CN101230068B - Application of polyether triterpene compound in preparing medicine for treating tumour - Google Patents

Application of polyether triterpene compound in preparing medicine for treating tumour Download PDF

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CN101230068B
CN101230068B CN2008100140919A CN200810014091A CN101230068B CN 101230068 B CN101230068 B CN 101230068B CN 2008100140919 A CN2008100140919 A CN 2008100140919A CN 200810014091 A CN200810014091 A CN 200810014091A CN 101230068 B CN101230068 B CN 101230068B
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extract
compound
polyether
ethyl acetate
triterpene compound
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CN101230068A (en
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王斌贵
季乃云
李晓明
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Institute of Oceanology of CAS
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Institute of Oceanology of CAS
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Abstract

The invention relates to a polyether triterpene compound and the preparation method and the application thereof, and belongs to the antineoplastic medicine field. The specific structural formula is as shown in (I). The preparation method adopts the steps that marine red algae and laurencia decumbens kuetz are flushed, dried in shade, and crushed, and then extracted for 2 to 5 times by using an organic solution, the extracting solution is combined for concentration to obtain a crude extract; the crude extract is added into distilled water so that the crude extract is suspended in water, extraction with ethyl acetate is performed for 2 to 5 times, the extract is concentrated to obtain a corresponding extract, silicagel column chromatography is performed to the extract, the organic solution is used for elution, the eluent is collected and is detected through thinlayer chromatography; components eluted with 1-4: 1 gradient are separated and purified through silicagel column chromatographyto obtain a target compound I. The natural polyether triterpene compound obtained through extraction and separation by using the marine red algae and the laurencia decumbens kuetz belongs to a micromolecule natural organic compound, and is easy to be prepared and obtained, experiments show that the compound has remarkable antineoplastic activity, and can be used as antineoplastic medicine.

Description

The application of polyether triterpene compound in the preparation antitumor drug
Technical field
The present invention relates to field of antineoplastic medicaments, specifically polyether triterpene compound and its production and application.
Background technology
In multiple disease, malignant tumour is one of serious disease that threatens human life's health always, and in the process of seeking the effective antitumour medicine, people more and more invest the marine organisms with special growing environment to sight.The Laurencia marine red alga is to be grown near the class marine algae plant of subtidal line, it is famous to produce the special halogenated compound of a large amount of structures, wherein, the halogenated polyether triterpene is a big compounds of concave crown algae secondary metabolism, because of its better antitumor activity receives much attention.
Summary of the invention
The purpose of this invention is to provide a kind of natural seaweed polyether triterpene compound and its production and application.
For achieving the above object, the technical solution used in the present invention is:
Polyether triterpene compound is shown in structural formula (I)
Figure S2008100140919D00011
The preparation method comprises the steps:
1) (60-80 order) washed, dries in the shade, pulverized to marine red alga pitching concave crown algae (Laurencia decumbens), then extract 2-5 time with organic solution, united extraction liquid concentrates, and obtains crude extract;
2) will the crude extract in the step 1) add in the distilled water it will be suspended in the water, with ethyl acetate extraction 2-5 time, extract concentrate extract accordingly, standby;
3) get step 2) in extract carry out silica gel column chromatography, carry out wash-out with organic solvent, collect elutriant, elutriant detects through thin-layer chromatography;
Described machine solvent is 100: 0-0: the sherwood oil-acetone of 100 gradients or petroleum ether-ethyl acetate;
4) with in the step 3) with 1-4: the component under 1 gradient elution is carried out silica gel column chromatography separating purification and is got target compound I.
Carry out isocratic elution with 4: 1 sherwood oil-acetone or 2: 1 petroleum ether-ethyl acetate during described step 4) silica gel column chromatography, judge, collect the component that Rf is 0.4-0.5 (petroleum ether-ethyl acetate 2: 1 for developping agent) according to the Rf value, be the target compound I behind the purifying.Organic solution extracting solution in the step 1) can be in chloroform, acetone, ethyl acetate, methyl alcohol or the ethanol one or more.
The application of polyether triterpene compound: described compound can be applicable to antitumor.
The present invention has the following advantages: the marine red alga pitching concave crown algae that the present invention relates to (Laurenciadecumbens K ü tzing) belongs to rhodophyta, Rhodomelaceae, Laurencia marine alga, mainly be distributed in areas such as South China Sea and Hawaiian Islands, generally be grown on the rock of tideland.The present invention belongs to the small molecules natural organic-compound by marine red alga pitching concave crown algae through extracting, separate the polyether triterpene natural compounds that obtains, and prepares easily, our experiments show that its half-inhibition concentration IC to mouse leukemia tumor cell line P388 50Be 0.6 mcg/ml, have notable antitumor activity, can be used as antitumor drug.
Embodiment:
Below in conjunction with embodiment the present invention is further elaborated.
Embodiment 1
The preparation method of polyether triterpene compound:
1) will gather fresh pitching concave crown algae and clean through seawater, and remove the grit and the assorted algae of surface attachment, shady and cool place airing is standby.Get sample 500 grams behind the airing, pulverize the back with about 3 liters of chloroform-methanols (volume ratio is 1: 1) 50 ℃ of extractions three times down, each three hours, the residue algae-residue continues to extract three times for 50 ℃ with 95% ethanol, each three hours, united extraction liquid obtained crude extract at 40 ℃ of left and right sides of temperature concentrating under reduced pressure.
2) crude extract is added it is suspended in the water, use ethyl acetate extraction again 2 times, the gained extract concentrate extract, standby;
3) ethyl acetate extract after will concentrating (18.0 gram) carries out silicagel column (200-300 order) chromatography, carry out wash-out with petroleum ether-ethyl acetate with 100: 0,30: 1,10: 1,5: 1,2: 1 to 0: 100 gradient, collect elutriant respectively, elutriant detects with thin-layer chromatography (TLC), judge, merge identical or similar portions according to the Rf value, when detecting, thin-layer chromatography (TLC) use aubepine-sulfuric acid as developer, developping agent is 2: 1 for the petroleum ether-ethyl acetate volume ratio, obtains six components (I-VI).
4) with component V, Rf=0.4-0.9 (petroleum ether-ethyl acetate is a developping agent at 2: 1), promptly carrying out silica gel column chromatography again with the component under 2: 1 gradient elutions of petroleum ether-ethyl acetate separates, in the time of will carrying out silica gel column chromatography with the component under 2: 1 gradient elutions of petroleum ether-ethyl acetate with the wash-out that carries out of 4: 1 gradients of sherwood oil-acetone, judge, collect the component that Rf is 0.4-0.5 (petroleum ether-ethyl acetate 2: 1 for developping agent) according to the Rf value, be the target compound I behind the purifying.Get 44.0 milligrams of pure polyether triterpene compounds.Through Spectrum Analysis, its structure is accredited as shown in (I), called after polyether triterpene compound laurenmariannol.
This compound has following physics and chemistry and spectral characteristic:
Clear crystal, fusing point 159-160 ℃, specific rotatory power [α] D 18=-15.7 (c 0.41, CHCl 3); Infrared spectra (KBr) v Max3413,2973,2866,1461,1373,1131,1102,1062cm -1Proton nmr spectra and carbon spectrum are as Table I; EI mass spectrum m/z 588 (0.3), 586 (0.3), and 573 (2), 571 (2), 570 (1), 568 (1), 555 (2), 553 (2), 524 (4), 245 (18), 227 (84), 209 (100), 143 (34), 125 (35), 85 (32); High resolution ESI mass spectrum m/z 605.3038 and 607.3049 (1: 1) [M+H] +(C 30H 54 79BrO 7Calculated value be 605.3053; C 30H 54 81BrO 7Calculated value be 607.3032).
The hydrogen nuclear magnetic resonance of Table I polyethers triterpene laurenmariannol A and carbon spectrum data
No 13C a 1H(m.J in Hz) a 13C b 1H(m.J in Hz) b
1 2 3 4a 4b 5a 5b 6 7 8a 8b 9a 9b 10 11 12a 12b 13a 13b 14 15 16a 16b 17a 17b 18 19 20a 20b 31.0q 74.9s 59.0d 28.3t 37.0t 74.4s 86.6d 23.0t 38.7t 71.5s 76.7d 21.3t 21.5t 75.3d 84.3s 35.7t 25.9t 86.4d 72.4s 33.8t 1.26(s) 3.89(dd，12.3， 4.0) 2.23(m) 2.10(m) 1.80(m) 1.52(m) 3.03(dd，11.4， 2.2) 1.70(m) 1.40(m) 1.72(m) 1.51(m) 3.54(dd，11.1， 7.2) 1.86(m) 1.50(m) 1.77(m) 1.73(m) 3.70(dd，8.3， 3.5) 1.98(m) 1.65(m) 1.79(m) 1.66(m) 3.72(dd，7.0， 3.7) 1.59(m) 1.52(m) 31.4q 75.5s 60.1d 29.0t 37.7t 75.3s 87.3d 23.8t 39.6t 72.0s 77.5d 22.1t 22.2t 75.8d 84.8s 36.7t 26.6t 86.7d 72.8s 37.1t 1.25(s) 4.02(dd，12.2，4.0) 2.28(m) 2.10(m) 1.80(m) 1.62(m) 3.11(dd，11.3，2.5) 1.71(m) 1.45(m) 1.70(m) 1.53(m) 3.64(dd，11.0，7.0) 1.82(m) 1.50(m) 1.88(m) 1.81(m) 3.76(dd，8.8，2.6) 2.00(m) 1.60(m) 1.83(m) 1.70(m) 3.78(dd，6.3，2.5) 1.70(m) 1.44(m)
21a 21b 22 23 24 25 26 27 28 29 30 HO-19 HO-22 HO-23 25.4t 78.5d 73.1s 23.3q 23.7q 20.1q 21.2q 21.7q 24.1q 26.6q 1.78(m) 1.66(m) 3.42(dd，10.6， 1.9) 1.16(s) 1.39(s) 1.19(s) 1.17(s) 1.08(s) 1.16(s) 1.22(s) 26.2t 79.9d 73.0s 24.9q 24.2q 20.5q 21.8q 21.7q 23.7q 26.2q 1.70(m) 1.33(m) 3.24(br d，9.7) 1.12(s) 1.40(s) 1.23(s) 1.18(s) 1.07(s) 1.10(s) 1.13(s) 2.93(br s) c 3.30(br s) c 3.58(br s) c
aIn deuterochloroform, measure, bIn deuterated acetone, measure, cCommutative with data in the hurdle.
Embodiment 2
Difference from Example 1 is:
1) will gather fresh pitching concave crown algae uses ethyl acetate-methyl alcohol (volume ratio is 5: 1) to extract three times down at 50 ℃ after crushed, each three hours, the residue algae-residue continues to extract three times for 50 ℃ with 95% ethanol, each three hours, united extraction liquid obtains crude extract at 40 ℃ of left and right sides of temperature concentrating under reduced pressure.
2) crude extract is added it is suspended in the water, use ethyl acetate extraction again 5 times, the gained extract concentrate extract, standby;
3) ethyl acetate extract after will concentrating (18.0 gram) carries out silicagel column (200-300 order) chromatography, carry out wash-out with sherwood oil-acetone with 100: 0,30: 1,10: 1,5: 1,2: 1 to 0: 100 gradient, collect elutriant respectively, elutriant detects with thin-layer chromatography (TLC), judges, merges identical or similar portions according to the Rf value.
4) with component VRf=0.4-0.9, promptly carrying out silica gel column chromatography again with the component under 2: 1 gradient elutions of sherwood oil-acetone separates, when being carried out silica gel column chromatography, elution fraction, is the target compound I behind the purifying with the isocratic elution that carries out of 2: 1 gradients of petroleum ether-ethyl acetate.
Embodiment 3
Difference from Example 1 is: it is that the mixed solution of 1: 1: 1 or 2: 1: 2 acetone, chloroform and ethyl acetate extracts that the fresh pitching concave crown algae after the pulverizing is adopted volume ratio.
Embodiment 4
Difference from Example 1 is: the fresh pitching concave crown algae after the pulverizing adopts the mixed solution of acetone, chloroform or ethyl acetate to extract.
Embodiment 5
Anti-tumor activity experiment: the P388 tumour cell, i.e. mouse leukemia tumor cell line can be used to the power of assessing compound anti-tumor activity, and is easy and simple to handle, favorable reproducibility.
Experimental technique:
Tetrazolium MTT a kind ofly can accept H +Yellow dyes.In the viable cell mitochondrial respiratory chain, succinodehydrogenase and cytochrome C can make the tetrazole ring opening of MTT, generate hepatic formazan crystallization, and do not contain this desaturase in the dead cell.Formazan crystalline growing amount is directly proportional with viable count, and this crystalline DMSO solution has maximum absorption band in 570 nanometers, so, can estimate the influence of medicine on cell proliferation by detecting formazan crystalline amount.
The tumour cell of taking the logarithm vegetative period transfers to 2 * 10 with cell density 5Individual cells/ml is inoculated in the 96 porocyte culture plates by every hole 200 microlitres, cultivates 4 hours in the incubator of 37 ℃ of feeding 5% carbonic acid gas.Sample is set 5 concentration gradients 10 respectively -8, 10 -7, 10 -6, 10 -5With 10 -4Mol/L, each concentration is established three parallel samples, and every hole adds sample liquid or each 2 microlitre of blank solution, cultivates 48 hours, and every then hole adds MTT liquid 10 microlitres that concentration is 5 mg/ml, continues to cultivate 4 hours, removes supernatant liquor.Every hole adds each 100 microlitre of DMSO, and concussion is 10 minutes on micro-oscillator, and after dissolving fully to crystallization, microplate reader is measured the light absorption value (OD value) of every hole 570 nanometers.Get the average OD value in three holes by IR%=(OD Blank-OD Sample)/OD BlankThe inhibiting rate (IR%) of * 100% formula calculation sample on cell proliferation, and calculation of half inhibitory concentration IC 50Value.
Experimental result:
The polyether triterpene compound of above-mentioned acquisition is to the half-inhibition concentration IC of mouse leukemia tumour cell P388 50Be 0.6 mcg/ml (referring to table 2).
Table 2 compound (I) is to the inhibiting rate of P388 growth of tumour cell
Concentration mol/L 10 -4 10 -5 10 -6 10 -7 10 -8
Inhibiting rate % 81.3 80.0 62.2 20.9 12.7

Claims (1)

1. the application of a polyether triterpene compound is characterized in that: polyether triterpene compound is as the application in the preparation antitumor drug; Described polyether triterpene compound is shown in structural formula (I)
Figure FSB00000032416500011
CN2008100140919A 2008-01-25 2008-01-25 Application of polyether triterpene compound in preparing medicine for treating tumour Expired - Fee Related CN101230068B (en)

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