CN102225921A - Cyclopentane polyketide simplextone A and its application - Google Patents

Cyclopentane polyketide simplextone A and its application Download PDF

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CN102225921A
CN102225921A CN2011101050659A CN201110105065A CN102225921A CN 102225921 A CN102225921 A CN 102225921A CN 2011101050659 A CN2011101050659 A CN 2011101050659A CN 201110105065 A CN201110105065 A CN 201110105065A CN 102225921 A CN102225921 A CN 102225921A
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simplextone
medicinal extract
extract
column chromatography
component
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CN102225921B (en
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林厚文
刘香芳
徐影
杨帆
朱彦
陈万生
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Second Military Medical University SMMU
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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

A kind of pentamethylene polyketides simplextone A and uses thereof
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 a kind ofly to live in low temperature, high pressure, high salt, lack 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, that wherein 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).But do not see the report that from this genus sponge, is separated to polyketone class compounds simplextone A so far.
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:
Figure BDA0000057488560000011
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 methyl alcohol diacolation extraction routinely, 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 reduces pressure once more, 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, 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, retention time 17.0min, get compound simplextone A, through identifying that it is a 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 medicine resource provides scientific basis.
Embodiment
Now in conjunction with the embodiments the present invention is done detailed description.
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 reduces pressure once more, 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 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 12.3mg.
Structure is identified
Routinely through various modern spectroscopic techniquess such as NMR, HRESIMS, CD, IR, X-ray single crystal diffractions, and the method for 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:
Figure BDA0000057488560000041
+ 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
Figure BDA0000057488560000051
The anti tumor activity in vitro experiment
Compound simplextone A of the present invention has been carried out the tumor cell proliferation inhibition 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 logarithmic phase respectively through 0.01% trysinization, adjust cell density to 2.0 * 10 routinely 3Individual/milliliter, be inoculated in 96 orifice plates respectively 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 plate is established 8 groups, i.e. positive controls, negative control group, 6 concentration groups of medicine.Positive control drug is a 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 concentration respectively with DMSO, 50,25,12.5,6.5, the drug solution of (3.125 mcg/ml), drug solution 20 microlitres of getting different concns respectively 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 again hole adds the MTT of the 5mg/ml of 20 microlitres, continuing at 37C hatched 3 hours, the solution in the hole is removed in suction, every again hole adds the DMSO dissolving of 100 microlitres, 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, with sigmoidaldose-response (varible slope) is model-fitting, and 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 used to prepare 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 methyl alcohol diacolation extraction routinely, 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, 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 reduces pressure once more, 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, 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.
CN 201110105065 2011-04-26 2011-04-26 Cyclopentane polyketide simplextone A and its application Expired - Fee Related CN102225921B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
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
JP2010064973A (en) * 2008-09-10 2010-03-25 Kazuyo Ukai Sponge-derived starfish repellent
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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
JP2010064973A (en) * 2008-09-10 2010-03-25 Kazuyo Ukai Sponge-derived starfish repellent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
孙晶波 等: "Halichondria属软海绵次生代谢产物及其生物活性", 《中草药》 *
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》 *
陈建涛 等: "海绵Haliclona oculata 化学成分的研究", 《药学实践杂志》 *

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