CN101519438A - Cyclic peptide compound in Hsisha sponge and application thereof - Google Patents
Cyclic peptide compound in Hsisha sponge and application thereof Download PDFInfo
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- CN101519438A CN101519438A CN200910048991A CN200910048991A CN101519438A CN 101519438 A CN101519438 A CN 101519438A CN 200910048991 A CN200910048991 A CN 200910048991A CN 200910048991 A CN200910048991 A CN 200910048991A CN 101519438 A CN101519438 A CN 101519438A
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Abstract
The invention relates to the technical field of medicaments, which is a novel cyclic peptide compound with antineoplastic activity produced from a marine animal Phakellia fusca in the territorial waters near Hsisha Islands. The chemical structural formula of the novel cyclic peptide compound is shown as the right formula. The in vitro activity test proves that the compound has certain inhibiting activity for various tumour cells, wherein the IC50 value of BEL-7402 cells is only 29.7 mu g/ml and is obviously superior to a positive control medicament vincristine, so the cyclic peptide compound can be used for preparing antitumor medicaments. The invention provides a lead compound for developing a novel antitumor medicament.
Description
Technical field
The present invention relates to medical technical field, is a kind of new cyclic peptide compound with anti-tumor activity that originates among the brown flat sponge Phakellia fusca of marine animal of surrounding waters, the Xisha Islands.
Background technology
Sponge is a kind of multicellular animals of low grade, and it is widely distributed but often contain the rare secondary metabolite with antitumour activity of a lot of structures, is the first-selected marine organisms research object of marine natural product chemistry man therefore always.The little axle of the medicine source material Phakellia ordinary guiding principle of fusca Sponge of the present invention (Demospongiae) Halichondrida (Halichondrida) Spongiidae (Axinellidae) sponge.2002,1 new cyclic peptide phakelliastatin 12 and patent applied for (application number: 01113389.9) once from the P.fusca sponge that gather on island, Yongxing, Xisha, China South Sea, had been found.All Phakellistatins class cyclic peptide compounds are before all belonged to the sponge from Phakellia by Pettit group of the upright university of State of Arizona, US to be found, but does not see relevant report with new cyclic peptide compound of anti-tumor activity so far.
Summary of the invention
The invention provides a kind of a kind of new cyclic peptide compound that is separated to from the brown flat sponge of surrounding waters, the Chinese Xisha Islands, its chemical structural formula is as follows:
The preparation method of The compounds of this invention is as follows:
1. extract the preparation total extract:
After the brown flat sponge of exsiccant (P.fusca) pulverized, extract with 95% ethanol cold soaking routinely, extracting solution, with extracting solution concentrate medicinal extract, add 50% the ethyl acetate aqueous solution and extract, get the ethyl acetate total extract;
2. separation and purification:
1) preparation crude extract: the ethyl acetate total extract with 90% methyl alcohol suspendible, routinely behind petroleum ether degreasing, is added water the methanol concentration of suspension is transferred to 60%, use dichloromethane extraction, concentrated extract must crude extract;
2) separation and purification cyclic peptide compound: above-mentioned crude extract is crossed Sephadex LH-20 gel column, use CH
2Cl
2-MeOH=1:1 wash-out, the result that inspection is known according to thin-layer chromatography, collection contains the elutriant part of cyclic peptide compound, carry out reversed-phase silica gel column chromatography again, with the volume ratio is the methanol mixed solvent gradient elution of 1:1-1:0, obtain The compounds of this invention C with reversed phase high efficiency liquid phase (the detection wavelength is 280nm for 58% methanol, flow velocity 1.5ml/min) again
44H
56N
8O
9
Activity test in vitro proves that The compounds of this invention all has certain inhibition activity to multiple different tumour cells such as P388, BEL-7402, SPC-A-1, HAC and Colo-26.Therefore can be used for preparing antitumor drug.
The The compounds of this invention preparation method is simple, and anti-tumor activity is remarkable.The present invention provides new lead compound for researching and developing new antitumor drug, for development and use China ocean medicine resource provides scientific basis.
Embodiment
Now in conjunction with the embodiments the present invention is described in detail.
Embodiment 1. preparation The compounds of this invention
Get the brown flat sponge 15kg after the drying and crushing, extract 8 times each week respectively with 95% ethanol 50L cold soaking, united extraction liquid, extracting solution gets medicinal extract through concentrating under reduced pressure, extracts with the 50% ethyl acetate aqueous solution, gets the ethyl acetate total extract, with the ethyl acetate total extract with 90% methyl alcohol suspendible, behind petroleum ether degreasing, add water the methanol concentration of suspension is transferred to 60%, with dichloromethane extraction 3 times, concentrated extract gets crude extract 55g;
Above-mentioned crude extract 55g is crossed Sephadex LH-20 gel column, use CH
2Cl
2-MeOH=1:1 wash-out, the result is known in inspection according to thin-layer chromatography, collection contains the elutriant of cyclic peptide compound, carry out reversed-phase silica gel column chromatography again, with the volume ratio is the methanol mixed solvent gradient elution of 1:1-1:0, prepare Compound C with reversed phase high efficiency liquid phase (the detection wavelength is 280nm for 58% methanol, flow velocity 1.5ml/min) again
44H
56N
8O
9Compound C
44H
56N
8O
9Physico-chemical property and nuclear magnetic resonance spectrum data as follows:
Compound C
44H
56N
8O
9: the white glass sprills show [M+Na] among the ESI-MS
+Peak 863.30, [2M+Na]
+Peak 1703.63 determines that its molecular weight is 840.The nuclear magnetic resonance spectrum data see Table.The nuclear magnetic resonance spectrum data see Table 1.
Nuclear magnetic resonance spectrum data (the DMSO-d of table 1 Compound C 44H56N8O9
6, 600MHz/150MHz)
The anti tumor activity in vitro experiment:
P388 (mouse leukemia), BEL-7402 (people's liver cancer), SPC-A-1 (people's lung cancer), HAC (rat liver cancer ascitic tumor), Colo-26 (mouse junction cancer) that the tumor cell line that experiment is used provides as Shanghai Tian Jia company.
Experimental technique adopts conventional tetramethyl-azo azoles salt (MTT) colorimetry, and platform is expected blue staining.Experiment divides 3 groups: blank group, positive controls and The compounds of this invention group.Positive control drug is a vincristine(VCR).The compounds of this invention and positive control drug are dissolved with DMSO respectively, be made into 100,50,25,12.5,6 kinds of concentration of 6.25,3.125 (mcg/ml), cell is cultivated with 10% calf serum earlier routinely, attached cell makes cell be in logarithmic phase with the digestion of 0.2% trysinization liquid when going down to posterity, and cell inoculation is in 96 well culture plates during experiment, 180 microlitres are inoculated in every hole, and concentration is 5 * 10
4The cell suspension of individual/milliliter.Put 37 ℃ CO
2After the pre-overnight incubation of incubator, every hole adds 20 microlitre drug solutions, and the blank group adds 20 microlitre DMSO, and every kind of concentration repeats 5 holes.Drug effect carries out mtt assay in cell after 3 days measures, and adding concentration in the every hole of 96 well culture plates is MTT working fluid 10 microlitres of 5 mg/ml, hatches 4 hours for 37 ℃, abandons supernatant liquor, adds 100 microlitre DMSO, measures the OD value with microplate reader under 570 nano wave lengths.Platform expects that blue row dyes method, adds platform and expects blue working fluid, living cell counting.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Half effective inhibition concentration IC
50Value adopts the Logit method to calculate, and the results are shown in Table 2:
Table 2 Compound C 44H56N8O9 is to the half effective inhibition concentration (μ g/ml) of tumour cell
By table 2 as seen, Compound C
44H
56N
8O
9Multiple different tumor cell line is shown that all certain restraining effect is arranged, wherein to the IC of BEL-7402 cell
50Value is 29.7 μ g/ml, obviously is better than contrasting the medicine vincristine(VCR), so can be used to prepare antitumor drug.The present invention provides new lead compound for developing new antitumour drug.
Claims (2)
1. cyclic peptide compound is characterized in that chemical structural formula is as follows:
2. the application of the described cyclic peptide compound of claim 1 in the preparation antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910048991XA CN101519438B (en) | 2009-04-09 | 2009-04-09 | Cyclic peptide compound in Hsisha sponge and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910048991XA CN101519438B (en) | 2009-04-09 | 2009-04-09 | Cyclic peptide compound in Hsisha sponge and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101519438A true CN101519438A (en) | 2009-09-02 |
| CN101519438B CN101519438B (en) | 2011-05-04 |
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| CN200910048991XA Expired - Fee Related CN101519438B (en) | 2009-04-09 | 2009-04-09 | Cyclic peptide compound in Hsisha sponge and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014059928A1 (en) * | 2012-10-16 | 2014-04-24 | Hong Kong Baptist University | Anticancer and anti-obesity cyclic peptide agents |
| CN111606975A (en) * | 2019-02-26 | 2020-09-01 | 上海交通大学医学院附属仁济医院 | Cyclic peptide compound extracted from Phakellia fusca and preparation method and application thereof |
| CN112521398A (en) * | 2020-07-30 | 2021-03-19 | 上海交通大学医学院附属仁济医院 | Sponge epiphyte-derived open-loop rearrangement steroid compound and preparation method and application thereof |
| CN114456237A (en) * | 2022-01-14 | 2022-05-10 | 上海交通大学医学院附属仁济医院 | Sponge cyclic peptide compound and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1152050C (en) * | 2001-07-12 | 2004-06-02 | 中国人民解放军第二军医大学 | Cyclopeptide compound phakellistatin 12 with anticancer activity |
-
2009
- 2009-04-09 CN CN200910048991XA patent/CN101519438B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014059928A1 (en) * | 2012-10-16 | 2014-04-24 | Hong Kong Baptist University | Anticancer and anti-obesity cyclic peptide agents |
| CN111606975A (en) * | 2019-02-26 | 2020-09-01 | 上海交通大学医学院附属仁济医院 | Cyclic peptide compound extracted from Phakellia fusca and preparation method and application thereof |
| CN111606975B (en) * | 2019-02-26 | 2021-12-24 | 上海交通大学医学院附属仁济医院 | Cyclic peptide compound extracted from Phakellia fusca and preparation method and application thereof |
| CN112521398A (en) * | 2020-07-30 | 2021-03-19 | 上海交通大学医学院附属仁济医院 | Sponge epiphyte-derived open-loop rearrangement steroid compound and preparation method and application thereof |
| CN112521398B (en) * | 2020-07-30 | 2022-03-15 | 上海交通大学医学院附属仁济医院 | Sponge epiphyte-derived open-loop rearrangement steroid compound and preparation method and application thereof |
| CN114456237A (en) * | 2022-01-14 | 2022-05-10 | 上海交通大学医学院附属仁济医院 | Sponge cyclic peptide compound and preparation method and application thereof |
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|---|---|
| CN101519438B (en) | 2011-05-04 |
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