CN102229585A - [Gamma]-butyrolactone polyketone compounds with antitumor activities - Google Patents
[Gamma]-butyrolactone polyketone compounds with antitumor activities Download PDFInfo
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- CN102229585A CN102229585A CN2011101050911A CN201110105091A CN102229585A CN 102229585 A CN102229585 A CN 102229585A CN 2011101050911 A CN2011101050911 A CN 2011101050911A CN 201110105091 A CN201110105091 A CN 201110105091A CN 102229585 A CN102229585 A CN 102229585A
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Abstract
The invention relates to the technical field of medicines, and relates to novel compounds plakortones H and plakortones J which are separated from a sea animal, sponge. The invention also relates to a preparation method and an application of the compounds. According to the results of in vitro antitumor tests, the compounds plakortones H and plakortones J have substantial inhibiting activities against human colon cancer cells, which are HCT-116 and SW480, therefore the compounds can be applied in the preparation of antitumor medicines. According to the present invention, novel lead compounds are provided for the development of antitumor medicines, and scientific basis is provided for the exploitation and utilization of marine medical resources of our nation.
Description
Technical field
The present invention relates to medical technical field, is a kind of gamma-butyrolactone polyketides plakortones H with anti-tumor activity that is separated to from the marine animal sponge and J 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 so far and from this genus sponge, be separated to gamma-butyrolactone polyketides plakortones H with anti-tumor activity and the report of J.
Summary of the invention
The invention provides a kind of new gamma-butyrolactone polyketides 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:
Its steric configuration is 3S, 4R, 5Z or 3S, 4S, 5E.
When steric configuration is 3S, 4R during 5Z, is compound plakortone H, and when steric configuration is 3S, 4S during 5E, is compound plakortone J.
The preparation method of compound plakortones H and J 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, obtains 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 95% methanol, and flow velocity 2.0ml/min gets compound plakortone H and component Fr.131;
5) component Fr.131 is further used the high performance liquid phase purifying, the high performance liquid phase purification condition is 85% acetonitrile/water, flow velocity 2.0ml/min, and retention time 66.9min obtains compound plakortone J.
Through identifying that compound plakortones H and J are gamma-butyrolactone polyketone class new compound.
Antitumor activity in vitro shows that compound plakortones H or J all have the activity of inhibition to human colon cancer cell HCT-116, therefore can be used for preparing antitumor drug.
The present invention provides new lead compound for developing new antitumor drug, and is significant for developing Chinese marine pharmaceutical organism resource.
Embodiment
Now in conjunction with the embodiments the present invention is described in detail.
Embodiment 1. preparation compound plakortones H and J
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 be scattered in become suspension in the water, suspension is used normal hexane, methylene dichloride, ethyl acetate and n-butanol extraction successively, concentrated extract respectively, normal hexane extraction medicinal extract 105g; 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 obtains 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 95% methanol, and flow velocity 2.0ml/min gets compound plakortone H 21.7mg and component Fr.131.
5) component Fr.131 is further used the high performance liquid phase purifying, the high performance liquid phase purification condition is 85% acetonitrile/water, flow velocity 2.0ml/min, and retention time 66.9min obtains compound plakortone J 8.3mg.
Structure is identified
Routinely through various modern spectroscopic techniquess such as NMR, HRESIMS, CD, IR, and chemical structure and the steric configuration of plakortones H and J have been determined in utilization chemical process Mosher reaction, the steric configuration of plakortone H is 3S, 4R, 5Z, the steric configuration of plakortone J is 3S, 4S, 5E
Plakortone H: colorless oil;
IR (KBr) v
Max3451,2960,2927,2873,1763,1655,1464,1412,1378,1343,1290,1248,1210,1182,1119,1103,1090,1071,1014,980,958,926,885,800cm
-1HRESIMS m/z 305.2094[M+Na]
+(calcd for C
17H
30O
3Na, 305.2093) .CD spectrum (c 1.1mg/mL, CH
3CN), 193nm (Δ ε-0.65), 222nm (Δ ε 0.84).
1H NMR (CDCl
3, 600MHz) and
13C NMR (CDCl
3, 150MHz) data see Table 1.
Plakortone J:colorless oil;
IR (KBr) v
Max3446,2961,2927,2874,1758,1655,1465,1400,1379,1342,1288,1252,1202,1166,1112,1063,1021,974,951,916,879,800cm
-1HRESIMSm/z 305.2091[M+Na]
+(calcd for C
17H
30O
3Na, 305.2093) .CD spectrum (c0.5mg/mL, CH
3CN), 196nm (Δ ε+5.16).
1H NMR (CDCl
3, 600MHz) and
13C NMR (CDCl
3, 150MHz) data see Table 1.
Table 1.Plakortones H and J's
1H and
13C nuclear magnetic resonance data table
The anti tumor activity in vitro experiment
One, experimental technique
Compound plakortones H of the present invention and J have 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) 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 plakortones H and plakortones J are by embodiment 1 preparation;
4. cell cultures
The HCT-116 cell that will grow in logarithmic phase is routinely adjusted cell density to 2.0 * 10 through 0.01% trysinization
3Individual/milliliter, be inoculated in 96 orifice plates with every hole 100 microlitres, the inoculation two boards places 5%CO
237 ℃ of 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 plakortone H or plakortone J are 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 37 ℃ of incubators, every again hole adds the MTT of the 5mg/ml of 20 microlitres, continuing at 37 ℃ 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 GraphpadPrism 4 calculates IC
50, the results are shown in Table 2.The positive control drug Zorubicin is to the IC of tumor cell line HCT-116
50Value is 0.039 μ M.
Two, experimental result
Compound plakortones H and J show the cell in vitro cytotoxic activity, and compound is to the IC of tumour cell HCT-116
50Value sees Table 2.
Table 2.Plakortones H and J are to the half effective inhibition concentration (μ g/ml) of tumour cell HCT-116
Above-mentioned experimental result shows: strain has obvious restraining effect to human colon cancer cell for compound plakortones H and plakortones J, therefore can be used to prepare antitumor drug.
Claims (3)
1. gamma-butyrolactone polyketides, its chemical structural formula is as follows:
Its steric configuration is 3S, 4R, 5Z or 3S, 4S, 5E.
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 Fr1 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 95% methanol, flow velocity 2.0ml/min, retention time 17.0min gets compound plakortone H and component Fr.131;
(5) component Fr.131 is further used the high performance liquid phase purifying, the high performance liquid phase purification condition is 85% acetonitrile/water, flow velocity 2.0ml/min, and retention time 66.9min gets compound plakortone J.
3. the application of the described compound of claim 1 in the preparation antitumor drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101050911A CN102229585A (en) | 2011-04-26 | 2011-04-26 | [Gamma]-butyrolactone polyketone compounds with antitumor activities |
| CN 201210056065 CN102617521B (en) | 2011-04-26 | 2012-03-06 | Gamma-butyrolactone polyketone compounds having antineoplastic activity |
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| CN 201210056065 Expired - Fee Related CN102617521B (en) | 2011-04-26 | 2012-03-06 | Gamma-butyrolactone polyketone compounds having antineoplastic activity |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103461981A (en) * | 2013-06-26 | 2013-12-25 | 杭州中赢科技集团有限公司 | Marine sponge traditional Chinese medicine health product |
| CN108218813A (en) * | 2018-04-10 | 2018-06-29 | 海南师范大学 | New gamma lactone derivatives quasi-compound and its preparation method and application |
| CN110437192A (en) * | 2019-07-31 | 2019-11-12 | 暨南大学 | A kind of compound, composition, preparation method and its usage for extracting from Spongia and belonging to sponge |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111196791B (en) * | 2020-01-20 | 2022-03-08 | 中山大学 | Chiral gamma-butyrolactone derivative and synthesis method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4731377A (en) * | 1986-01-31 | 1988-03-15 | Harbor Branch Oceanographic Institute, Inc. | Antitumor cyclic peroxides |
| JP2001213875A (en) * | 2000-01-27 | 2001-08-07 | Sagami Chem Res Center | Derivative of 3,6-dihydro-1,2-dioxin and antitumor agent |
| AU3387301A (en) * | 2000-02-16 | 2001-08-27 | Pharma Mar Sa | Oxy-and amino-substituted tetrahydrofuryl derivatives with antitumour activity |
-
2011
- 2011-04-26 CN CN2011101050911A patent/CN102229585A/en active Pending
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103461981A (en) * | 2013-06-26 | 2013-12-25 | 杭州中赢科技集团有限公司 | Marine sponge traditional Chinese medicine health product |
| CN103461981B (en) * | 2013-06-26 | 2015-03-11 | 杭州中赢科技集团有限公司 | Marine sponge traditional Chinese medicine health product |
| CN108218813A (en) * | 2018-04-10 | 2018-06-29 | 海南师范大学 | New gamma lactone derivatives quasi-compound and its preparation method and application |
| CN108218813B (en) * | 2018-04-10 | 2021-07-06 | 海南师范大学 | Gamma-lactone derivative compound and preparation method and application thereof |
| CN110437192A (en) * | 2019-07-31 | 2019-11-12 | 暨南大学 | A kind of compound, composition, preparation method and its usage for extracting from Spongia and belonging to sponge |
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|---|---|
| CN102617521A (en) | 2012-08-01 |
| CN102617521B (en) | 2013-11-06 |
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Open date: 20111102 |