CN1887899A - Amino alcohol as chemical modifier for ursolic acid - Google Patents
Amino alcohol as chemical modifier for ursolic acid Download PDFInfo
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- CN1887899A CN1887899A CN 200610047236 CN200610047236A CN1887899A CN 1887899 A CN1887899 A CN 1887899A CN 200610047236 CN200610047236 CN 200610047236 CN 200610047236 A CN200610047236 A CN 200610047236A CN 1887899 A CN1887899 A CN 1887899A
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- ursolic acid
- amino alcohol
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- chemical modifier
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Abstract
The amino alcohol chemically modified ursolic acid is one semi-synthesized product, and is prepared through the following steps: 1. reaction between ursolic acid and acetic anhydride to produce acetoxy ursolic acid; 2. reaction between acetoxy ursolic acid and oxalyl chloride and further reaction with corresponding amino alcohol to produce intermediate products; and 3. hydrolyzing the intermediate products to obtain amino alcohol chemically modified ursolic acids as the target compounds. The present invention obtains serial ursolic acid analogs, which are proved through pharmacological tests to have HELA human body cervical carcinoma cell inhibiting activity higher than that of ursolic acid.
Description
Technical field
The present invention relates to a kind of natural product and its semisynthetic, particularly relate to a kind of amino alcohol as chemical modifier for ursolic acid with anti-tumor activity.
Background technology
(ursolic acid, UA) (Compound I) has another name called urson, ursonic acid to ursolic acid, belongs to pentacyclic triterpenoid.It is widely distributed at occurring in nature, and has the various biological effect, and neural system is had obviously stable and cooling effect; External to G
+And G
-Bacterium and yeast all have anti-microbial activity; Have reducing blood-fat, study of anti-atherogenic effect; Protect the liver in addition, antihepatitic activity.The chemical structural formula of ursolic acid is:
Studies show that ursolic acid not only has resistant function to multiple carcinogenic, short cancer thing, and multiple malignant tumour such as P-388 and L-1210 leukemia cell, A-549 human lung adenocarcinoma cell are had the growth of inhibition effect; Can induce the F9 teratocarcinoma cell to become the endoderm cell; T cell lymphoma Jurkat cell strain had the restraining effect of killing and wounding; In addition, also has the effect that antineoplastic vascular generates.
Summary of the invention
The object of the present invention is to provide a kind ofly to have multiple bioactive ursolic acid, design a kind of amino alcohol as chemical modifier for ursolic acid with anti-tumor activity as lead compound.
The objective of the invention is to be achieved through the following technical solutions:
Amino alcohol as chemical modifier for ursolic acid, its structural formula is as follows:
Wherein: R
1Be hydroxyl or ethanoyl, R
2Be substituted-amino alcohol or hydroxyl.
Aforesaid amino alcohol as chemical modifier for ursolic acid is prepared by following steps:
(1) ursolic acid compound (I) and the acetic anhydride 3-acetoxyl group ursolic acid (II) that is;
(2) 3-acetoxyl group ursolic acid and oxalyl chloride reaction is again with the compound (III-VI) of corresponding amino alcohol reaction;
(3) compound (III-VI) gets compound (VII-X) through hydrolysis.
Aforesaid amino alcohol as chemical modifier for ursolic acid, they have anti-tumor activity, can be used for treating tumor disease.
Advantage of the present invention and effect are:
The present invention carries out chemically modified to the natural product ursolic acid, obtains the analog of a series of ursolic acid, shows that through pharmacological testing they have better inhibited activity to the HELA human body cervical carcinoma cell, and all is better than the parent compound ursolic acid.
Embodiment
Below the present invention is described in detail.
The present invention finishes through the following steps:
1. the extraction using alcohol medicinal extract of Loquat Leaf is with sherwood oil, 1% sodium hydroxide with to be washed to elutant colourless, the dehydrated alcohol heating for dissolving, and activated carbon decolorizing, filtrate placement is separated out white crystals, gets Compound I with recrystallization from hot methanol.
2. Compound I and acetic anhydride get Compound I I
3. Compound I I and oxalyl chloride at room temperature react, and the further following and amino alcohol reaction in alkaline condition gets compound III-VI
Wherein: R
2Be substituted-amino alcohol
4. compound III-VI gets compound VI I-X through hydrolysis
Wherein: R
2Be substituted-amino alcohol
Such pentacyclic triterpenoid carries out antineoplastic pharmacological testing, proves that it has the obvious suppression effect to the HELA human body cervical carcinoma cell, and the structural modification thing of ursolic acid suppresses the HELA activity and all is higher than the parent compound ursolic acid.The human cancer cell tests the employing mtt assay.The in vitro tests result is by shown in the table 1.
Table 1 ursolic acid structural modification thing is to the restraining effect (inhibiting rate %) of HELA human body cervical carcinoma cell strain
| Compound concentration | 10 -5mol/l | 10 -6mol/l | 10 -7mol/l | 10 -8mol/l |
| I II III IV | 12.36 37.83 50.34 58.38 | 2.24 6.22 33.00 13.74 | 0.26 2.76 11.53 9.95 | 0.16 2.07 6.54 7.52 |
| V VI VII VIII IX X | 44.64 77.52 34.16 24.74 26.56 25.98 | 18.19 16.08 18.07 17.76 21.92 22.40 | 12.03 11.72 8.05 16.74 16.14 20.68 | 5.25 7.41 3.61 8.44 8.28 16.33 |
Illustrate below:
Embodiment 1
The preparation of Compound I I: in 50ml exsiccant eggplant type bottle, add 200mg ursolic acid (0.44mmol),, add the 1ml pyridine with the THF dissolving, a little DMAP, stirred 4.5 hours under the room temperature, steaming desolventizes, and resistates adds an amount of water, hydrochloric acid with 2N is transferred pH3～4, suction filtration, the washing filter cake is to neutrality, column chromatography purification, get Compound I I (182mg, 82.94%).
1HNMR(300MHz，CDCl
3)δ：5.23(1H，t，H-12)，4.47～4.52(1H，t，H3)，2.04(3H，s，CH
3CO)，1.07(3H，s)0.95(6H，s)0.86(3H，s)0.84(6H，s)0.76(3H，s)(7×CH
3)。
Embodiment 2
The preparation of compound III: 90mg (0.18mmol) the Compound I I dissolving that adds methylene chloride, add the 0.08ml oxalyl chloride, room temperature reaction 24 hours, after reaction mixture removes the gas of methylene dichloride and reaction generation under reduced pressure, add methylene dichloride dissolving resistates again, add triethylamine and transfer pH 8～9, add thanomin 0.05ml, reaction finishes, and adds 4ml water in the reaction solution, transfer pH 3～4 with 2N hydrochloric acid, remove methylene dichloride under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, column chromatography purification gets compound III (47mg, 48%).
1HNMR(300MHz，DMSO-d
6)，δ：7.05(1H，d，NH)，5.19(1H，t，H-12)，4.60～4.62(1H，s，CH
2OH)，4.37～4.40(1H，t，H-3)3.30～3.33(2H，t，CH
2OH)，3.00～3.09(1H，m，NHCH2)2.96～2.98(1H，m，NHCH2)，2.00(3H，s，CH3CO)，1.04(3H，s)，0.90(6H，s)，0.83(3H，s)，0.81(3H，s)，0.70(3H，s)，(7×CH3)。
Embodiment 3
The preparation of compound VI I: compound III 33mg hydrolysis in the alkaline solution of methyl alcohol/tetrahydrofuran (THF), react completely, in mixture, add an amount of water, transfer pH 3～4 with 2N hydrochloric acid, remove methyl alcohol/tetrahydrofuran (THF) under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, get compound VI I (26.7mg, 87.8%).
1HNMR (300MHz, DMSO-d
6), δ: 7.05 (1H, t, NH), 5.20 (1H, t, H-12), 4.63 (1H, t, CH
2OH), 4.29 (1H, d, 3 of-OH), 3.6 (1H, t, H-3), 3.6 (2H, t, CH
2OH), 3.11 (1H, m, NHCH
2), 2.99 (1H, m, NHCH
2), 1.02 (3H, s), 0.89 (6H, s), 0.85 (6H, s), 0.69 (3H, s), 0.67 (3H, s), (7 * CH
3).
Claims (3)
1. amino alcohol as chemical modifier for ursolic acid is characterized in that structural formula is as follows:
Wherein: R
1Be hydroxyl or ethanoyl, R
2Be substituted-amino alcohol or hydroxyl.
2. amino alcohol as chemical modifier for ursolic acid according to claim 1 is characterized in that being prepared by following steps:
(1) ursolic acid compound (I) and the acetic anhydride 3-acetoxyl group ursolic acid (II) that is;
(2) 3-acetoxyl group ursolic acid and oxalyl chloride reaction is again with the compound (III-VI) of corresponding amino alcohol reaction;
(3) compound (III-VI) gets compound (VII-X) through hydrolysis.
3. amino alcohol as chemical modifier for ursolic acid according to claim 1 is characterized in that they have anti-tumor activity, can be used for treating tumor disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610047236 CN1887899A (en) | 2006-07-19 | 2006-07-19 | Amino alcohol as chemical modifier for ursolic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610047236 CN1887899A (en) | 2006-07-19 | 2006-07-19 | Amino alcohol as chemical modifier for ursolic acid |
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|---|---|
| CN1887899A true CN1887899A (en) | 2007-01-03 |
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ID=37577181
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|---|---|---|---|
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101157715B (en) * | 2007-11-20 | 2010-10-13 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
| CN101891794A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid piperazine derivative having antitumor activity and preparation method thereof |
| CN101891795A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid diethanol amine derivative with anti-tumor activity and preparation method thereof |
| CN102532245A (en) * | 2011-12-31 | 2012-07-04 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| TWI386415B (en) * | 2010-02-02 | 2013-02-21 | Univ Kaohsiung Medical | Ursolic acid derivative and pharmaceutical composition thereof |
| RU2617123C1 (en) * | 2016-03-14 | 2017-04-21 | Федеральное государственное автономное образовательное учреждение высшего образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) | Drug with anti-inflammatory activity |
| RU2739559C1 (en) * | 2020-07-30 | 2020-12-25 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | ((3β-acetoxy-urs-12-en-28-oyl-oxyacetoxy)methyl)-1h-1,2,3-triazol-1-yl)methyl)-4-methyl-1,2,5-oxadiazol-2-oxide, having selective anticancer activity against mcf-7 breast cancer cells |
-
2006
- 2006-07-19 CN CN 200610047236 patent/CN1887899A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101157715B (en) * | 2007-11-20 | 2010-10-13 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
| TWI386415B (en) * | 2010-02-02 | 2013-02-21 | Univ Kaohsiung Medical | Ursolic acid derivative and pharmaceutical composition thereof |
| CN101891794A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid piperazine derivative having antitumor activity and preparation method thereof |
| CN101891795A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid diethanol amine derivative with anti-tumor activity and preparation method thereof |
| CN101891794B (en) * | 2010-07-29 | 2012-04-25 | 福州大学 | Ursolic acid piperazine derivative having antitumor activity and preparation method thereof |
| CN102532245A (en) * | 2011-12-31 | 2012-07-04 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| CN102532245B (en) * | 2011-12-31 | 2013-05-15 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| RU2617123C1 (en) * | 2016-03-14 | 2017-04-21 | Федеральное государственное автономное образовательное учреждение высшего образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) | Drug with anti-inflammatory activity |
| RU2739559C1 (en) * | 2020-07-30 | 2020-12-25 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | ((3β-acetoxy-urs-12-en-28-oyl-oxyacetoxy)methyl)-1h-1,2,3-triazol-1-yl)methyl)-4-methyl-1,2,5-oxadiazol-2-oxide, having selective anticancer activity against mcf-7 breast cancer cells |
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