CN102516368A - Cyclopeptide-7 compounds and application thereof in preparation of anti-tumor medicines - Google Patents

Cyclopeptide-7 compounds and application thereof in preparation of anti-tumor medicines Download PDF

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CN102516368A
CN102516368A CN2011104337896A CN201110433789A CN102516368A CN 102516368 A CN102516368 A CN 102516368A CN 2011104337896 A CN2011104337896 A CN 2011104337896A CN 201110433789 A CN201110433789 A CN 201110433789A CN 102516368 A CN102516368 A CN 102516368A
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compound
compounds
tumor
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鞠建华
陈子明
黄洪波
宋永相
张长生
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South China Sea Institute of Oceanology of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention discloses cyclopeptide-7 compounds and applications thereof in preparations of anti-tumor medicines. According to the invention, 3 active compounds are separated and purified from a fermentation extract of a marine fungus acremonium persicinum SCSIO 115. According to structural analysis, the 3 compounds are cyclopeptide-7 compounds, wherein the 3 compounds have specific structures represented as a formula (I). In the compound 1, R1=H, R2=H. in the compound 2, R1=OH, R2=H. In the compound 3, R1=OH, R2=Me. As results of anti-tumor activity evaluations upon the compound 1, the compound 2 and the compound 3, the compound 1, the compound 2 and the compound 3 provides substantial inhibiting effects against glioma cell strains (SF-268), breast cancer cell strains (MCF-7), and human large-cell lung cancer cell strains (NCI-H460). Especially, the inhibiting effects provided by the compound 1 and the compound 3 against the tumor cell strains SF-268 and MCF-7 are better than a clinical first-line chemotherapeutic medicine cisplatin, such that the compounds can be used for preparing anti-tumor medicines. Therefore, compound options for treating tumors and for developing novel anti-tumor medicines are provided. The formula (I) is presented as the following.

Description

Ring seven peptide compounds and the application in the preparation antitumor drug thereof
Technical field:
The invention belongs to the natural product field, be specifically related to three ring seven peptide compounds and the application in the preparation antitumor drug thereof.
Background technology:
Malignant tumour is one of principal disease of present serious harm human life and quality of life, has become China resident's underlying cause of death at present, accounts for the cause of death more than 20%.Since the second half in 20th century, world's malignant tumour and death are all in rising trend, and especially after the seventies, malignant tumour is with average annual 3%～5% speed increase.World Health Organization's prediction to the year two thousand twenty, will have 2,000 ten thousand New Development malignant tumour cases, and wherein death toll reaches 1,200 ten thousand, and the overwhelming majority will occur in developing country.In three big therapies of malignant tumour, pharmacological agent takies consequence.Majority is a lead compound with the natural antitumor activeconstituents all in synthetic chemistry class medicine.It is reported that natural product accounted for more than 60% of antitumor drug of listing to nineteen ninety-five in 1984; 1995-1999; 3 natural product verivates this shows that as new antitumor drug listing natural product is the important source of the novel structure and the antitumor drug of effect uniqueness.
Summary of the invention:
First purpose of the present invention provides three ring seven peptide compounds and pharmaceutical salts thereof with anti-tumor activity.
Ring seven peptide compounds of the present invention and pharmaceutical salts thereof, its structure is suc as formula shown in (I):
Figure BDA0000123330380000021
Formula (I)
Wherein, compound 1:R 1=H, R 2=H; Or compound 2:R 1=OH, R 2=H; Or compound 3:R 1=OH, R 2=Me.
The inventor is on the basis of the active secondary metabolite screening of thalassiomycetes; The fermented product extract of finding fungi Acremonium persicinum SCSIO 115 has the activity of inhibition to neuroglial cytoma strain (SF-268) and breast carcinoma cell strain (MCF-7), is tracked as guidance with activity, separation and purification to 3 active compound; Through structural analysis; 3 active compounds are the ring seven peptide compounds, and concrete structure is suc as formula shown in (I), wherein compound 1:R 1=H, R 2=H; Compound 2:R 1=OH, R 2=H; Compound 3:R 1=OH, R 2=Me.Through anti-tumor activity evaluation to compound 1, compound 2 and compound 3; Find that compound 1, compound 2 and 3 pairs of neuroglial cytoma strains of compound (SF-268), breast carcinoma cell strain (MCF-7) and National People's Congress's sclc cell line (NCI-H460) have obvious restraining effect, especially the restraining effect of compound 1 and 3 couples of tumor cell line SF-268 of compound and MCF-7 is better than clinical linearize treatment medicine cis-platinum.
Therefore second purpose of the present invention provides suc as formula the compound 1 shown in (I), compound 2 or compound 3, or the application of its pharmaceutical salts in the preparation antitumor drug.
The 3rd purpose of the present invention provides a kind of antitumor drug, it is characterized in that, comprise significant quantity as active ingredient suc as formula the compound 1 shown in (I), compound 2 or compound 3, or its pharmaceutical salts and acceptable carrier pharmaceutically.
Ring seven peptide compounds-compound of the present invention 1, compound 2 and compound 3 are new compounds; Tumour cell had the obvious suppression effect; Can be used to prepare antitumor drug; Be used to treat tumour, so the present invention provides compound candidate for the new antitumor drug of exploitation, exploitation China sea ocean drug resource has been had great importance.
Fungi Acremonium persicinum SCSIO 115 of the present invention; This bacterial strain is stored in Chinese Academy of Science Nanhai Ocean Research Institute's Living marine resources can continue to utilize key lab; Address: No. 164, Haizhu District New Port West Road, Guangzhou, Guangdong Province, China city; Postcode: 510301, this bacterial strain is for sale, the public can buy this bacterial strain from this preservation center.
Embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1:
Preparation and structure suc as formula the compound 1 shown in (I), compound 2 and compound 3 are identified
One, suc as formula the preparation of the compound 1 shown in (I), compound 2 and compound 3
1. seed culture:
(1) preparation seed culture medium: potato (peeling) 200g, glucose 20g, sea salt 30g adds the water constant volume to 1L, and average mark is loaded in the Erlenmeyer flask of 10 500mL, sterilizes 25 minutes for 121 ℃, obtains the seed culture medium of sterilization.
(2) cultivation of seed: the bacterial strain of thalassiomycetes Acremonium persicinum SCSIO 115 is linked in the above-mentioned seed culture medium, under 28 ℃ temperature, puts on the shaking table with the rotating speed of 150rpm, cultivated 48 hours seed culture fluid.
2. fermentation culture:
(1) preparation fermention medium: potato (peeling) 1500g, glucose 150g, sea salt 225g, peptone 37.5g adds the water constant volume to 7.5L, and average mark is loaded on the Erlenmeyer flask of 30 1000mL, sterilizes 25 minutes for 121 ℃, obtains the fermention medium of sterilization.
(2) fermentation culture:
In Bechtop; The access of 50mL seed culture fluid is equipped with in the 1000mL Erlenmeyer flask of 250mL fermention medium, places on 28 ℃ of shaking tables, with the rotating speed of 150rpm; Cultivated 7 days, and obtained the fermenting culture of thalassiomycetes Acremonium persicinum SCSIO 115.
3. extraction separation:
Above-mentioned fermenting culture crossed filter thalline and fermented liquid, fermented liquid is used ethanol (2L) wash-out macroporous adsorbent resin 3 times then with 2kg macroporous resin adsorption three times, and ethanol eluate gets fermented liquid medicinal extract being lower than 50 ℃ of following concentrating under reduced pressure; Thalline extracts three times with acetone (1L), and acetone extract gets thalline medicinal extract being lower than 50 ℃ of following concentrating under reduced pressure, merges fermented liquid medicinal extract and thalline medicinal extract (8.28g).This medicinal extract adopts chloroform-methanol (volume ratio 100: 0,95: 5,9: 1,8: 2,1: 1,0: 100) gradient elution through silica gel (100-200 order) column chromatography for separation, behind concentrating under reduced pressure, obtains cut Fr.1～Fr.6 accordingly.Cut Fr.2 (volume ratio is the cut of 95: 5 chloroform-methanol wash-out) through gel sephadex LH-20 column chromatography, adopts chloroform-methanol (volume ratio is 1: 1) as the permanent gradient elution of eluent, instructs to merge through TLC to obtain cut Fr.2-1～Fr.2-4.Fr.2-1 is (between the principal point RF value 0.2-0.3; Developping agent is that volume ratio is 95: 5 a chloroform-methanol), through silica gel (100-200 order) column chromatography, with chloroform-methanol as eluent; From 100: 0 → 95: 5 gradient elutions of volume ratio, instruct merging to obtain cut Fr.2-1-1～Fr.2-1-7 through TLC.Fr.2-1-6 (volume(tric)fraction is the cut of 96: 4 chloroform-methanol wash-out) is through the anti-phase medium pressure column chromatography, with ODS chromatographic column (20 * 90mm, 40-63 μ m; YMC), with methanol-water as eluent, flow velocity 15mL/min; 0-50min, volume ratio 30: 70 → 80: 20 obtains compound 1 (t R24min, 15.6mg).Fr.2-1-7 (volume(tric)fraction is the cut of 95: 5 chloroform-methanol wash-out) through silica gel (100-200 order) column chromatography, as eluent, from 98: 2 → 95: 5 gradient elutions of volume ratio, obtains cut Fr.2-1-7-1～Fr.2-1-7-4 with ETHYLE ACETATE-methyl alcohol.Fr.2-1-7-2 (volume(tric)fraction is the cut of ETHYLE ACETATE-methanol-eluted fractions of 97: 3) prepares liquid phase through anti-phase again, with ODS chromatographic column (YMC-Pack ODS-A, 250 * 10mm, 5 μ), with CH 3CN-H 2O is as the eluent gradient elution, flow velocity 2.5mL/min, 0-30min, volume ratio 50: 50 → 100: 0, compound 3 (t R14.9min, 6.7mg).Fr.2-1-7-3 (volume(tric)fraction is the cut of ETHYLE ACETATE-methanol-eluted fractions of 96: 4) is again through the anti-phase medium pressure column chromatography, with ODS chromatographic column (20 * 90mm; 40-63 μ m, YMC), with methanol-water as eluent; Flow velocity 15mL/min; 0-60min, volume ratio 40: 60 → 100: 0 obtains compound 2 (t R33min, 86.2mg).
Two, the structure of compound 1, compound 2 and compound 3 is identified
Compound 1, compound 2 and compound 3 are carried out the structural analysis test, obtain following physico-chemical property data:
Compound 1. white crystals;
Figure BDA0000123330380000051
(c=0.2, CHCl 3); 1H NMR (500MHz, CDCl 3) and 13C NMR (500MHz, CDCl 3) data, see table 1; HR-ESI-MS m/z 864.4648 ([M-H] -, C 48H 63N 7O 8, theoretical value 864.4665).
Compound 2. white needles solids;
Figure BDA0000123330380000052
(c=0.2, CHCl 3-MeOH=1: 1); 1H NMR (500MHz, CDCl 3) and 13C NMR (500MHz, CDCl 3) data, see table 1; HR-ESI-MS m/z 882.4777 ([M+H] +, C 48H 63N 7O 9, theoretical value 861.4687).
Compound 3. white needles solids;
Figure BDA0000123330380000053
(c=0.2, CHCl 3); 1H NMR (500MHz, CDCl 3) and 13C NMR (500MHz, CDCl 3) data, see table 1; HR-ESI-MS m/z 896.4925 ([M+H] +, C 49H 65N 7O 9, theoretical value 896.4917).
The X crystalline diffraction structural analysis of compound 1: C 49H 69N 7O 10, M 864, and spacer is P2 1, unit cell parameters a=12.4995 (14) B=13.3874 (14)
Figure BDA0000123330380000055
C=14.8616 (15)
Figure BDA0000123330380000056
α=90 °, β=99.9697 (11) °, γ=90 °, V=2449.31 (5) Z=2, D Calcd=1.242g/cm 3, μ=0.711mm -1, F (000)=984. unit cell volume 0.34 * 0.23 * 0.18mm 3. independent point diffraction 8779 [R Int=0.0881]. final index R 1=0.0426, wR 2=0.1061 [I＞2 σ (I)].
Table 1: (500/125MHz, TMS are interior mark to the NMR data of ring seven peptide compound 1,2,3, ppm)
Figure BDA0000123330380000061
aOverlapped?with?3.03.
Can know that according to above physicochemical data analysis the concrete structure of compound 1, compound 2 and compound 3 is suc as formula shown in (I):
Figure BDA0000123330380000072
Formula (I)
Wherein, compound 1:R 1=H, R 2=H; Or compound 2:R 1=OH, R 2=H; Or compound 3:R 1=OH, R 2=Me.
Embodiment 2:
Experiment to the antitumor cell of ring seven peptide compounds-compound 1, compound 2 and the compound 3 of embodiment 1
Adopt international tumor cell line, that is: neuroglial cytoma strain (SF-268), breast carcinoma cell strain (MCF-7) and National People's Congress's sclc cell line (NCI-H460).TP is international srb assay: according to the cell speed of growth; The tumour cell that will be in logarithmic phase is inoculated in 96 orifice plates with 180 μ L/ holes, adherent growth dosing again in 24 hours (physiological salt soln of the compound 1 of different concns, compound 2 and compound 3) 20 μ L/ holes.Each concentration is established 3 multiple holes.And the saline water solvent of establishing respective concentration contrasts and acellular withered hole.Tumour cell is at 37 ℃, 5% CO 2Cultivated 72 hours under the condition, the nutrient solution that inclines, every hole adds the 50% cold TCA solid cell of 50 μ L, adopts 0.4% SRB to dye then 30 minutes, the acetate washing with 1% 5 times, dry air.The Tris solution that adds 200 μ L/ holes at last, ELIASA 570nm wavelength is measured the OD value.With cis-platinum as positive control.Experimental result is seen table 2:
Restraining effect (the IC of 1,2,3 pairs of tumor cell lines of table 2 compound 50, μ M)
Figure BDA0000123330380000081
a＞100μM. bPositive?control.
Above-mentioned experimental result shows that compound 1, compound 2 and 3 pairs of tumour cells of compound have obvious restraining effect, and especially the restraining effect of the compound 1 and the 3 couples of tumor cell line SF-268 and MCF-7 is better than a clinical linearize and treats the medicine cis-platinum.
Therefore the present invention provides new lead compound for the new antitumor drug of development, and exploitation China sea ocean drug resource is had great importance.

Claims (3)

1. suc as formula ring seven peptide compounds and pharmaceutical salts thereof shown in (I):
Figure FDA0000123330370000011
Formula (I)
Wherein, compound 1:R 1=H, R 2=H; Or compound 2:R 1=OH, R 2=H; Or compound 3:R 1=OH, R 2=Me.
2. claim 1 is described suc as formula the compound 1 shown in (I), compound 2 or compound 3, or the application of its pharmaceutical salts in the preparation antitumor drug.
3. an antitumor drug is characterized in that, comprise significant quantity as activeconstituents suc as formula the compound 1 shown in (I), compound 2 or compound 3, or its pharmaceutical salts and acceptable carrier pharmaceutically.
CN2011104337896A 2011-12-21 2011-12-21 Cyclopeptide-7 compounds and application thereof in preparation of anti-tumor medicines Pending CN102516368A (en)

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CN103205367A (en) * 2013-05-10 2013-07-17 国家海洋局第三海洋研究所 Acremonium persicinum hansfordii S2915 and preparation method of antifungal active protein of acremonium persicinum hansfordii S2915
CN104640873A (en) * 2012-10-16 2015-05-20 香港浸会大学 Anticancer and anti-obesity cyclic peptide agents
CN113185580A (en) * 2021-03-09 2021-07-30 扬州大学 Cyclic peptide compound derived from artemisia annua endophytic fungi and application of cyclic peptide compound as antitumor drug
CN114957401A (en) * 2021-01-28 2022-08-30 广东轻工职业技术学院 Peptide compound derived from marine fungi as well as preparation method and application thereof
CN115286590A (en) * 2022-08-18 2022-11-04 上海市农业科学院 Ferro-ferrichrome compound and derivative thereof, pharmaceutical composition and application thereof

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104640873A (en) * 2012-10-16 2015-05-20 香港浸会大学 Anticancer and anti-obesity cyclic peptide agents
CN104640873B (en) * 2012-10-16 2018-04-27 香港浸会大学 Anticancer and anti-fat ring-type peptide agent
CN103205367A (en) * 2013-05-10 2013-07-17 国家海洋局第三海洋研究所 Acremonium persicinum hansfordii S2915 and preparation method of antifungal active protein of acremonium persicinum hansfordii S2915
CN103205367B (en) * 2013-05-10 2014-09-17 国家海洋局第三海洋研究所 Acremonium persicinum hansfordii S2915 and preparation method of antifungal active protein of acremonium persicinum hansfordii S2915
CN114957401A (en) * 2021-01-28 2022-08-30 广东轻工职业技术学院 Peptide compound derived from marine fungi as well as preparation method and application thereof
CN114957401B (en) * 2021-01-28 2023-04-28 广东轻工职业技术学院 Peptide compound from marine fungi and preparation method and application thereof
CN113185580A (en) * 2021-03-09 2021-07-30 扬州大学 Cyclic peptide compound derived from artemisia annua endophytic fungi and application of cyclic peptide compound as antitumor drug
CN113185580B (en) * 2021-03-09 2024-02-13 扬州大学 Cyclopeptide compound derived from endophytic fungi of artemisia annua and application of cyclopeptide compound as antitumor drug
CN115286590A (en) * 2022-08-18 2022-11-04 上海市农业科学院 Ferro-ferrichrome compound and derivative thereof, pharmaceutical composition and application thereof
CN115286590B (en) * 2022-08-18 2024-04-02 上海市农业科学院 De-iron high-iron pigment compound, derivative thereof, pharmaceutical composition and application thereof

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