WO2012130481A1 - INHIBITION OF NF-kB ACTIVITY BY TRITERPENE COMPOUNDS - Google Patents

INHIBITION OF NF-kB ACTIVITY BY TRITERPENE COMPOUNDS Download PDF

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WO2012130481A1
WO2012130481A1 PCT/EP2012/050203 EP2012050203W WO2012130481A1 WO 2012130481 A1 WO2012130481 A1 WO 2012130481A1 EP 2012050203 W EP2012050203 W EP 2012050203W WO 2012130481 A1 WO2012130481 A1 WO 2012130481A1
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compounds
triterpenic
activity
ene
triterpenes
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PCT/EP2012/050203
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French (fr)
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Burak Erman
Gulacti TOPCU
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Koc Universitesi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the NF- ⁇ activity-inhibiting effect of some triterpenes obtained from the plant Salvia kronenburgii. These triterpenes are 1 ⁇ ,2 ⁇ ,3 ⁇ , 11 ⁇ - tetrahydroxy-urs-12-ene, 3-acetyl and 1 ⁇ ,2 ⁇ ,3 ⁇ , 1 1 ⁇ -tetrahydroxy-olean-12-ene, 3-acetyl.
  • the present invention describes the use of triterpenic compounds with the following chemical formula as an inhibitor of the NF- ⁇ activity,
  • R 2 are hydrogen and/or methyl.
  • the present invention further relates to the use of pharmaceutical compositions which are prepared from said triterpenes as an inhibitor of the NF- ⁇ activity.
  • the present invention is based on the notion that the NF- ⁇ activity inhibition effect of those triterpenes which have an ursane or oleanane skeleton stems from the presence of an acetate group at C-3 and a hydroxyl group on C-1 1.
  • the presence of an acetyl group at position 3 and a hydroxyl group at position 11 in urs-12-ene or olean-12-ene triterpenes imparts the respective compound an NF- ⁇ (NF-KappaB) activity inhibition effect.
  • Triterpenes are compounds composed of 6 isoprene units containing 30 carbon atoms, which are represented with around 4000 compounds having around 40 different skeletons. Although there are triterpenes with a wide range of skeletons, the Salvia species give place mainly to those triterpenes having the oleanane and ursane skeleton.
  • Triterpenes show different biological activities based on their different skeletal structures and particularly their different functional groups, or even their different stereoisomers.
  • the present invention describes the NF- ⁇ activity-inhibiting effect of 1 ⁇ ,2 ⁇ ,3 ⁇ , 11 ⁇ - tetrahydroxy-urs-12-ene, 3-acetyl and ⁇ ,2a ⁇ , 11 a-tetrahydroxy-olean-12-ene, 3-acetyl triterpenes obtained from the plant Salvia kronenburgii and that the NF- ⁇ activity- inhibiting effect of these triterpenes stems from the presence of an acetate group (-OAc) on the 3 rd carbon atom and an hydroxy group (-OH) on the 11 th carbon atom.
  • -OAc an acetate group
  • -OH hydroxy group
  • the present invention relates to the use of triterpenic compounds with the following chemical formula as an inhibitor of the NF- ⁇ activity,
  • F ⁇ and R 2 are hydrogen or methyl.
  • the present invention more specifically relates to the NF- ⁇ activity-inhibiting effect of two compounds with a triterpene structure isolated from the roots of the Salvia kronenburgii plant.
  • the formulas of the molecules with documented activity are given below.
  • the 6 th fraction among these was composed of the fractions obtained while the main column was washed with 1-5% methanol, and amounted to 350 mg.
  • Two active triterpenes inhibiting the N F-KB activity (74 mg total) were separated from each other and purified in a dichloromethane- methanol (75:25) system by means of preparative TLC from this 6 th fraction, such that two isomers were obtained, i.e. 1 ⁇ ,2 ⁇ ,3 ⁇ , 1 1 ⁇ -tetrahydroxy-urs-12-ene, 3 ⁇ -acetyl (35 mg)", which has an ursane skeleton (35 mg), and the oleanane isomer thereof (13 mg).
  • the structures of these compounds were characterized by 1 D and 2D-NMR ( 1 H; COSY, 13C BB and APT, HMQC and HMBC techniques) and HRMS spectral measurements.
  • a tissue culture cell line reporter system has been developed to determine the roles of the medical chemical compounds on the NF- ⁇ signal transduction pathways.
  • This reporter system comprises HEK293 human kidney cell lines transfected with a stable reporter plasmid expressed with green fluorescent protein when the NF- ⁇ is activated.
  • the plasmid was linearized and transfected into HEK293 cells according to the technique described in the Ph.D. thesis of Xi Cheng, titled "High-Throughput Functional Analysis of Human Gene Promoters Using Transfected Cell Arrays", Max Planck Institute, Molecular Genetics, 2010.
  • the roles of the medical chemical compounds were identified by administering increasing doses (3 fold) of the compounds dissolved in methanol to HEK293+GFP cells. Some compounds in diluted concentrations inhibited the expression of GFP in a reproducible manner. This finding shows that these compounds do inhibit a stage of the activation of the NF- ⁇ signal transduction pathway.
  • the preparation, activation, and quantification processes were performed according to the study of the thesis referred to above.
  • the triterpenic compounds according to the present invention are suitable for therapeutic use as an inhibitor of the NF- ⁇ activity.
  • these compounds may be administered in suitable pharmaceutical dosage forms with effective doses.
  • These forms may comprise tablets, capsules, gels, granules, powders, creams, ointments, etc. which are known to those skilled in the art.
  • various formulations of the compounds according to the present invention may be prepared using pharmaceutically acceptable carriers.
  • the present invention provides a method for the treatment of diseases associated with the activation of NF- ⁇ . These comprise the diseases in which infectious conditions come into question.
  • NF- ⁇ activation includes inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive lung disease (COLD), fibrotic disorders, dermatosis, autoimmune disorders, various viral diseases, AIDS, tissue and organ rejection, Alzheimer's diseases, etc..

Abstract

The present invention relates to the NF-κΒ activity-inhibiting effect of some triterpenes obtained from the plant Salvia kronenburgii. These triterpenes are 1β,2α,3β, 11 α-tetrahydroxy-urs-12-ene, 3-acetyl and 1β,2α,3β, 11α-tetrahydroxy-olean-12-ene, 3-acetyl. The present invention further relates to the use of pharmaceutical compositions which are prepared from said triterpenes as an inhibitor of the NF-κΒ activity.

Description

DESCRIPTION
INHIBITION OF NF-κΒ ACTIVITY BY TRITERPENE COMPOUNDS
Field of Invention
The present invention relates to the NF-κΒ activity-inhibiting effect of some triterpenes obtained from the plant Salvia kronenburgii. These triterpenes are 1 β,2α,3β, 11 α- tetrahydroxy-urs-12-ene, 3-acetyl and 1 β,2α,3β, 1 1α-tetrahydroxy-olean-12-ene, 3-acetyl.
The present invention describes the use of triterpenic compounds with the following chemical formula as an inhibitor of the NF-κΒ activity,
Figure imgf000002_0001
wherein and R2 are hydrogen and/or methyl.
The present invention further relates to the use of pharmaceutical compositions which are prepared from said triterpenes as an inhibitor of the NF-κΒ activity.
The present invention is based on the notion that the NF-κΒ activity inhibition effect of those triterpenes which have an ursane or oleanane skeleton stems from the presence of an acetate group at C-3 and a hydroxyl group on C-1 1. The presence of an acetyl group at position 3 and a hydroxyl group at position 11 in urs-12-ene or olean-12-ene triterpenes imparts the respective compound an NF-κΒ (NF-KappaB) activity inhibition effect.
Prior Art Triterpenes are compounds composed of 6 isoprene units containing 30 carbon atoms, which are represented with around 4000 compounds having around 40 different skeletons. Although there are triterpenes with a wide range of skeletons, the Salvia species give place mainly to those triterpenes having the oleanane and ursane skeleton.
Triterpenes show different biological activities based on their different skeletal structures and particularly their different functional groups, or even their different stereoisomers.
A study of Topcu et al. reports the isolation and structural characterization of 8 triterpenes with ursane and oleanane skeletons from the plant Salvia kronenburgii, among which 6 are novel compounds ("Terpenoids from Salvia kronenburgii", J. Nat. Prod. 1999, 62, 1605-1608). That study discloses the triterpenoid compounds ' ^-acetoxy-urs-12-ene- 1 β,2α, 11 α-ίποΙ" and '^-acetoxy-olean-12-ene-^,2a, 1 1a-trio"l with an inhibiting effect against the NF-κΒ activity, which also constitute the subject matter of the present invention.
The patent application no. WO 2007 103727 A2 makes mention of some triterpenes (Formula 2), which are an inhibitor of the nuclear factor kappa B.
Figure imgf000003_0001
The patent application no. WO02055016A2, in turn, describes the administration of monoterpene compositions comprising a triterpene inhibiting the NF-κΒ activation to a cell.
A paper titled "Ursolic Acid Inhibits Nuclear Factor-κΒ Activation Induced by Carcinogenic Agents through Suppression of ΙκΒα Kinase and p65 Phosphorylation: Correlation with Down-Regulation of Cyclooxygenase 2, Matrix Metalloproteinase 9, and Cyclin D1" studies the effect of ursolic acid on the NF-κΒ activation induced by different carcinogenic agents in different cell types. The effect of ursolic acid on the different stages of the TNF- induced NF-κΒ activation pathway is also studied. The results indicate that ursolic acid inhibits the NF-κΒ activation. The chemical structure of ursolic acid is given below (Formula 3).
Figure imgf000004_0001
Another paper titled "Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages" reports more than 80 newly-synthesized triterpenoids, as well as their oleanolic and ursolic acid derivatives as potential anti-inflammatory and chemopreventive agents. The molecules reported in that paper are given below (Formula 4).
Figure imgf000004_0002
These triterpenes are found to suppress the NF-κΒ activation in nuclear extracts obtained from primary macrophages.
The present invention describes the NF-κΒ activity-inhibiting effect of 1 β,2α,3β, 11 α- tetrahydroxy-urs-12-ene, 3-acetyl and ^,2a^, 11 a-tetrahydroxy-olean-12-ene, 3-acetyl triterpenes obtained from the plant Salvia kronenburgii and that the NF-κΒ activity- inhibiting effect of these triterpenes stems from the presence of an acetate group (-OAc) on the 3rd carbon atom and an hydroxy group (-OH) on the 11th carbon atom. Detailed Description of Invention
The present invention relates to the use of triterpenic compounds with the following chemical formula as an inhibitor of the NF-κΒ activity,
Figure imgf000005_0001
wherein F^ and R2 are hydrogen or methyl.
The present invention more specifically relates to the NF-κΒ activity-inhibiting effect of two compounds with a triterpene structure isolated from the roots of the Salvia kronenburgii plant. The formulas of the molecules with documented activity are given below.
Figure imgf000005_0002
Figure imgf000006_0001
It has been shown in the experiments that these two molecules inhibit one stage of the TNF-activated NF-κΒ signal transduction pathway. In the present invention, computational drug screening tests have been conducted to determine the potential inhibitors of the NF-κΒ family, wherein a series of ursane and oleanane triterpene molecules, isolated from Salvia kronenburgii and having different substituents, have been screened, and resultantly, two triterpenes with urs-12-ene and olean-12-ene structures having a hydroxyl group on C1 , C2, and C11 , and an acetate group on C3 have been determined as the most effective inhibitors on the NF-κΒ pathway.
These two triterpenes found to be active, as isolated from the Salvia kronenburgii plant, are "1 β,2α,3β,1 1a-tetrahydroxy-urs-12-ene,3-acetyl" and '"^,2a^, 11 a-tetrahydroxy- olean-12-ene, 3-acetyl". The NF-κΒ activity-inhibiting effect of these triterpenes stems from the presence of an acetyl group on the 3rd carbon atom and a hydroxyl group (-OH) on the 1 1th carbon atom.
Extraction of Triterpenic Compounds
The aerial parts and roots of the Salvia kronenburgii plant collected from the east of Turkey (Van) for this study were dried in shadow and separately ground into powder, and extracted by means of maceration, first with acetone and then with methanol. As a result, 5 g acetone root, 4.5 g methanol root extract and 7 g aerial (acetone + methanol) extracts were obtained. Both extracts of the aerial parts were run in combination (7 g) since they gave similar spots on silica gel plates by thin layer chromatography (TLC). It was started by eluting the acetone phase-root extract (5 g) loaded into a column with a silica gel adsorbent with hexane, the elution was continued by adding dichloromethane so as to decrease the polarity in a gradual manner, it was then started to add methanol in small percentages once dichloromethane reached 100% and the elution process was completed with 100% methanol. Those fractions which were similar among a total of 60 collected fractions were analyzed by TLC, the similar ones were combined in 8 main fractions and the triterpenes of the plant were obtained mainly from fractions 5, 6, and 7. The 6th fraction among these was composed of the fractions obtained while the main column was washed with 1-5% methanol, and amounted to 350 mg. Two active triterpenes inhibiting the N F-KB activity (74 mg total) were separated from each other and purified in a dichloromethane- methanol (75:25) system by means of preparative TLC from this 6th fraction, such that two isomers were obtained, i.e. 1 β,2α,3β, 1 1α-tetrahydroxy-urs-12-ene, 3β-acetyl (35 mg)", which has an ursane skeleton (35 mg), and the oleanane isomer thereof (13 mg). The structures of these compounds were characterized by 1 D and 2D-NMR (1 H; COSY, 13C BB and APT, HMQC and HMBC techniques) and HRMS spectral measurements.
A tissue culture cell line reporter system has been developed to determine the roles of the medical chemical compounds on the NF-κΒ signal transduction pathways. This reporter system comprises HEK293 human kidney cell lines transfected with a stable reporter plasmid expressed with green fluorescent protein when the NF-κΒ is activated.
The plasmid was linearized and transfected into HEK293 cells according to the technique described in the Ph.D. thesis of Xi Cheng, titled "High-Throughput Functional Analysis of Human Gene Promoters Using Transfected Cell Arrays", Max Planck Institute, Molecular Genetics, 2010. The roles of the medical chemical compounds were identified by administering increasing doses (3 fold) of the compounds dissolved in methanol to HEK293+GFP cells. Some compounds in diluted concentrations inhibited the expression of GFP in a reproducible manner. This finding shows that these compounds do inhibit a stage of the activation of the NF-κΒ signal transduction pathway. The preparation, activation, and quantification processes were performed according to the study of the thesis referred to above.
The triterpenic compounds according to the present invention are suitable for therapeutic use as an inhibitor of the NF-κΒ activity. For this purpose, these compounds may be administered in suitable pharmaceutical dosage forms with effective doses. These forms may comprise tablets, capsules, gels, granules, powders, creams, ointments, etc. which are known to those skilled in the art. To this end, various formulations of the compounds according to the present invention may be prepared using pharmaceutically acceptable carriers. The present invention provides a method for the treatment of diseases associated with the activation of NF-κΒ. These comprise the diseases in which infectious conditions come into question. Other conditions, in which the inhibition of NF-κΒ activation is effective according to the prior art, include inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive lung disease (COLD), fibrotic disorders, dermatosis, autoimmune disorders, various viral diseases, AIDS, tissue and organ rejection, Alzheimer's diseases, etc..

Claims

1 . Use of triterpenic compounds with the following chemical formula as an inhibitor of the N F-KB activity,
Figure imgf000009_0001
wherein and R2 are hydrogen or methyl.
2. The use according to Claim 1 , wherein the triterpenic compound is 1 β,2α,3β, 11 α- tetrahydroxy-urs-12-ene, 3-acetyl.
3. The use according to Claim 1 , wherein the triterpenic compound is 1 β,2α,3β, 11 α- tetrahydroxy-olean-12-ene, 3-acetyl.
4. The use according to Claim 1 , wherein an acetate group on C3 and a hydroxyl group on C11 of said triterpenic compounds have the NF-κΒ activity-inhibiting effect
5. The use according to Claim 1 , wherein the triterpenic compounds are obtained from the roots of Salvia kronenburgii.
6. The use according to Claim 1 , wherein the triterpenic compounds are used in the treatment of diseases which are associated with NF-κΒ activation.
7. The use according to Claim 1 , wherein the triterpenic compounds are used in the manufacture of a medicament together with a pharmaceutically acceptable carrier.
8. A method for inhibiting the NF-κΒ activity, comprising the administration of a triterpenic compounds with the following chemical formula to a patient in the need thereof,
Figure imgf000010_0001
wherein F^ and R2 are hydrogen or methyl.
9. The method according to Claim 8, wherein the triterpenic compound is 1 β,2α,3β, 1 1α- tetrahydroxy-urs-12-ene, 3-acetyl.
10. The method according to Claim 8, wherein the triterpenic compound is 1 β,2α,3β, 1 1α- tetrahydroxy-olean-12-ene, 3-acetyl.
11. The method according to Claim 8, wherein the triterpenic compounds are obtained from the roots of Salvia kronenburgii.
12. The method according to Claim 8, wherein an acetate group on C3 and a hydroxyl group on C11 of said triterpenic compounds have NF-kB activity-inhibiting effect.
13. The method according to Claim 8, wherein the triterpenic compounds are used in the treatment of diseases which are associated with NF-κΒ activation.
14. The method according to Claim 8, wherein the triterpenic compounds are used in the manufacture of a medicament together with a pharmaceutically acceptable carrier.
PCT/EP2012/050203 2011-03-30 2012-01-09 INHIBITION OF NF-kB ACTIVITY BY TRITERPENE COMPOUNDS WO2012130481A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055016A2 (en) 2000-11-17 2002-07-18 Res Dev Foundation INHIBITION OF NF-λB BY TRITERPENE COMPOSITIONS
WO2007103727A2 (en) 2006-03-03 2007-09-13 Savipu Pharmaceuticals Triterpene derivatives for the treatment of cancer and inflammatory disease by inhibition of nf-kb

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055016A2 (en) 2000-11-17 2002-07-18 Res Dev Foundation INHIBITION OF NF-λB BY TRITERPENE COMPOSITIONS
WO2007103727A2 (en) 2006-03-03 2007-09-13 Savipu Pharmaceuticals Triterpene derivatives for the treatment of cancer and inflammatory disease by inhibition of nf-kb

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Terpenoids from Salvia kronenburgii", J. NAT. PROD., vol. 62, 1999, pages 1605 - 1608
GÜLAÇTI TOPÇU ET AL: "Highly Hydroxylated Triterpenes from Salvia k ronenburgii", JOURNAL OF NATURAL PRODUCTS, vol. 67, no. 1, 1 January 2004 (2004-01-01), pages 118 - 121, XP055025276, ISSN: 0163-3864, DOI: 10.1021/np030359b *
GÜLAÇTI TOPÇU ET AL: "Terpenoids from Salvia kronenburgii", JOURNAL OF NATURAL PRODUCTS, vol. 62, no. 12, 1 December 1999 (1999-12-01), pages 1605 - 1608, XP055024902, ISSN: 0163-3864, DOI: 10.1021/np990165p *
SALMINEN A ET AL: "Terpenoids: natural inhibitors of NF-Î B signaling with anti-inflammatory and anticancer potential", CMLS CELLULAR AND MOLECULAR LIFE SCIENCES, BIRKHÄUSER-VERLAG, BA, vol. 65, no. 19, 31 May 2008 (2008-05-31), pages 2979 - 2999, XP019652098, ISSN: 1420-9071, DOI: 10.1007/S00018-008-8103-5 *
TOPCU G: "BIOACTIVE TRITERPENOIDS FROM SALVIA SPECIES", JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 69, no. 3, 9 March 2006 (2006-03-09), pages 482 - 487, XP009069214, ISSN: 0163-3864, DOI: 10.1021/NP0600402 *
VIVEK R. YADAV ET AL: "Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer", TOXINS, vol. 2, no. 10, 1 October 2010 (2010-10-01), pages 2428 - 2466, XP055025275, DOI: 10.3390/toxins2102428 *
XI CHENG: "Molecular Genetics", 2010, MAX PLANCK INSTITUTE, article "High-Throughput Functional Analysis of Human Gene Promoters Using Transfected Cell Arrays"

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