claim 7, wherein said cancer overexpresses TrxR1.

9. The method of claim 7, wherein said cancer is a hematologic cancer or disorder.

10. The method of claim 9, wherein said cancer is multiple myeloma.

11. The method of claim 9, wherein said cancer is a B-lymphocyte lineage malignancy or disorder.

12. The method of claim 11, wherein said cancer is a leukemia or a lymphoma.

13. A method for inducing oxidative stress in a cancerous cell comprising contacting said cancerous cell with a composition according to claim 1 or claim 6, or a composition comprising chaetocin, chaetomin, or gliotoxin, or a pharmaceutically acceptable salt or derivative thereof.

14. The method of claim 13, wherein said cancer overexpresses TrxR1.

15. The method of claim 13, wherein said cancerous cell is a multiple myeloma cell.

16. A method for inducing apoptosis in a cancerous cell comprising contacting said cancerous cell with a composition according to claim 1 or claim 6, or a composition comprising chaetocin, chaetomin, or gliotoxin, or a pharmaceutically acceptable salt or derivative thereof.

17. A kit comprising a composition according to claim 1 or claim 6.

18. The kit of claim 17 wherein said composition is in the form of an injectible composition.

19. An article of manufacture comprising a composition according to claim 1 or claim 6, wherein said composition is provided for administration to a mammal in the form of a pill, a tablet, a capsule, or a syringe.

20. The method of claim 7, wherein said cancer is a solid tumorous cancer.

21. The method of claim 20, wherein said solid tumorous cancer is selected from the group consisting of lung, breast, prostate, hepatoma, thyroid, colon, cervical, pancreatic, and sarcoma solid tumors.

22. The method of claim 10, wherein said B-lymphocyte lineage malignancy or disorder is selected from MGUS, amyloidosis, heavy chain diseases, cryoglobulinemia, and Waldenstrom'"'"'s macroglobulinemia.

6. A composition of matter comprising a compound having the structure of chaetocin, chaetomin, or gliotoxin, or a pharmaceutically acceptable salt or derivative thereof, and an anticancer drug.