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Gamma-butyrolactone compound and pharmaceutical composition thereof

a technology of gamma-butyrolactone and compound, which is applied in the direction of drug compositions, plant/algae/fungi/lichens ingredients, biocide, etc., can solve the problems of abnormal chromosome pairing, cell death, and cancer agents such as 5-fluorouracil, and achieves the inhibition of tumor growth, cytotoxic effect of tumors, and the effect of inhibiting telomerase activity and htert expression

Inactive Publication Date: 2006-04-13
BUDDHIST TZU CHI GEN HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014] A further aspect of the present invention is to provide the γ-butyrolactone compound and pharmaceutical composition thereof which are cytotoxic to Paclitaxel-resistance tumour cell line with high specificity without causing harmful effects to the liver and kidney functions.
[0024] Furthermore, the inhibition of telomerase activity is observed in TRAP assay after the addition of γ-butyrolactone compound and pharmaceutical composition thereof. It is found that γ-butyrolactone compound and pharmaceutical composition thereof are capable of effectively inhibiting the telomerase activity and hTERT expression on human lung cancer cell lines A549, suggesting the potential of γ-butyrolactone compound to produce highly specific cytotoxicity to tumor cells.
[0025] In particular, after adding chaihulactone to Paclitaxel-resistant tumor cells such as A549-T12 cells (A549 cells resistant to Paclitaxel), it is found that the γ-butyrolactone compound and the pharmaceutical composition thereof are capable of inducing apoptosis of Paclitaxel-resistant tumor cells. From the results of flow cytometric analysis and Western blotting analysis to study the mechanism of Bupleurum scorzonerifolium extracts containing the γ-butyrolactone compound, it is found that Bupleurum scorzonerifolium extracts can induce high expression of tumor suppressors p21 and p53. As a result, the tumor cells are arrested at the spindle polymerisation stage (G2 / M stage) of the cell cycle. Thus, in view of cell cycle regulation, the γ-butyrolactone compound and pharmaceutical composition thereof can serve as a microtubule stabilizing agent, having a mechanism similar to that of paxlitaxel, as both enhance microtubule polymerization. Accordingly, the tumor cells are arrested at G2 / M stage and subsequently become junk cells leading to apoptosis.

Problems solved by technology

And with increasing pollutions, the incidence of developing ovarian carcinoma, lung cancer, liver cancer and skin cancer has also increased.
And when the telomere shortens to a critical length, the telomere that covers the terminal end of the chromosome becomes sticky and causes abnormal pairing of the chromosomes and even a cell death in some cases.
Also, other anti-cancer agents such as 5-fluorouracil, epothilone, cisdiammine dichloroplatinum (Cisplatin), procarbazine and cyclophosphamide when clinically used alone or in conjunction with paclitaxel cannot provide a satisfactory outcome in terms of killing the cancer cells developed with drug resistant to paclitaxel.
Results from cell culture experiment also indicate that it is difficult to effectively inhibit proliferation of Paclitaxel-resistant tumour cells using current anti-cancer drugs.
However this would result in high degree of necrosis for the normal cells due to its strong cytotoxicity possessed by the drug.

Method used

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  • Gamma-butyrolactone compound and pharmaceutical composition thereof
  • Gamma-butyrolactone compound and pharmaceutical composition thereof
  • Gamma-butyrolactone compound and pharmaceutical composition thereof

Examples

Experimental program
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first embodiment

Extraction Method of Antineoplastic Extracts and Compounds from Bupleurum scorzonerifolium

[0071]Bupleurum scorzonerifolium used in this invention is radix Bupleuri of Umbelliferae family. After drying and grinding of the Buleurum scorzonerifolium plant tissue, 6 kg of Bupleurum scorzonerifolium powder is submerged and stirred within 20 L acetone at room temperature for 4 hours and extracted 4 times repeatedly to obtain the Bupleurum scorzonerifolium-acetone crude extract (BS-AE). Methanol is added to the residues to obtain Bupleurum scorzonerifolium-methanol extract (BS-ME). Then water is added to the residue to obtain Bupleurum scorzonerifolium-water extract (BS-WE). Then 95% methanol solvent is used to dissolve BS-AE, followed by partitioning with n-hexane for 3 times so as to isolate Bupleurum scorzonerifolium-hexane extract (BS-HE) and Bupleurum scorzonerifolium-methanol water extract (BS-MWE). 500 ml of distilled water is then added to the BS-MWE to remove the methanol therein...

second embodiment

Structure of Active Tumor Inhibitory Component in Buplerum scorzonerifolium

[0074] Mass Spectrum and Nuclear Magnetic Resonance Spectrum (NMR) are employed to determine the molecular weight and structure of the third, eighth, fourteenth and fifteenth components isolated from the BS-AE, the mass spectrum is shown in the table 2 below:

TABLE 2the components isolated from the antineoplastic compounds in BS-AELow pressure liquidMolecular weight andchromatographyStructure formulaestructureComponent 3398.41 ChaihulactoneComponent 8398.41 IsochaihulactoneComponent 14ChaihunaphthoneComponent 15Isokaeophyllin

[0075] After analyzing the molecular structures, it is appreciated that the pure compounds isolated from Bupleurum scorzonerifolium having inhibitory effect on tumor cells of human hepatoma, ovarian cancer, lung cancer, malignant glioblastoma and colorectal carcinoma are heterocyclic compounds having a γ-butyrolactone core, and Z or E configuration for its carbon 2(5) location. From the...

third embodiment

The Effect of Bupleurum scorzonerifolium Extracts on Cell Proliferation

[0080] BS-AE, BS-ME and BS-8 are added to cell cultures of J5, Ovcar-3. A549, DBTRG-05, and HT-29, respectively to observe growth inhibition of the cancer cell lines during the 7 days treatment. The present embodiment is described with lung cancer cell line A549 and colon cancer cell line HT-29 as examples. It was found that the cancer cell lines administered with 60 μg of BS-AE had their tumor cell counts reduced to a similar level as the cancer cell lines administered with 600 μg of BS-ME three days after the extracts were given, indicating that the tumor inhibitory component in BS-ME is much lower than that in BS-AE. Therefore it is concluded that the most effective tumor inhibitory compounds from Bupleurum scorzonerifolium are mainly present in BS-AE.

[0081] Furthermore, flow cytometry is employed to observe the changes in cell cycle before and after the addition of different extracts from Bupleurum scorzone...

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Abstract

A γ-butyrolactone compound as shown in Formula (I) and pharmaceutical composition thereof: wherein X═N, O, S, Se; and A and B are selected from substituents having the following formula: wherein R1, R2, R3, R4, and R5 are selected from a hydrogen atom, a halogen atom, a hydroxyl group, a mercapto group, an amino group, an alkoxy group, and a nitro group. The γ-butyrolactone compound and pharmaceutical composition thereof butyrolactone have inhibitory effects on hepatoma, ovarian cancer, breast cancer, lung cancer, malignant glioblastoma or colorectal carcinoma, and are cytotoxic with high specificity to inhibit Paclitaxel-resistant tumour cells at later stage of chemotherapy without any damage on normal cells.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a novel compound and pharmaceutical composition thereof for treating mammalian cell proliferative disorders, chemo-therapy resistance and virus infections, particularly a novel γ-butyrolactone compound and pharmaceutical composition thereof for treating human malignant tumours such as hepatoma, lung cancer, ovarian cancer, breast cancer, human malignant glioblastoma, colorectal cancer, malignant brain spongiocyte lump and the like; chemo-therapy resistance such as paclitaxel and for treating RNA virus infections. BACKGROUND OF THE INVENTION [0002] Cancer, a cell proliferative disorder, is the leading cause of death worldwide. In 1993, Boring et al. estimated approximately 526,000 deaths from cancer alone in the U.S. each year. For example, breast cancer has been the leading cause of death from cancer in woman between the age of 40 and 55. And with increasing pollutions, the incidence of developing ovarian carcinoma, lung...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/365C07D405/02A61K36/00A61K36/23C07D407/06A61P35/00A61P43/00C07D407/04
CPCA61K36/23A61P35/00A61P43/00
Inventor LIN, SHINN-ZONGHARN, HORNG-JYH
Owner BUDDHIST TZU CHI GEN HOSPITAL
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