Inhibition of NF-kappaB by triterpene compositions

• US 20060148732A1
• Filed: 11/16/2001
• Published: 07/06/2006
• Est. Priority Date: 11/17/2000
• Status: Abandoned Application

• Current Assignee: Research & Development Foundation
• Original Assignee: Research & Development Foundation
• Inventors: Haridas, Valsala, Gutterman, Jordan U.
• Application Number:
  US09/992,556
• Publication Number:
  US 20060148732A1
• Time in Patent Office: Days
• US Class Current: 514/33
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/702 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides methods for the inhibition of inflammation by providing, to a cell, in need thereof, monoterpene compositions that inhibit NF-κB. These compositions may also contain a carrier moiety that renders the monoterpene composition membrane permeable. The carrier may include triterpenoid moieties, sugars, lipids, or even additional monoterpenoid moieties. The composition can also contain additional chemical functionalities. Methods for using these compounds to prevent and treat a wide range of inflammatory conditions, especially, premalignant inflammatory conditions are described.

Claims

1. A method of inhibiting inflammation comprising administering to a cell a monoterpene composition that inhibits NF-κ

B.

2. The method of claim 1, wherein said NF-κ

B is induced by TNF.

3. The method of claim 1, wherein said composition further comprises a carrier moiety.

4. The method of claim 3, wherein said carrier moiety comprises a lipid.

5. The method of claim 3, wherein said carrier moiety comprises a membrane permeable composition.

6. The method of claim 3, wherein said carrier moiety comprises a sugar.

7. The method of claim 3, wherein said carrier moiety comprises a triterpene moiety.

8. The method of claim 1, wherein the monoterpene composition further comprises a triterpene moiety.

9. The method of claim 1, wherein the monoterpene composition further comprises a sugar.

10. The method of claim 1, wherein the monoterpene composition further comprises a second monoterpene moiety.

11. The method of claim 8, wherein said triterpene moiety comprises the formula:

12. The method of claim 11, wherein R₁ and R₂ each comprise an oligosaccharide.

13. The method of claim 12, wherein R₁ and R₂ each comprise a monosaccharide, a disaccharide, a trisaccharide or a tetrasaccharide.

14. The method of claim 13, wherein R₁ and R₂ each comprise an oligosaccharide comprising sugars which are separately and independently selected from the group consisting of glucose, fucose, rhamnose, arabinose, xylose, quinovose, maltose, glucuronic acid, ribose, N-acetyl glucosamine, and galactose.

15. The method of claim 14, wherein at least one sugar is methylated.

16. The method of claim 11, wherein R₄ is attached to the triterpene moiety through one of the methylene carbons attached to the triterpene moiety.

17. The method of claim 11, wherein said triterpene moiety further comprises at least one double bond.

18. The method of claim 11, wherein said isomer is a stereoisomer.

19. The method of claim 11, wherein said isomer is an optical isomer.

20. The method of claim 8, wherein said triterpene moiety is an acacic acid ester, a oleanolic acid ester, a betulinic acid ester, an ursolic acid ester, a quinovic acid ester, a pomolic acid ester, a rotundic acid ester, a rotungenic acid ester, a madasiatic acid ester, an asiatic acid ester, an euscaphic acid ester, a tormentic acid ester, madecassic acid ester, a lupeolic acid ester, a cylicodiscic acid ester, a mollic acid ester, a jessic acid ester, an echinocystic acid ester, or an entagenic acid ester.

21. The method of claim 1, wherein said monoterpene moiety comprises the formula:

22. The method of claim 21, wherein said isomer is a cis isomer.

23. The method of claim 1, wherein said isomer is a trans isomer.

24. The method of claim 21, wherein R₃ is a sugar.

25. The method of claim 24, wherein the sugar is selected from the group consisting of glucose, fucose, rhamnose, arabinose, xylose, quinovose, maltose, glucuronic acid, ribose, N-acetyl glucosamine, and galactose.

26. The method of claim 24, further comprising a monoterpene moiety attached to the sugar.

27. The method of claim 21, wherein R₃ has the following formula:

28. The method of claim 27, wherein R₅ is a hydrogen or a hydroxyl.

29. The method of claim 21, wherein said isomer is a stereoisomer.

30. The method of claim 21, wherein said isomer is an optical isomer.

31. The method of claim 21, wherein R₃ has the following formula:

32. The method of claim 21, wherein R₃ has the following formula:

33. The method of claim 1, wherein said composition comprises the formula:

34. The method of claim 33, wherein said isomer is a stereoisomer.

35. The method of claim 33, wherein said isomer is an optical isomer.

36. The method of claim 1, wherein said composition comprises the formula:

37. The method of claim 1, wherein said composition comprises the formula:

38. The method of claim 1, wherein said composition comprises the formula:

39. The method of claim 1, wherein said inflammatory responses are inhibited when said composition is administered to said cell at a concentration of from about 0.5 to about 2.0 μ

g/ml.

40. The method of claim 1, wherein said cell is in a subject having an inflammatory disease.

41. The method of claim 40, wherein said subject is a human.

42. The method of claim 40, wherein said inflammatory disease is selected from the group comprising premalignant inflammatory disease, arthereosclerosis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Parkinson'"'"'s disease, and Alzheimer'"'"'s disease.

43. The method of claim 42, wherein said premalignant inflammatory disease is Barretts esophagitis, inflammatory bowel disease, chronic pancreatitis, chronic prostatitis, familial polyposis, actinic keratosis.

44. The method of claim 1, wherein said composition inhibits COX-2.

45. The method of claim 1, wherein said composition inhibits iNOS.

46. The method of claim 1, wherein said administering is local.

47. The method of claim 46, wherein said administering is by injection.

48. The method of claim 46, wherein said administering is topical.

49. The method of claim 1, wherein said administering is systemic.

50. The method of claim 1, wherein said administering is oral.

51. The method of claim 1, wherein said composition is a pharmaceutical composition in a pharmacologically acceptable medium.

52. The method of claim 51, wherein said pharmacologically acceptable medium is a buffer, a solvent, a diluent, an inert carrier, an oil, a creme, or an edible material.

53. The method of claim 52, wherein said pharmaceutical composition further comprises a targeting agent.

54. The method of claim 53, wherein said targeting agent directs delivery of said pharmaceutical composition to an inflamed cell.

55. The method of claim 7, wherein said triterpene moiety is an acacic acid ester, a oleanolic acid ester, a betulinic acid ester, an ursolic acid ester, a quinovic acid ester, a pomolic acid ester, a rotundic acid ester, a rotungenic acid ester, a madasiatic acid ester, an asiatic acid ester, an euscaphic acid ester, a tormentic acid ester, madecassic acid ester, a lupeolic acid ester, a cylicodiscic acid ester, a mollic acid ester, a jessic acid ester, an echinocystic acid ester, or an entagenic acid ester.