CN102225921B - Cyclopentane polyketide simplextone A and its application - Google Patents
Cyclopentane polyketide simplextone A and its application Download PDFInfo
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- CN102225921B CN102225921B CN 201110105065 CN201110105065A CN102225921B CN 102225921 B CN102225921 B CN 102225921B CN 201110105065 CN201110105065 CN 201110105065 CN 201110105065 A CN201110105065 A CN 201110105065A CN 102225921 B CN102225921 B CN 102225921B
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Abstract
Belonging to the technical field of medicine, the invention relates to a cyclopentane polyketide simplextone A separated from marine animal sponges, a preparation method and application thereof. And simplextone A is identified as a new cyclopentane polyketide. Anti-tumor tests in vitro indicate that the compound simplextone A shows inhibitory activity to human colorectal cancer cells HCT-116 and SW480, human stomach cancer cell SGC7901 and human cervical cancer cell Hela, so simplextone A can be used to prepare anti-tumor drugs. Simplextone A of the invention provides a new lead compound for development of anti-tumor drugs, and also provides scientific support for developing and utilizing marine medicinal resources of our country.
Description
Technical field
The present invention relates to medical technical field, is a kind of pentamethylene polyketides simplextone A that is separated to from the marine animal sponge and its production and use.
Background technology
Sponge is one way of life at low temperature, high pressure, high salt, lacks the multicellular animals such as low under the sunlight, often contains that many structures are rare a meta-bolites that has than strong biological activity.Can provide potential resources for the research of natural drug.Simple and easy flat plate sponge (Plakortis simplex) belongs to Demospongiae (Demospongiae) with bone sponge order (Hamosclerophorida) many plates Spongiidae (Plakinidae) sponge.From this genus sponge, separated and obtained a large amount of polyketone class secondary metabolites, wherein that most characteristic is polyketone class cyclic peroxide (Rahm F, Hayes P.Kitching W Metabolites from marine sponges of the genus Plakortis, Heterocycles 2004,64,523-575).From this genus sponge, be separated to the report of polyketone class compounds simplextone A but so far there are no.
Summary of the invention
The invention provides a kind of new pentamethylene polyketides simplextoneA that is separated to from the simple and easy flat plate sponge in marine site, South China Sea Xisha, its chemical structural formula is as follows:
The preparation method of the compounds of this invention simpextone A is as follows:
1. prepare simple and easy flat plate sponge extract medicinal extract
Simple and easy flat plate sponge (Plakortis simplex) after the drying and crushing with routinely diacolation extraction of methyl alcohol, is got extracting solution, the extracting solution concentrating under reduced pressure is got extract medicinal extract;
2. separation and purification
1) said extracted thing medicinal extract is scattered in becomes suspension in the water, suspension is used normal hexane, methylene dichloride, ethyl acetate and n-butanol extraction successively, concentrated extract gets normal hexane extraction medicinal extract, dichloromethane extraction medicinal extract, ethyl acetate extraction medicinal extract and n-butanol extraction medicinal extract respectively;
2) with dichloromethane extraction medicinal extract through the decompression column chromatography, with methylene dichloride: methyl alcohol=50: 1,25: 1,15: 1,5: 1,2: 1, be solvent gradient elution at 1: 1, colour developing merges similar stream part according to TLC, obtains 4 component Fr.1～Fr.4;
3) to the component Fr.1 column chromatography that again reduces pressure, with sherwood oil: ethyl acetate=50: 1,20: 1,10: 1,5: 1,3: 1, be solvent gradient elution at 1: 1, colour developing merges similar flow point according to TLC, gets 4 component Fr.11～Fr.14;
4) component Fr.13 is carried out positive and negative phase silica gel column chromatography, gel column chromatography repeatedly, use again the high performance liquid phase purifying, the high performance liquid phase purification condition is 60% acetonitrile/water, flow velocity 2.0ml/min, retention time 17.0min, get compound simplextone A, through identifying, it is pentamethylene polyketone class new compound.
Antitumor activity in vitro shows, compound simplextone A all has human colon cancer cell HCT-116 and SW480, gastric carcinoma cells SGC7901 and human cervical carcinoma cell Hela and suppresses active, therefore can be used for preparing antitumor drug.
The present invention provides new lead compound for the development antitumor drug, for development and use China Ocean Medicinal Resource Supply scientific basis.
Embodiment
Now in conjunction with the embodiments the present invention is described in detail.
Embodiment 1. preparation compound simplextone A
1. prepare simple and easy flat plate sponge extract medicinal extract
(1) preparation extracting solution:
Get simple and easy flat plate sponge (Plakortis simplex) 2.0kg after the drying and crushing, extract 4 times with 15L methyl alcohol diacolation respectively, each diacolation 3 days, united extraction liquid;
(2) preparation extract medicinal extract
Concentrating under reduced pressure said extracted liquid obtains extract medicinal extract 500g;
2. separation and purification
1) said extracted thing medicinal extract is scattered in becomes suspension in the water, suspension is used normal hexane, methylene dichloride, ethyl acetate and n-butanol extraction successively, concentrated extract obtains normal hexane extraction medicinal extract 105g respectively; Dichloromethane extraction medicinal extract 41g; Ethyl acetate extraction medicinal extract 1.2g and n-butanol extraction medicinal extract 22g;
2) with dichloromethane extraction medicinal extract through the decompression column chromatography, with methylene dichloride: methyl alcohol=50: 1,25: 1,15: 1,5: 1,2: 1, be solvent gradient elution at 1: 1, colour developing merges similar stream and part obtains 4 component Fr.1～Fr.4 according to TLC.
3) to the component Fr.1 column chromatography that again reduces pressure, with sherwood oil: ethyl acetate=50: 1,20: 1,10: 1,5: 1,3: 1, be solvent gradient elution at 1: 1, colour developing merges similar flow point and gets 4 component Fr.11～Fr.14 according to TLC;
4) component Fr.13 is carried out positive and negative phase silica gel column chromatography, gel column chromatography repeatedly, use the high performance liquid phase purifying, the high performance liquid phase purification condition is 60% acetonitrile/water, flow velocity 2.0ml/min again, retention time 17.0min gets compound simplextone A 12.3mg.
Structural Identification
Routinely through various modern spectroscopic techniquess such as NMR, HRESIMS, CD, IR, X-ray single crystal diffractions, and the method for the chemical process such as recrystallization, Mosher reaction and quantum calculation ECD has been determined chemical structure and the steric configuration of simplextone A, its absolute configuration is 3S, 4S, 5S, 6R, 8S, 9R.
Simpextone A:
+ 28 (c 0.085, MeOH); IR (KBr) v
Max3406,2959,2928,1751,1465,1226,1086,968cm
-1HRESIMS m/z 335.2200[M+Na]
+(calcd for C
18H
32O
4Na, 335.2198);
1H NMR (CDCl
3, 500MHz) and
13C NMR (CDCl
3, 125MHz) data see Table 1.
Table 1.Simplextone A's
1H and
13C nuclear magnetic resonance data table
The anti tumor activity in vitro experiment
Compound simplextone A of the present invention has been carried out the Cytostatic to tumor cell test, and test method adopts conventional mtt assay.
1. tumor cell line: HCT-116 (human colon cancer cell), SW480 (human colon cancer cell), SGC7901 (gastric carcinoma cells), Hela (human cervical carcinoma cell) is provided by the biological company limited of Shanghai Tian Jia;
2. experiment reagent, consumptive material and instrument: DMSO and MTT (sigma company), culture dish, transfer pipet and 96 orifice plates (Corning company)
3. experimental drug: compound simplextone A is by embodiment 1 preparation;
4. cell cultures
The 4 strain cell HCT116, SW480, SGC7901, Hela that will grow in respectively logarithmic phase through 0.01% trysinization, adjust cell density to 2.0 * 10 routinely
3Individual/milliliter, be inoculated in respectively 96 orifice plates with every hole 100 microlitres, 4 96 orifice plates are placed 5%CO
237C overnight incubation in the incubator.
5. cell viability test experience
Every 96 orifice plates are established 8 groups, i.e. positive controls, negative control group, 6 concentration groups of medicine.Positive control drug is Zorubicin, is mixed with the solution that concentration is 0.4 grams per milliliter with DMSO, and it is 100 that experimental drug thing simplextone A is mixed with respectively concentration with DMSO, 50,25,12.5,6.5, the drug solution of (3.125 mcg/ml), drug solution 20 microlitres of getting respectively different concns join in the hole of the corresponding group of 96 orifice plates, and negative control group adds equal-volume DMSO, and positive controls adds Zorubicin solution 20 microlitres, each concentration is established three multiple holes, at 5%CO
2Cultivated 72 hours in the 37C incubator, every hole adds the MTT of the 5mg/ml of 20 microlitres again, continuing at 37C hatched 3 hours, suck the solution in the hole, every hole adds the DMSO dissolving of 100 microlitres again, use SpectraMAX 340 microplate reader to detect absorbance value L1 in wavelength 550nm, detect absorbance value L2 in reference wavelength 690nm, poor (L1-L2) of absorbance value mapped to the inhibitor different concns, take sigmoidaldose-response (varible slope) as model-fitting, application software Graphpad Prism 4 calculates IC
50, the results are shown in Table 2.The positive control drug Zorubicin is to tumor cell line HCT-116, SW480, SGC7901, the IC of Hela
50Value is respectively 0.039 μ M, 65 μ M, 22 μ M and 0.62 μ M.
Table 2.Simplextone A is to the half effective inhibition concentration (μ g/ml) of tumour cell
Above-mentioned experimental result shows: compound simplextone A all has obvious restraining effect to four kinds of different tumor cell lines, therefore can be for the preparation of antitumor drug.
Claims (3)
1. pentamethylene polyketides simplextone A, its chemical structural formula is as follows:
2. the preparation method of the described compound of claim 1, step is as follows:
1) the simple and easy flat plate sponge extract medicinal extract of preparation
Simple and easy flat plate sponge after the drying and crushing with routinely diacolation extraction of methyl alcohol, is got extracting solution, the extracting solution concentrating under reduced pressure is got extract medicinal extract;
2) separation and purification
(1) said extracted thing medicinal extract is scattered in becomes suspension in the water, suspension is used normal hexane, methylene dichloride, ethyl acetate and n-butanol extraction successively, concentrated extract obtains normal hexane extraction medicinal extract, dichloromethane extraction medicinal extract, ethyl acetate extraction medicinal extract and n-butanol extraction medicinal extract respectively;
(2) with dichloromethane extraction medicinal extract through the decompression column chromatography, with methylene dichloride: methyl alcohol=50:1,25:1,15:1,5:1,2:1,1:1 are solvent gradient elution, merge similar stream part according to TLC colour developing, obtain 4 component F r.1～Fr.4;
(3) to the component Fr.1 column chromatography that again reduces pressure, with sherwood oil: ethyl acetate=50:1,20:1,10:1,5:1,3:1,1:1 are solvent gradient elution, colour developing merges similar stream part according to TLC, gets 4 component Fr.11～Fr.14;
(4) component Fr.13 is carried out positive and negative phase silica gel column chromatography, gel column chromatography repeatedly, use the high performance liquid phase purifying again, the high performance liquid phase purification condition is 60% acetonitrile/water, flow velocity 2.0ml/min, and retention time 17.0min gets compound simplextone A.
3. the application of the described compound simplextone of claim 1 A in the preparation antitumor drug.
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Citations (2)
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|---|---|---|---|---|
| CN1222525A (en) * | 1998-11-26 | 1999-07-14 | 中国科学院广州化学研究所 | Cholesterol acetate extracted from sponge and its preparation |
| CN101883763A (en) * | 2007-10-03 | 2010-11-10 | 卫材R&D管理有限公司 | Intermediates and methods for the synthesis of halichondrin b analogs |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010064973A (en) * | 2008-09-10 | 2010-03-25 | Kazuyo Ukai | Sponge-derived starfish repellent |
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2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222525A (en) * | 1998-11-26 | 1999-07-14 | 中国科学院广州化学研究所 | Cholesterol acetate extracted from sponge and its preparation |
| CN101883763A (en) * | 2007-10-03 | 2010-11-10 | 卫材R&D管理有限公司 | Intermediates and methods for the synthesis of halichondrin b analogs |
Non-Patent Citations (7)
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| Halichondria属软海绵次生代谢产物及其生物活性;孙晶波 等;《中草药》;20050430;第36卷(第4期);609-613 * |
| JP特开2010-64973A 2010.03.25 |
| 孙晶波 等.Halichondria属软海绵次生代谢产物及其生物活性.《中草药》.2005,第36卷(第4期),609-613. |
| 我国南海总合草苔虫和海绵中新的抗肿瘤活性成分的研究;易杨华 等;《第二军医大学学报》;20020331;第23卷(第3期);236-239 * |
| 易杨华 等.我国南海总合草苔虫和海绵中新的抗肿瘤活性成分的研究.《第二军医大学学报》.2002,第23卷(第3期),236-239. |
| 海绵Haliclona oculata 化学成分的研究;陈建涛 等;《药学实践杂志》;20100125;第28卷(第1期);52-54 * |
| 陈建涛 等.海绵Haliclona oculata 化学成分的研究.《药学实践杂志》.2010,第28卷(第1期),52-54. |
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