CN101270154B - Cyclo-pentapeptide with antineoplastic activity - Google Patents
Cyclo-pentapeptide with antineoplastic activity Download PDFInfo
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- CN101270154B CN101270154B CN2008100279921A CN200810027992A CN101270154B CN 101270154 B CN101270154 B CN 101270154B CN 2008100279921 A CN2008100279921 A CN 2008100279921A CN 200810027992 A CN200810027992 A CN 200810027992A CN 101270154 B CN101270154 B CN 101270154B
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Abstract
The present invention discloses a cyclic pentapeptide with anti-tumour activity, which is cyclic (leucyl-N-methylleucyl-leucyl-leucyl-N-methylleucyl) and the constitutional formula of which is shown in the formula (I). The cyclic pentapeptide of the present invention is separated from galaxaura filamentosa in the South China Sea, and in vitro experiments show that the cyclic pentapeptide has strong inhibiting effect on human hepatoma cell lines (HepG2), human hepatoma cell lines (BEL-7402), human mammary cancer cell lines (MCF-7), human colon cancer cell lines (LOVO), human lung cancer cell lines (PC84045) and human nasopharyngeal cancer (CNE) and can keep the mitotic cycle of BEL-7402 hepatoma cells in G2/M phase. The present invention provides a pilot compound for the research and the development of new anti-tumour drugs and is valuable for the exploitation of the marine pharmaceutical resources of China.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of ring pentapeptide that from the marine organisms marine alga, extracts with anti-tumor activity.
Background technology
Cyclic peptide is as the class that characteristics are arranged in the peptides most, because its metastable conformation, thereby aspect the selectivity of action receptor and internal metabolism stable, all being better than the linear peptides compounds, cyclic peptide is antimycotic and kill tumour cell etc. and all show natural advantage aspect a lot.
The cyclic peptide multi-source is in terricole, plant, microorganism in the previous patent, resource-constrained, and kind is single, as CN99815515.2, CN02114663.2 etc.Marine organisms have become the huge treasure-house of biologically active substance with the advantages such as diversity of the chemical structure of the diversity of its species and meta-bolites thereof.Marine organisms are different from terrestrial life, are containing a large amount of novel structures, chemical property is special, biological activity is extremely strong material in the marine organisms.The peptides that marine organisms are contained, particularly cyclic peptide compound, aspect antitumor, antiviral, antibiotic and inhibitor activity reality great potential.
From people (Ireland, C. such as American scholar Chris Ireland in 1980; Scheuer, P.J., J.Am.Chem.Soc., 1980,102,5688-5691) report separates from Ascidian and has obtained since first cyclic peptide Ulithiacyclamide with anti-tumor activity, from 1980 to the end of the year 1996, from marine organisms, separate and identified many lead compounds with unique texture and physiologically active, inhibited as from sea hare Dolabella auricularia, separating Dolastatin 3, Dolastatin 13 and 10 couples of leukemia cells of Dolastatin of obtaining, the anti-tumor biological that tool is very strong; Separate cyclic peptide GeodiamolideA and the Geodiamolide B that obtains from sponge Geodia sp., they are very strong to the L-1210 cytotoxic activity, are respectively 0.032ug/ml and 0.0026ug/ml; Isolated 3 kinds of cyclic peptide Didemnin A～C among the colony Ascidian Trididemnum sp. from the marine site, California and the Caribbean Sea, they all have in the body and extracorporeal antivirus effect and anti-tumor activity, wherein the activity of Didemnin B is the strongest, to mammary cancer, ovarian cancer tool obvious inhibiting activity, simultaneously, it also has tangible immunosuppressive activity, activity in vivo is strong 1000 times than Ciclosporin A, and DideminB can carry out manually complete synthesis, is expected to become new antitumoral new drug (Liu Yunguo, Li Bafang etc. most, Chinese Journal of Marine Drugs, 2006,24 (3), 51-57.).
Marine alga is extended familys of marine resources, kind surplus the whole world has 30,000 approximately, China marine site is vast, marine algae resource is particularly abundant, and marine alga can produce diversified compound, and as sterol, terpene, fatty compounds etc., these compounds have diversified physiologically actives such as antibiotic, antitumor, antiviral mostly, therefore extract cyclic peptide compounds from algae such as green alga, red algae, utilization has a extensive future.Ring pentapeptide of the present invention is to separate first to obtain from the thread galaxaura of marine organisms marine alga (Galaxaura filamentosa).Thread galaxaura belongs to the rhodophyta galaxaura and belongs to, and the research that belongs to for galaxaura is both at home and abroad reported seldom, has not yet to see the report that extracts cyclic peptide from galaxaura.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of new ring pentapeptide with anti-tumor activity that is extracted from the thread galaxaura is provided.
Another object of the present invention is to provide the application of above-mentioned ring pentapeptide in the preparation antitumor drug.
Ring pentapeptide of the present invention is that [the english abbreviation expression formula is cyclo-(Leu-N-Me-Leu-Leu-Leu-N-Me-Leu) to ring (leucyl-N-methyl leucyl-leucyl-leucyl-N-methyl leucyl), wherein: Leu is a leucine, Me is a methyl], be white needle-like crystals, molecular formula is C32H59N5O
5, [M+H]
+M/z:594.4, mp:208～210 ℃,
1H and
13The nucleus magnetic resonance of C is as shown in table 1, and by two dimensional NMR spectrum (TOCSY, DQCOSY, HMQC and NOESY), has determined these all carbon atoms of ring pentapeptide and the ownership of hydrogen atom and the chemical structure of this ring pentapeptide, and its structural formula is suc as formula shown in (I).
Table 1 ring pentapeptide (I)
1H and
13The nuclear magnetic resonance data of C
Annotate: 1. this nuclear magnetic resonance data is the nuclear magnetic resonance measuring that adopts 600MHz, and sample dissolution is in deuterated dichloromethane.
2. the division of each side group in the table 1 is suc as formula shown in (II).
Ring pentapeptide of the present invention is to separate first to obtain from the thread galaxaura of marine organisms marine alga (Galaxaurafilamentosa), and its separation preparation process is as follows:
(1) the thread galaxaura of soaked in solvent gets extractive substance;
(2) the above-mentioned extractive substance of concentrating under reduced pressure, through organic solvent extraction, extraction liquid concentrate crude extract;
(3) above-mentioned crude extract must be encircled the crude product of (leucyl-N-methyl leucyl-leucyl-leucyl-N-methyl leucyl) through column chromatography for separation, promptly get through recrystallization again and encircle (leucyl-N-methyl leucyl-leucyl-leucyl-N-methyl leucyl) monomer.
In the above-mentioned steps (1), the solvent that soaks thread galaxaura is a usual vehicle, one or more in preferred alcohol, methyl alcohol, propyl alcohol, the acetone.
In the above-mentioned steps (1), it is 7～15 days that thread galaxaura soaks extraction time, and temperature is 20 ℃～40 ℃.
In the above-mentioned steps (2), extraction liquid is an organic solvent, a kind of in ethyl acetate, propyl carbinol, acetone, methyl alcohol, chloroform, sherwood oil, the ether, or adopt wherein that more than one solvents extract respectively, remerge extraction liquid.
In the above-mentioned steps (2), the thickening temperature of extraction liquid is 20 ℃～120 ℃.
In the above-mentioned steps (3), column chromatography for separation is one or more in silica gel column chromatography, ion exchange resin, macroporous resin, the C18 reverse-phase chromatographic column.
In the above-mentioned steps (3), can adopt in methyl alcohol, ethyl acetate, the chloroform one or more to the recrystallization of crude product.
Adopt tetramethyl-azo azoles salt trace enzyme reaction colorimetry (mtt assay) that ring pentapeptide of the present invention is carried out the anti tumor activity in vitro test, test-results proves, ring pentapeptide of the present invention has strong restraining effect to human hepatoma cell strain HepG2, human hepatoma cell strain BEL-7402, human breast cancer cell strain MCF-7, human colon cancer cell strain LOVO, human lung carcinoma cell line PC84045 and KB cell CNE, and the cell-cycle arrest that can make the BEL-7402 liver cancer cell is at G
2/ M the phase.
Compared with prior art, the present invention has following beneficial effect: 1. the present invention extracts a kind of new ring pentapeptide from thread galaxaura, this ring pentapeptide has strong anti-tumor activity, provide lead compound for researching and developing new antitumor drug, also the marine pharmaceutical resource that develops China has been had important value simultaneously; 2. the extracting method of ring pentapeptide of the present invention prepares by simple organic solvent fractional separation, and it is simple to have preparation technology, the advantage that production cost is low.
Embodiment
The preparation of embodiment 1 ring pentapeptide
The preparation method of ring pentapeptide, its concrete steps are as follows:
(1) thread galaxaura is soaked extraction in ethanol, temperature is 20 ℃, after 45 days with the soaked extracting solution concentrating under reduced pressure;
(2) extractive substance after will concentrating is after the ethyl acetate solution extraction, and 20 ℃ of concentrating under reduced pressure get crude extract;
(3) above-mentioned crude extract must be encircled the crude product of pentapeptide through silica gel column chromatography, promptly get through recrystallizing methanol again and encircle the pentapeptide monomer.
This ring pentapeptide is a white needle-like crystals, and molecular formula is C
32H
59N
5O
5, [M+H]
+M/z:594.4, mp:208～210 ℃,
1H and
13The nucleus magnetic resonance of C is as shown in table 1, and by two dimensional NMR spectrum (TOCSY, DQCOSY, HMQC and NOESY), has determined these all carbon atoms of ring pentapeptide and the ownership of hydrogen atom and the chemical structure of this ring pentapeptide, and its structural formula is suc as formula shown in (I).
The test of embodiment 2 anti tumor activity in vitro
Adopt tetramethyl-azo azoles salt trace enzyme reaction colorimetry (mtt assay), the ring pentapeptide (I) that embodiment 1 is obtained and human hepatoma cell strain HepG2, human breast cancer cell strain MCF-7, human hepatoma cell strain BEL-7402, human colon cancer cell strain LOVO, KB cell CNE and human lung carcinoma cell PC84045, respectively 72 hours action time, the result is as shown in table 2.
Table 2 ring pentapeptide (I) is to the medium effective concentration (IC of tumour cell
50)
Embodiment 3 ring pentapeptides are to the effect test in BEL-7402 liver cancer cell cycle
Adopt iodate third ingot (PI) staining, the ring pentapeptide (the ring pentapeptide that embodiment 1 prepares) of different concns was acted on the BEL-7402 liver cancer cell after 48 hours, the cells were tested by flow cytometry cell cycle, the result was as shown in table 3, and the concentration of wherein encircling pentapeptide is respectively 2.5 * 10
-6Mol/L and 5.0 * 10
-6Mol/L.
The table 3 different concns effect Bel-7402 cell cycle each the time phase ratio (%)
From the result of embodiment 2 and embodiment 3 as can be seen, ring pentapeptide of the present invention shows that through the anti tumor activity in vitro test it has strong anti-tumor activity, the present invention provides lead compound for researching and developing new antitumor drug, and the marine pharmaceutical resource that develops China is had important value.
Claims (2)
1. one kind is encircled pentapeptide, and the molecular formula that it is characterized in that this ring pentapeptide is C
32H
59N
5O
5, structural formula is suc as formula shown in (I).
2. the application of the described ring pentapeptide of claim 1 in the preparation antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101270153B (en) * | 2008-05-09 | 2011-11-09 | 暨南大学 | Cyclo-pentapeptide and synthesizing method |
| CN102329376B (en) * | 2011-07-07 | 2013-07-10 | 暨南大学 | Cyclo(phenylalanine-N-methylleucyl-leucyl-N-methylleucyl-leucyl), and synthesis method and application thereof |
| CN102532268B (en) * | 2012-03-12 | 2013-12-18 | 胡海波 | Oligopeptide with breast cancer resistant activity and application thereof |
| CN103965299B (en) * | 2014-04-24 | 2016-07-13 | 暨南大学 | A kind of ring pentapeptide and synthetic method thereof and application |
| CN108484728A (en) * | 2018-03-23 | 2018-09-04 | 哈尔滨师范大学 | A kind of road Deng Su straight chains derivative, its preparation method and purposes |
| CN113185582A (en) * | 2021-05-17 | 2021-07-30 | 暨南大学 | Cyclic pentapeptide Galaxamide, preparation method thereof and application thereof in preparation of antitumor drugs |
| CN114315963B (en) * | 2021-12-14 | 2023-11-17 | 河北科技大学 | LSH series cyclic pentapeptide ester and synthetic method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616484A (en) * | 2004-09-27 | 2005-05-18 | 沈阳药科大学 | Novel cyclopeptide anti-tumor, anti-virus antibiotic active compound |
| CN1690076A (en) * | 2004-04-23 | 2005-11-02 | 中国科学院海洋研究所 | Use of ocean green algae in extraction of cyclic peptide components with anti-tumor activity |
| CN1763083A (en) * | 2005-10-11 | 2006-04-26 | 暨南大学 | Cyclopentapeptide extraction method and its uses in preparing anti-tumour medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1690076A (en) * | 2004-04-23 | 2005-11-02 | 中国科学院海洋研究所 | Use of ocean green algae in extraction of cyclic peptide components with anti-tumor activity |
| CN1616484A (en) * | 2004-09-27 | 2005-05-18 | 沈阳药科大学 | Novel cyclopeptide anti-tumor, anti-virus antibiotic active compound |
| CN1763083A (en) * | 2005-10-11 | 2006-04-26 | 暨南大学 | Cyclopentapeptide extraction method and its uses in preparing anti-tumour medicine |
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