Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from artemisia
Reexamination Certificate
2003-01-28
2004-10-26
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from artemisia
C514S462000, C514S468000, C549S264000, C549S268000, C549S297000, C549S263000
Reexamination Certificate
active
06808724
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel compound isolated from
Artemisia Sylvatica
, isolation method, and use thereof, and more particularly, to a novel compound isolated from
Artemisia Sylvatica
, which is expressed by the formula 1, a method of isolation thereof, and its use of inhibiting farnesyl transferase activity, which is essential for activating Ras oncogene and repressing cancer cell growth.
2. Description of the Related Art
The exact causes of most cancers have not been identified yet, but researches have been only able to reveal a few carcinogens or carcinogenic factors so far. Innate carcinogenic factors residing in an individual can be turned on during his growth and cause a mutation when subjected to various carcinogenic environments, and may ultimately develop into a cancer. Therefore, it is very important to know the cause of a cancer in order to prevent and detect onset of an oncocogenesis from cancer-vulnerable groups via early diagnosis.
Three major treatments for cancers are surgery, radiotherapy, and chemotherapy. Besides, there are immunotherapy, hormonotherapy, or biological therapies (the biological therapies include transition inhibition, CDK inhibition, blood-vessel formation inhibition, and signal-transfer inhibition, etc.). One or more therapies may be used depending on the type of cancers. The kind of cancer, its location, transition, age and physical condition of a patient, and other factors are considered in selecting the most appropriate treatment.
Over the last decade, there have been outstanding research results on normal cells and mutated cells. In particular, regarding the oncogenic functions, how the normal proto-oncogene function, how they are changed into oncogenes, how the signal transfer regulates division, and differentiation and death of cells are now well elucidated. In short, cancers can be described as cells that are divided abnormally, whose growth and differentiation are not under control. In normal cells, cell division is orchestrated by an elaborate signal regulation of the cell's inner and external growth factors. However, in cancer cells, at least one of the growth regulation factors remains activated (switched on) or deactivated (switched off). These cell division-related signals are transferred via the protein-protein interaction.
Cancers are known to develop by mutation of these cell division-related proteins. Among the cancer-related proteins, the Ras protein accounts for about 30% of all human cancers.
The Ras protein, which plays the most important role in signal transfer of cell growth regulation factors, is composed of 188-189 amino acids. Its molecular weight is 21 kDa and it can be bound to guanine nucleotides (GDP or GTP). The Ras protein transfers a cell signal to regulate proliferation and differentiation of cells. Like many other G-proteins, the Ras protein acts as the signal transferer when bound to GTP (switched “on”), and it is deactivated (switched “off”) when GTP is hydrolyzed to GDP by GAP (GTPase activating protein).
The Ras protein is located in the plasma membrane, bound to lipids, and transfers signal to the next stage. Cysteine (Cys-186), the 186th amino acid of the Ras protein is covalently bonded to the lipid (carbon number=15 or 20) by thioester linkage. The lipid has its own GTPase activity and is triggered by GAP and GTPase activation proteins. As such, the Ras protein is bound to the inner surface of the plasma membrane. In this process, binding with GTP and hydrolysis mediates regulation of cell growth. The cysteine, where this lipidation takes place, is the 4th residue of the Ras protein from the carboxyl or C-terminal. After two aliphatic amino acids comes methionine or serine. The lipid transferase transfers C
15
or C
20
lipids to the “Cys-AAX motif”. The C
15
-carbon isoprenoid group (farnesyl group) is transferred by farnesyltransferase; and if the X, the last residue of the Ras protein, is leucine, a special soluble enzyme transfers the C
20
-carbon isoprenoid group (geranylgeranyl group) [Joseph L. Goldstein, et al., “Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase”
The Journal of Biological Chemistry,
266, 15575-15578, (1991); John A. Glomset and Christopher C. Farnsworth, “Role of Protein Modification Reactions in Programming Interactions between RAS-related GTPases and Cell Membranes”,
Annu. Rev. Cell Biol.,
10, 181-205, (1994)].
The endoprotease, which has affinity to lipid-bound substrate, catalyzes proteolytic cleavage of -AAX peptide from the lapidated -CysAAX sequence, while the methyl transferase catalyzes methylesterification of the cleaved cysteine residue to the carboxyl group. In doing so, the —COOH terminal of the Ras protein becomes lipophilic and is bound to the membrane. Thus, it can be readily accessed to the Ras protein. All the lipids bound to the Ras protein are trans FPPs (farnesyl pyrophosphates) formed from mevalonate intermediate during cholesterol biosynthesis.
This consecutive lipidation of -AAX peptide hydorolysis and methylation is called the post-translation process. The development of a drug that can effectively regulate these reactions, i.e. the signal transfer process, will lead to development of new anticancer drug. Even if the Ras protein has been mutated for a long time in the activated form, it should be fixed to the membrane by prenylation (farnesyl or geranylgeranyl lipid) to be able to transfer signals required for cell growth or differentiation. And, the regulation of the three enzymes can be the target site of inhibiting signal transfer of the Raf protein [Yimin, Q.; Sebti, S. M; Andrew, D. H.
Biopoly.
1997, 43, 25-41, Christoph, W. M.; Morgan, M. A.; Lothar, B.
Blood.
2000, 96, 1655-1669., Cox A. D.; Garcia, A. M.; Westwick, J. K.; Kowalczyk, J. J.; Lewis, M. A.; Brenner, D. A.; Der, C. J.
J. Biol. Chem.
1994, 269, 19203-19206., Lebowitz P. F.; Sakamuro, D.; Prendergast, G. C.
Cancer Res.
1997, 57, 708-713., Mark, M.; Moasser M. M.; Sepp-Lorenzio, L.; Kohl, N. C.; Oliff, A.; Balog, A.; Su, D. S.; Danishefsky, S. J.; Rosen, N.
Proc. Natl. Acad. Sci. USA.
1998, 95, 1369-1374.]
For the raw material of this anticancer drug, medicinal plants like yaw tree or periwinkle are used. The active ingredients of these plants were identified as paclitaxel (product name=Taxol) and vinblastine [
Natural Product Report
2000, 17, 215-234].
SUMMARY OF THE INVENTION
The inventors discovered a compound with anticancer activity from
Artemisia Sylvatica
in the process of searching for anticancer substances from medicinal plants. We isolated the compound and analyzed its structure to realize that it is a new compound expressed by the formula 1.
An object of this invention is to provide a new compound isolated from
Artemisia Sylvatica
, isolation method, and use thereof.
Another object of this invention is to provide a drug composition for prevention and treatment of cancers, containing the new compound as an active ingredient.
REFERENCES:
patent: 6020365 (2000-02-01), Adekenov
Cox, Adrienne D. et al., The CAAX Pepidomimetic Compound B581 Specifically Blocks Farnesylated, but Not Geranylgeranylated or Myristylated, Oncogenic Ras Signaling and Transformation,The Journal of Biological Chemistry, Jul. 29, 1994, vol. 269, No. 30, pp. 19203-19206.
Goldstein, Jospeh L. et al., Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase,The Journal of Biological Chemistry, Aug. 25, 1991, vol. 266, No. 24, pp. 11575-15578.
Qian, Yimin et al., Farnesyltransferase as a Target for Anticancer Drug Design,Biopoly43:1997, pp. 25-41.
Reuter, Christoph W. et al., Targeting the Ras signaling pathway: a rational , mechanism-based treatment for hematologic malignancies?Blood, Sep. 1, 2000, vol. 96, No. 5, pp. 1655-1669.
Glomset, John A. et al., Role or Protein Modification Reactions in Programming Interactions Between Ras-Related Gtpases and Cell Membranes,Annu. Rev. Cell. Biol., 1994, pp. 181-205.
Lebowitz, Peter F. et
Han Dong-Choi
Jeon Sun Bok
Kang Hyun-Mi
Kim Jong-Han
Kwon Byoung-Mog
Jones Day
Korea Research Institute of Bioscience and Biotechnology
Oh Taylor V.
Trinh Ba K.
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