CN103193852A - Compound used for treating colon cancer, and preparation method thereof - Google Patents
Compound used for treating colon cancer, and preparation method thereof Download PDFInfo
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- CN103193852A CN103193852A CN2012100023678A CN201210002367A CN103193852A CN 103193852 A CN103193852 A CN 103193852A CN 2012100023678 A CN2012100023678 A CN 2012100023678A CN 201210002367 A CN201210002367 A CN 201210002367A CN 103193852 A CN103193852 A CN 103193852A
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Abstract
The invention discloses a compound used for treating colon cancer, and a preparation method thereof. The compound can be easily dissolved in water, and can be highly efficiently absorbed by organisms. The compound is also characterized in high targeting performance, low side effect, fast treatment effect, low production cost, and the like. The compound has good inhibition effect against cancer cell growth, and has good treatment effect and high safety in treating colon cancer.
Description
Technical field
The present invention relates to a kind of new compound with treatment colorectal carcinoma purposes, and the preparation method of this compound.
Background technology
Over nearly more than 20 years, majority state colorectal cancer (mainly being colorectal carcinoma) sickness rate is in rising trend in the world.Along with the raising of people's living standard, the change of food habits and structure, the influence of aging population trend in addition, China's colorectal cancer number of the infected and death toll also are growing trend.According to statistics, the annual new cases of China surpass 170,000, are the malignant neoplastic diseases that China's sickness rate ranked fourth the position.Than America and Europe about ten years in advance, young patient saw that than American-European this is that colorectal cancer is in characteristics of China to the meta age of onset of colorectal cancer more in China.The cause of disease of colorectal cancer is unclear fully as yet, thinks it mainly is the result of comprehensive actions such as inherited genetic factors, environmental factors, immune factor at present.
The Full Name in English of 11 carbonyl-beta-acetyl masticinic acids is: Acetyl-11-keto-β-boswellic acid, be called for short Ak β BA.It is one of important composition of containing of colloidal resin-frankincense of plant cassette Boswellia carterii.
Olibanum extract is used as anti-inflammatory agent in traditional medicine, as the treatment to sacroiliitis and patients of ulcerative colitis.Masticinic acid is owing to its antiproliferative effect receives publicity in addition, and masticinic acid can suppress several leukemia cell lines external, melanomatous growth and apoptosis.To studies show that of masticinic acid, and the most significant 5-LOX inhibition of 11 carbonyl-beta-acetyl masticinic acids demonstration activity (British J Pharmacology, 1996,117,615-618).
Enriching and purifying Ak β BA has been described in International Patent Application WO 03/0746 from natural Boswellia carterii extract, United States Patent (USP) 20030199581 and International Patent Application WO 03/077860.More highly purified product can obtain by chromatographic separation and recrystallization.
The solubleness of 11 carbonyl-beta-acetyl masticinic acids in water is less, and deliquescent problem has limited his further application.The invention provides 11 carbonyl-beta-acetyl masticinic acid sodium salts, this sodium salt has more excellent solvability in water, and can make easily, and this compound is applied to treat the colorectal carcinoma medicine.
Enriching and purifying Ak β BA has been described in International Patent Application WO 03/0746 from natural Boswellia carterii extract, United States Patent (USP) 20030199581 and International Patent Application WO 03/077860.More highly purified product can obtain by chromatographic separation and recrystallization.
The solubleness of 11 carbonyl-beta-acetyl masticinic acids in water is less, and deliquescent problem has limited its further application.Colorectal carcinoma drug manufacture cost height is treated in existing treatment, targeting is poor and the water-fast shortcoming of 11 carbonyl-beta-acetyl masticinic acids, the invention provides a kind of mineral salt medicine for the treatment of colorectal carcinoma and preparation method thereof in order to overcome.This medicine is the effective monomer composition of carrying from natural phant, soluble in water, side effect is little, production cost is low, and can optionally suppress the expression of transcribed nucleic acid factor NF-kappa B, thereby suppress growth, the diffusion of tumour cell, reach the purpose for the treatment of colorectal carcinoma.That this medicine and preparation thereof have is soluble in water, efficient absorption, easy to use, advantage such as targeting is strong, effect is remarkable and side effect is little.
Summary of the invention
The invention discloses a kind of new compound: 11 carbonyl-beta-acetyl masticinic acid sodium salts (
AKBA-Na), have the molecule formula I:
（Ⅰ）
And 11 carbonyl-beta-acetyl masticinic acid sylvite (
AKBA-K), have molecular formula (∥):
（∥）
The preparation method of described compound makes by the aqueous solution of adding alkali in 11 carbonyl-beta-acetyl masticinic acids or the non-aqueous solution reaction of alkali, and described alkali is R
1OH or R
1H or R
1HMDS or R
1OR
2, R wherein
1Be Na or K, wherein R
2For containing the alkyl of 1-4 carbon atom.
The application of described compound in preparation treatment treatment colorectal carcinoma medicine.
The present invention has following beneficial effect: described compound is crossed expression by suppressing transcribed nucleic acid factor NF-kappa-B thereby the required transcribed nucleic acid factor takes place, develops the inhibition tumour cell, reaches the purpose for the treatment of colorectal carcinoma.
This medicine and preparation thereof have soluble in water, efficient absorption, advantage such as easy to use to the treatment of colorectal carcinoma.
Specifically, the present invention relates to 11 carbonyl-beta-acetyl masticinic acid sodium salts, namely
AKBA-Na:
1, according to experiment, the water by in 11 carbonyl-beta-acetyl masticinic acids, adding alkali or non-aqueous solution can make 11 carbonyl-beta-acetyl masticinic acid sodium salts (
AKBA-Na), described alkali is NaOH or NaH or NaHMDS or NaOR
2, R wherein
2For containing the alkyl of 1-4 carbon atom;
2, according to test, use this compound, the NF-kappa-B of the mouse of activating in the in vitro tests, human colon cancer cell strain activation is suppressed, and the NF-kappaB of colorectal carcinoma tumor-bearing mice is suppressed in the live test simultaneously;
3, according to experiment, this compound suppresses the tumour cell generation, the required transcribed nucleic acid factor of development is crossed expression, and AKBA-Na suppresses the release of colon cancer cell line division, propagation accordingly according to the difference of time, dosage in vitro tests;
4, according to experiment, use this compound, AKBA-Na promotes the apoptosis (Annexin V+ cell is apoptotic cell) of colon cancer cell line in the experiment in vitro.
5, according to experiment, use this compound water solution, obviously improve the growth that has suppressed the mouse colon tumor.
Description of drawings
Fig. 1: the nuclear-magnetism spectrum of 11 carbonyl-beta-acetyl masticinic acid sodium salts;
Fig. 2: the mass spectrum of 11 carbonyl-beta-acetyl masticinic acid sodium salts;
Fig. 3: the NF-kappa-B of the mouse of activating in the in vitro tests, human colon cancer cell strain activation is suppressed, and the NF-kappaB of colorectal carcinoma tumor-bearing mice is suppressed in the live test simultaneously;
Fig. 4: use 11 carbonyl-beta-acetyl masticinic acid sodium salts, AKBA-Na time, dose-dependently ground suppress the release of colon cancer cell line division, propagation in vitro tests;
Fig. 5: use 11 carbonyl-beta-acetyl masticinic acid sodium salts, AKBA-Na promotes the apoptosis (Annexin V+ cell is apoptotic cell) of colon cancer cell line in the experiment in vitro;
Fig. 6: use 11 carbonyl-beta-acetyl masticinic acid sodium-salt aqueous solutions, obviously improve the growth that has suppressed the mouse colon tumor;
Fig. 7: use the 11 carbonyl-beta-acetyl masticinic acid sylvite aqueous solution, obviously improve the growth that has suppressed the mouse colon tumor.
Embodiment
Further illustrate the present invention by the following examples.
Embodiment 1:The preparation of AKBA-Na
51.2mg(0.05mmol under 50 ℃ of stirrings) 11 carbonyl-beta-acetyl masticinic acids are dissolved in the 1.0mL methyl alcohol, add the 0.5M aqueous sodium hydroxide solution of 0.1mL.Stir and be spin-dried for after one hour, obtain white solid salt.
HNMR?(300?MHz，CD3OD)?5.48?(s,?1H),?5.30?(S,?1H),?2.45-2.13?(m,?4H),?2.03?(s,?3H),?1.99-1.61?(m,?4H),?1.60-1.41?(m,?7H),?1.40-1.30?(m,?5H),?1.30-1.15?(m,?8H),?1.11?(s,?3H),?1.11-1.00?(m,?1H),?1.00-0.90?(m,?4H),?0.83-0.75?(m,?6H)。
MS?（ESI，m/z）513.4，?535.5，?567.5。
Embodiment 2:The preparation of AKBA-Na
51.2mg(0.05mmol under 50 ℃ of stirrings) 11 carbonyl-beta-acetyl masticinic acids are dissolved in the 1.0mL methyl alcohol, add the 0.5M sodium hydrate methanol solution of 0.1mL.Stir and be spin-dried for after one hour, obtain white solid salt.
Embodiment 3:The preparation of AKBA-Na
51.2mg(0.05mmol under 50 ℃ of stirrings) 11 carbonyl-beta-acetyl masticinic acids are dissolved in the 1.0mL methyl alcohol, add the 2.7mg sodium methylate.Stir and be spin-dried for after one hour, obtain white solid salt.
Embodiment 4:The preparation of AKBA-K
51.2mg(0.05mmol under 50 ℃ of stirrings) 11 carbonyl-beta-acetyl masticinic acids are dissolved in the 1.0mL methyl alcohol, add the 0.5M potassium hydroxide methanol solution of 0.1mL.Stir and be spin-dried for after one hour, obtain white solid salt.
Embodiment 5:AKBA-Na is external, the interior test (Fig. 3) that suppresses NF-kappaB of body
Get a certain amount of AKBA-Na and be dissolved in 1 ' PBS, be prepared into the solution of 500mmol.Adding AKBA-Na(concentration: 75mmol) and do not add under the condition of AKBA-Na reorganization IL-6 with 100ng/mL and stimulate colon cancer cell line to extract albumen after six hours to be used for Western Blooting analysis.Extremely significantly suppress the activation of the NF-kappaB of colon tumor cell in the AKBA-Na experiment in vitro.
| ? | ? | Control |
AKBA- |
| 1 |
|
107.545（AU） | 3.532（AU） |
| 2 | Cell strain 2 | 95.877（AU） | 0.727（AU） |
Annotate: AU, Arbitrary units.
Get the age of 10 lotus knurls, the mouse of gender matched (5 treatment group, 5 control groups).The next day abdominal injection 200mL AKBA-Na(concentration: 100mmol) and under the condition of abdominal injection 200mL 1 ' PBS 15 days, get the mouse tumor position then and extract albumen and be used for Western Blooting and analyze, test repeats 2 times, is divided into test group 1,2.(be called for short: Phospho-IkB) draw the activation that has suppressed NF-kappaB in the AKBA-Na body by the IkB α that analyzes phosphorylation.
| ? | ? | Control | AKBA-Na |
| 1 |
|
85.233（AU） | 12.122（AU） |
| 2 | Test group 2 | 101.758（AU） | 11.546（AU） |
Annotate: AU, Arbitrary units.
Embodiment 6:The division of AKBA-Na vitro inhibition colorectal carcinoma tumour cell, proliferation test (Fig. 4)
Get a certain amount of AKBA-Na and be dissolved in 1 ' PBS, be prepared into the solution of 100mmol.Under the condition of the AKBA-Na that adds different concns in different time point (12 hours, 24 hours, 48 hours; H, hour) with the division growth of CCK8 analysis of cells.Find that by analyzing AKBA-Na time, dose-dependently ground have suppressed division, the propagation of tumour cell.
| ? | ? | The 12H inhibiting rate | The 24H inhibiting rate |
The |
| 1 | 45mmol | 2.53% | 17.99% | 31.37% |
| 2 | 60mmol | 21.32% | 42.53% | 69.78% |
| 3 | 75mmol | 53.77% | 79.88% | 97.34% |
| 4 | 90mmol | 81.63% | 92.37% | 99.76% |
Embodiment 7:The apoptosis test (Fig. 5) of the external promotion colorectal carcinoma of AKBA-Na tumour cell
Get a certain amount of AKBA-Na and be dissolved in 1 ' PBS, be prepared into the solution of 100mmol.Cultivated the mouse junction cancer tumour cell 24 hours under the AKBA-Na of 50mmol and 250mmol concentration, draw with Annexin V and PI analysis of cells apoptosis situation, the AKBA-Na of 2 kinds of concentration all can promote the apoptosis of colorectal carcinoma tumour cell.
| ? | AKBA-Na |
50 |
250 mmol |
| ? | Apoptosis rate | 25.28% | 55.5% |
Embodiment 8:AKBA-Na in vivo suppresses the test (Fig. 6) of colon tumor growth
Transplant the mouse colonic cell strain and go into subcutaneous 2 weeks of C57BL/6J mouse, get the age of 6 lotus knurls, the mouse of gender matched (3 treatment group, 3 control groups).The next day abdominal injection 200mL AKBA-Na(concentration: 100mmol) and under the condition of abdominal injection 200mL 1 ' PBS 15 days, dissect the back and take out tumour and observe to draw in the AKBA-Na body and suppressed growth of tumor.
| ? | Test 1(tumor weight) | Test 2(tumor weight) | Test 3 (tumor weights) |
| Control | 0.412g | 0.676g | 0.539g |
| AKBA-Na | 0.105g | 0.198g | 0.203g |
Embodiment 9:AKBA-K in vivo suppresses the test (Fig. 7) of colon tumor growth
Transplant the mouse colonic cell strain and go into subcutaneous 2 weeks of C57BL/6J mouse, get the age of 8 lotus knurls, the mouse of gender matched (4 treatment group, 4 control groups).The next day abdominal injection 200mL AKBA-K(concentration: 100mmol) and under the condition of abdominal injection 200mL 1 ' PBS 15 days, dissect the back and take out tumour and observe to draw in the AKBA-K body and suppressed growth of tumor.
Above-mentioned example is in order to illustrate technical conceive of the present invention and characteristics, and purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (4)
1. compound has the molecule formula I:
（Ⅰ）
。
2. compound has molecular formula (∥):
（∥）
。
3. the preparation method of the described compound of claim 1-2 makes by the aqueous solution of adding alkali in 11 carbonyl-beta-acetyl masticinic acids or the non-aqueous solution reaction of alkali, and described alkali is R
1OH or R
1H or R
1HMDS or R
1OR
2, R wherein
1Be Na or K, wherein R
2For containing the alkyl of 1-4 carbon atom.
4. the application of the described compound of claim 1-2 in preparation treatment colorectal carcinoma medicine.
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| CN2012100023678A CN103193852A (en) | 2012-01-06 | 2012-01-06 | Compound used for treating colon cancer, and preparation method thereof |
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|---|---|---|---|
| CN2012100023678A CN103193852A (en) | 2012-01-06 | 2012-01-06 | Compound used for treating colon cancer, and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017076332A1 (en) * | 2015-11-05 | 2017-05-11 | 苏州博创园生物医药科技有限公司 | Pentacyclic triterpenoid compound providing acc1 protein regulating effect and uses of the compound |
| CN108752412A (en) * | 2018-06-23 | 2018-11-06 | 沈阳药科大学 | Boswellic acid derivatives and its application |
| WO2022228352A1 (en) * | 2021-04-25 | 2022-11-03 | 江苏博创园生物医药科技有限公司 | Pentacyclic triterpenoid crystal and preparation method therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002066491A1 (en) * | 2001-02-15 | 2002-08-29 | Sabinsa Corporation | Water soluble boswellic acids, their preparation and use for treating imflammatory conditions |
| WO2003077860A2 (en) * | 2002-03-13 | 2003-09-25 | Biophysica, Inc. | BOSWELLIN COMPOSITIONS ENHANCED WITH 3-β-ACETYL-11-KETO-β-BOSWELLIC ACID (“AKBA”), INDUSTRIAL MANUFACTURE AND THEIR USES |
-
2012
- 2012-01-06 CN CN2012100023678A patent/CN103193852A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002066491A1 (en) * | 2001-02-15 | 2002-08-29 | Sabinsa Corporation | Water soluble boswellic acids, their preparation and use for treating imflammatory conditions |
| WO2003077860A2 (en) * | 2002-03-13 | 2003-09-25 | Biophysica, Inc. | BOSWELLIN COMPOSITIONS ENHANCED WITH 3-β-ACETYL-11-KETO-β-BOSWELLIC ACID (“AKBA”), INDUSTRIAL MANUFACTURE AND THEIR USES |
Non-Patent Citations (1)
| Title |
|---|
| RAJBIR KAUR,ET AL.: "A comparative study of proapoptotic potential of cyano analogues of boswellic acid and 11-keto-boswellic acid", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 46, 3 February 2011 (2011-02-03), pages 1356 - 1366 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017076332A1 (en) * | 2015-11-05 | 2017-05-11 | 苏州博创园生物医药科技有限公司 | Pentacyclic triterpenoid compound providing acc1 protein regulating effect and uses of the compound |
| CN106674323A (en) * | 2015-11-05 | 2017-05-17 | 苏州博创园生物医药科技有限公司 | Pentacyclic triterpenes compound with ACC1 protein regulation effect and use of pentacyclic triterpenes compound |
| CN106674323B (en) * | 2015-11-05 | 2019-10-22 | 苏州博创园生物医药科技有限公司 | Pentacyclic triterpenoid and application thereof with ACC1 protein regulation effect |
| CN108752412A (en) * | 2018-06-23 | 2018-11-06 | 沈阳药科大学 | Boswellic acid derivatives and its application |
| CN108752412B (en) * | 2018-06-23 | 2020-10-13 | 沈阳药科大学 | Boswellic acid derivatives and their use |
| WO2022228352A1 (en) * | 2021-04-25 | 2022-11-03 | 江苏博创园生物医药科技有限公司 | Pentacyclic triterpenoid crystal and preparation method therefor |
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Application publication date: 20130710 |