CN106265693A - The application in preparing cancer therapy drug of the bufadienolide compound with amino acid chain - Google Patents
The application in preparing cancer therapy drug of the bufadienolide compound with amino acid chain Download PDFInfo
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Abstract
Describe the growth inhibited effect to colon cancer cell line HT-29 and gastric cancer HGC-27 cell of the presence or absence impact on Cutis Bufonis compound anti-cancering activity of amino acid chain and the bufadienolide compound fraction with amino acid chain herein.Bufadienolide compound as herein described include with amino acid chain with without the bufadienolide fraction mixture of amino acid chain and the bufadienolide 1-11 fraction with amino acid chain that utilizes high performance liquid chromatography to separate.In vitro cell experiment shows, bufadienolide compound with amino acid chain is more notable to the growth inhibited effect of colon cancer and gastric cancer compared to the bufadienolide compound without amino acid chain, some has obvious inhibiting effect with the bufadienolide fraction of amino acid chain to colon cancer cell ball and stomach cancer cell ball simultaneously, therefore may be used for preparation treatment colon cancer and the medicine of gastric cancer.
Description
Technical field
Describe the presence or absence of amino acid chain herein to the impact of Cutis Bufonis compound anti-cancering activity and bufadienolide
The growth inhibited effect to colon cancer cell line HT-29 and gastric cancer HGC-27 cell of the compound fraction.Described herein
The bufadienolide compound fraction of band amino acid chain include the bufadienolide with amino acid chain
Class fraction mixture and utilize the bufadienolide with amino acid chain that high performance liquid chromatography separates
1-11 fraction.
Background technology
Cutis Bufonis is the natural resources of Chinese medicinal materials that China is important, in recent years, about the report of the Anticancer Activities of Cutis Bufonis
Attract wide attention.Cutis Bufonis has really in terms of the cancers such as treatment hepatocarcinoma, gastric cancer, esophageal carcinoma and colon cancer
The curative effect cut, and bufadienolide compound and polarity nitrogen-containing compound are considered as most effective in Cutis Bufonis
Pharmaceutical component.But Cutis Bufonis composing quantity is huge, complicated component, some anaphylaxis even can be caused,
If can be by means of advanced screening active ingredients appraisement system, screening has the composition of definite antitumor action, will be favourable
In the antitumor drug that exploitation is new.
For the research of cancer therapy drug, major part is all based on the drug test of 2D cell, although operational approach
Simple and convenient, but accuracy and repeatability aspect still suffer from some limitation.And with traditional 2D cell medicine
Thing test is compared, and the activity of 3D cell growth is more good, and setting up of this model is more efficient and stable, energy
Relevantly solid tumor cell interphase interaction in analogue body, the most intercellular adhesion, this is permissible
Effectively evaluate the cancer therapy drug operative condition to cell.In the present invention, we have employed a kind of simple,
Quickly, repeatable and standardized 3D cell ball form technology, bufadienolide in systematic study Cutis Bufonis
The inhibitor against colon carcinoma cells of compounds fraction and gastric cancer activity.(Vinci M,Gowan S,Boxall F,et al.
Advances in establishment and analysis of three-dimensional tumor
spheroid-based functional assays for target validation and drug
evaluation[J].BMC biology,2012,10(1):29.)
Resisting about the bufadienolide compound fraction with amino acid chain mentioned in the present invention at present
Colon cancer and gastric cancer activity are not yet reported
Summary of the invention
Describe the presence or absence of amino acid chain herein on the impact of Cutis Bufonis compound anti-cancering activity with amino acid chain
The growth inhibited effect to colon cancer cell line HT-29 and gastric cancer HGC-27 cell of the bufadienolide compound,
One of purpose is to provide the bufadienolide compound medicine with inhibitor against colon carcinoma cells and Effect on Gastric Cancer.Outer thin
Born of the same parents' experiment shows, with the bufadienolide compound of amino acid chain compared to the Bufo siccus without amino acid chain
Bufadienolides compound is more notable to the growth inhibited effect of colon cancer and gastric cancer, and some is with aminoacid simultaneously
The bufadienolide fraction of chain has obvious inhibiting effect, therefore to colon cancer cell ball and stomach cancer cell ball
May be used for preparation treatment colon cancer and the medicine of gastric cancer.
The present invention provides the bufadienolide compound of a kind of band amino acid chain to answer in preparing cancer therapy drug
With.
Described cancer therapy drug is to become with the bufadienolide compound fraction with amino acid chain for activity
Divide and be prepared from.
Described cancer therapy drug is mainly the medicine of inhibitor against colon carcinoma cells and/or gastric cancer.
Described cancer therapy drug also includes pharmaceutically acceptable carrier or excipient.
In the bufadienolide compound of described band amino acid chain includes the bufadienolide with amino acid chain
Ester type compound or the mixture of compound fraction or utilize the band that high performance liquid chromatography separates from Cutis Bufonis
There is the bufadienolide fraction of amino acid chain.
The bufadienolide compound of described band amino acid chain is for utilizing high performance liquid chromatography from Cutis Bufonis
The bufadienolide fraction with amino acid chain of middle separation, its separation process is:
Weigh the Cutis Bufonis shredded and add reflux, extract, after pure methanol soaks, extracting solution concentrating under reduced pressure is always evaporated
Extract;After total extract is dissolved with 65-75% methanol-water (V/V), extract with normal heptane, methanol portion
Concentrating under reduced pressure is divided to be evaporated to obtain sample;Sample is dissolved in ethanol and passes through Click XIon column sectional eluting, and first paragraph is
The fraction of straight alcohol eluting, it is without amino acid whose bufadienolide fraction, and second segment is volumetric concentration
The fraction of 45-55% ethanol elution, it is for carrying amino acid whose bufadienolide fraction;
0.22 will be dissolved with amino acid whose bufadienolide fraction volumetric concentration 20-35% alcohol-water
After the organic membrane of μm, the chromatographic column of component XCharge C18 through film separates, flowing be methanol mutually with
The system of water, condition of gradient elution is 0~80~82~96~100~120min, corresponding methanol volume
Concentration 50%-70%-100%-100%-60%-60% methanol, collects 18.5~26.5min
Fraction in time period is No. 3 samples, and the fraction collected in 26.5~32.2min time periods is No. 4 samples, receives
Fraction in the 32.2~42.9min time periods of collection is No. 5 samples, collects evaporating in 42.9~51.9min time periods
Being divided into No. 6 samples, the fraction collected in 51.9~67.7min time periods is No. 7 samples, collects 67.7~72.9
Fraction in the min time period is No. 8 samples, and the fraction collected in 72.9~82.8min time periods is No. 9 samples,
The fraction collected in 82.8~87.5min time periods is No. 10 samples;
Wherein said No. 3 samples, No. 4 samples and No. 5 samples, No. 6 samples, No. 7 samples, No. 8 samples, No. 9
With one or two or more kinds in No. 10 samples, there is active anticancer to can be used for preparing in cancer therapy drug.
The bufadienolide compound of described band amino acid chain be it is however emphasized that to be protected preferred fraction be
6, one or two or more kinds in 7 and No. 8 samples has active anticancer and can be used for preparing in cancer therapy drug.
Accompanying drawing explanation
Fig. 1 Cutis Bufonis extract is the chromatographic fractionation figure of segmentation on Click XIon post;
The ultraviolet of Fig. 2 Cutis Bufonis extract first paragraph fraction that segmentation obtains on Click XIon post and mass spectrum table
Levy collection of illustrative plates;
The ultraviolet of Fig. 3 Cutis Bufonis extract second segment fraction that segmentation obtains on Click XIon post and mass spectrum table
Levy collection of illustrative plates;
Fig. 4 prepares fraction figure with the separation on XCharge C18 of the amino acid whose bufadienolide fraction
Spectrum;
It is bent that the HT-29 cell of Fig. 5 different vaccination density cultivates the cell ball formed growth over time through 3D
Line;
It is bent that Fig. 6 different vaccination density HGC-27 cell cultivates the cell ball formed growth over time through 3D
Line;
The 3D cell ball warp high-concentration and low-concentration of Fig. 7 HT-29 is without amino acid chain bufadienolide (10 μMs/1
μM) process after growth curve over time;
The 3D cell ball warp high-concentration and low-concentration of Fig. 8 HT-29 is with amino acid chain bufadienolide (10 μMs/1
μM) process after growth curve over time;
The 3D cell ball warp high-concentration and low-concentration of Fig. 9 HGC-27 is without amino acid chain bufadienolide (10 μMs/1
μM) process after growth curve over time;
The 3D cell ball warp high-concentration and low-concentration of Figure 10 HGC-27 is with amino acid chain bufadienolide (10 μMs/1
μM) process after growth curve over time;
The 3D cell ball warp high concentration of Figure 11 HT-29 is with amino acid chain bufadienolide fraction 1-11
(10 μMs) metamorphosis figure in time;
The 3D cell ball warp low concentration of Figure 12 HT-29 is with amino acid chain bufadienolide fraction 1-11
(1 μM) metamorphosis figure in time;
The 3D cell ball warp high concentration of Figure 13 HGC-27 is with amino acid chain bufadienolide fraction 1-11
Number (10 μMs) metamorphosis figure in time;
The 3D cell ball warp low concentration of Figure 14 HGC-27 is with amino acid chain bufadienolide fraction 1-11
Number (1 μM) metamorphosis figure in time;
Agent after No. 6 of 3D cell ball warp variable concentrations, No. 7 and No. 8 sample treatment of Figure 15 HGC-27
Amount-effect curve.
Detailed description of the invention
In conjunction with example, the present invention will be further described.Example is only limitted to illustrate the present invention, rather than to this
The restriction of invention.
Embodiment 1: Cutis Bufonis fraction preparation process
Skin of Bufo bufo gargarizans picks up from Linyi, Shandong, through department of Chinese medicine institute of the China little flat mirror of Xiyuan TCM Research Office poplar
It is set to certified products.
Weigh the Cutis Bufonis 200g shredded, by solid-liquid ratio 1:7, add the pure methanol of 1.4L, soak two days, 80 DEG C
Micro-boiling backflow 4h, filters to get filtrate, and filtering residue adds the pure methanol of 1.4L again, 80 DEG C of micro-boiling backflow 4h,
Filtering to get filtrate, extract altogether twice, merged by the extracting solution of twice and there are 2730mL, 60 DEG C of concentrating under reduced pressure steam
Do to obtain 7g total extract.After total extract is dissolved with 160mL 65-75% methanol-water (V/V), with 160
ML normal heptane extracts, and methanol fractions extracts with 160mL normal heptane again, coextraction twice, then methanol portion
Divide 60 DEG C of concentrating under reduced pressure to be evaporated to obtain 4g sample, and be dissolved in ethanol.By Click XIon column sectional eluting, the
One section is fraction (corresponding to without amino acid whose bufadienolide the fraction) (elution time of straight alcohol eluting
For 20min), second segment is that the fraction of volumetric concentration 45-55% ethanol elution is (corresponding to carrying amino acid whose toad
Bufonid toad bufadienolides fraction) (elution time is 10min), separation chromatography figure is shown in Fig. 1.Dividing by C18HCE post
From, use UV-detector and mass detector respectively first paragraph fraction and second segment fraction to be characterized,
Phenogram is shown in Fig. 2 and Fig. 3 respectively.As can be seen from Figure 2 first paragraph fraction is under characteristic absorption wavelength 300nm
There is an absorption, and by the molecular weight of the mass spectrum (Fig. 2 C-E) of different time points it can be seen that first paragraph
The molecular weight of fraction is all about 400, according to the molecular weight with amino acid whose bufadienolide compound
About 700 without the molecular weight of amino acid whose bufadienolide compound about 400, permissible
Infer that the fraction that straight alcohol eluting 20min obtains is without amino acid whose bufadienolide fraction;From Fig. 3
In can be seen that second segment fraction has absorption under characteristic absorption wavelength 300nm, and pass through different time points
The molecular weight of mass spectrum (Fig. 3 C-E) it can be seen that the molecular weight of second segment fraction is all about 700, root
According to the molecular weight with amino acid whose bufadienolide compound about 700 without amino acid whose
The molecular weight of bufadienolide compound, about 400, may infer that 50% ethanol elution 10min obtains
Second segment fraction be with amino acid whose bufadienolide fraction.
24.7 will be dissolved to amino acid whose bufadienolide fraction volumetric concentration 20-35% alcohol-water
Mg/mL, the chromatographic column of the component XCharge C18 passing through film after crossing the organic membrane of 0.22 μm separates,
Flowing is the system of first alcohol and water mutually, and flow velocity is 60mL/min, and detection wavelength is 300nm, gradient elution bar
Part is 0~80~82~96~100~120min, corresponding volume concentration 50%-70%-100%-
100%-60%-60% methanol.The time period that 1-11 fraction is corresponding respectively accesses the time 5.7~10.5
Min, 10.5~18.5min, 18.5~26.5min, 26.5~32.2min, 32.2~42.9min, 42.9~51.9
Min, 51.9~67.7min, 67.7~72.9min, 72.9~82.8min, 82.8~87.5min and 87.5~105
min.Concrete separation is prepared figure and is seen Fig. 4.
The foundation of embodiment 2:3D cell ball screening model
Human colon cancer cell HT-29 and gastric carcinoma cells HGC-27 is purchased from Chinese Academy of Sciences's Shanghai cell bank;
ULA-96 orifice plate is purchased from Corning;Cutis Bufonis fraction is the 1-11 fraction that embodiment 1 obtains;Inverted microscope
It is purchased from OLYMPUS.
The HT-29 cell and HGC-27 cell that are in exponential phase are inoculated in ULA-96 orifice plate respectively, make
Obtain cell quantity in every orifice plate and be respectively 20K, 10K, 5K, 2.5K, 1.25K and 0.625K, inoculation
Volume is 200 μ L/well, and the culture medium that HT-29 cell uses is that McCOY's 5A contains 10% hyclone,
HGC-27 cell use culture medium be that RPMI-1640 contains 20% hyclone, each cell density in triplicate,
Every the 24h utilization microphotograph of inverted microscope record 3D cell ball form, record 4 days continuously.Its knot
Fruit is as shown in Figure 5 and Figure 6.State according to the growth in continuous 4 days of 3D cell ball and the size of the 4th day cell ball,
Determine optimal cell density.Optimal cell density generally cell ball have optimum growth speed and
When the 4th day, the diameter of cell ball fell among scope 300 μm~500 μm, because in this scope
The state of interior 3D cell ball, closer to the state with in-vivo tumour, is more beneficial for the screening of cancer therapy drug.According to
It is all 1.25K/ hole that Fig. 5 and Fig. 6 can be seen that two kinds of cell lines meet the optimum cell density of above-mentioned requirements.
Embodiment 3: the presence or absence of the research amino acid chain impact on Cutis Bufonis compound anti-cancering activity
HT-29 and the HGC-27 cell of optimum density (1.25K/ hole) is inoculated in ULA-96 orifice plate, training
Supporting 4 days, the culture medium that HT-29 cell uses is that McCOY's 5A is containing 10% hyclone, HGC-27 cell
The culture medium used is that RPMI-1640 contains 20% hyclone, after growing to the 3D cell ball of optimum grain-diameter,
The fresh culture of 100 μ L is replaced in every hole, be separately added into by Click XIon column sectional eluting with
The bufadienolide of amino acid chain evaporates and without the bufadienolide fraction sample of amino acid chain, each evaporates
Final concentration of 10 μMs and 1 μM of the scalping (in fraction, the mean molecule quantity of compound presses 500Da calculating) divided,
Each fraction sample is in triplicate.The size of inverted microscope record 3D cell ball is used, continuously every 24h
Record 6 days.Its result is as shown in Fig. 7-Figure 10.Compared with HT-29 cell, bufadienolide fraction
Growth inhibited effect to HGC-27 cell becomes apparent from.Wherein, with the bufadienolide of amino acid chain
Fraction has more superior active anticancer compared with the bufadienolide fraction without amino acid chain, even low dense
Also the effect of suppression growth of tumour cell is had in the case of degree.
With the bufadienolide fraction of amino acid chain than the bufadienolide fraction without amino acid chain
There is higher inhibitor against colon carcinoma cells and gastric cancer activity.
Embodiment 4: scalping embodiment 1 with the bufadienolide fraction 1-11 of amino acid chain to 3D cell
The inhibitory action of ball growth
HT-29 and the HGC-27 cell of optimum density (1.25K/ hole) is inoculated in ULA-96 orifice plate, cultivates
4 days, the culture medium that HT-29 cell uses was that McCOY's 5A contains 10% hyclone, and HGC-27 cell makes
Culture medium be that RPMI-1640 contains 20% hyclone, after growing to the 3D cell ball of optimum grain-diameter,
The fresh culture of 100 μ L is replaced in every hole, is separately added into 1-11 sample, and the scalping of each sample is the denseest
Degree is 10 μMs and 1 μM (in fraction, the mean molecule quantity of compound is calculated by 500Da), each sample
In triplicate.The size of inverted microscope record 3D cell ball is used, continuously record 6 days every 24h.
Its result is as shown in figures 11-14.3D cell ball model based on HT-29, for amino acid chain
Bufadienolide fraction 1-11 sample carry out activity examination, find No. 3, No. 5, No. 6, No. 7,8
Number, No. 9, No. 10 and No. 11 samples growth of tumour cell is all had a certain impact, make tumor cell form
There is significant change.And 3D cell ball model of based on HGC-27, for the Bufo siccus two with amino acid chain
Alkene lactone fraction 1-11 sample carry out activity examination, find No. 3, No. 4, No. 5, No. 6, No. 7,8
Number and No. 10 sample active anticancers relatively other samples more preferably.In the case of 1 μM of concentration, these fractions pair
The growth inhibited effect of tumor cell is also apparent from.
Embodiment 5: have the fraction 6 of strong active anticancer, the agent of No. 7 and No. 8 sample suppression 3D cell ball growths
Magnitude relation
Different agent by fraction No. 6, No. 7 and No. 8 samples the strongest to two kinds of tumor models rejection ability
Amount acts on the 3D cell ball of HGC-27.The HGC-27 cell of optimum density (1.25K/ hole) is inoculated
In ULA-96 orifice plate, cultivating 4 days, the culture medium that HT-29 cell uses is that McCOY's 5A is containing 10% tire cattle
Serum, the culture medium that HGC-27 cell uses is that RPMI-1640 contains 20% hyclone, grows to optimal grain
After the 3D cell ball in footpath, the fresh culture of 100 μ L is replaced in every hole, is separately added into scalping medicine (6
Number, No. 7 and No. 8 samples) 10 μ L, the final concentration gradient of each sample be respectively 100 μMs, 33.3 μMs,
11.1 μMs, 3.70 μMs, 1.23 μMs, 0.411 μM and 0.137 μM, each sample each dense
Degree is in triplicate.The size of inverted microscope record 3D cell ball is used, continuously record 6 days every 24h,
Its result is as shown in figure 15.According to dose-effect curve, obtain the IC50 value of No. 6, No. 7 and No. 8 samples
It is respectively 0.094 ± 0.020 μM, 0.078 ± 0.014 μM, 0.874 ± 0.089 μM.Can
Seeing, the 3D cell ball of HGC-27 is grown and has obvious inhibiting effect by No. 6, No. 7 and No. 8 samples, has relatively
Strong active anticancer.
Claims (7)
1. the bufadienolide compound of band amino acid chain is applied in preparing cancer therapy drug.
2. according to the application described in claim 1, it is characterised in that: described cancer therapy drug is with ammonia
The bufadienolide compound fraction of base acid chain is that active component is prepared from.
3. according to the application described in claim 1, it is characterised in that: described cancer therapy drug is mainly resistive connection
Intestinal cancer and/or the medicine of gastric cancer.
4. according to the application described in claim 1,2 or 3, it is characterised in that: in described cancer therapy drug also
Including pharmaceutically acceptable carrier or excipient.
5. according to the application described in claim 1, it is characterised in that:
In the bufadienolide compound of described band amino acid chain includes the bufadienolide with amino acid chain
Ester type compound or the mixture of compound fraction or utilize the band that high performance liquid chromatography separates from Cutis Bufonis
There is the bufadienolide fraction of amino acid chain.
6. according to the application described in claim 1,2,3 or 5, it is characterised in that:
The bufadienolide compound of described band amino acid chain is for utilizing high performance liquid chromatography from Cutis Bufonis
The bufadienolide fraction with amino acid chain of middle separation, its separation process is:
Weigh the Cutis Bufonis shredded and add reflux, extract, after pure methanol soaks, extracting solution concentrating under reduced pressure is always evaporated
Extract;After total extract is dissolved with 65-75% methanol-water (V/V), extract with normal heptane, methanol portion
Concentrating under reduced pressure is divided to be evaporated to obtain sample;Sample is dissolved in ethanol and passes through Click XIon column sectional eluting, and first paragraph is
The fraction of straight alcohol eluting, it is without amino acid whose bufadienolide fraction, and second segment is volumetric concentration
The fraction of 45-55% ethanol elution, it is for carrying amino acid whose bufadienolide fraction;
0.22 will be dissolved with amino acid whose bufadienolide fraction volumetric concentration 20-35% alcohol-water
After the organic membrane of μm, the chromatographic column of component XCharge C18 through film separates, flowing be methanol mutually with
The system of water, condition of gradient elution is 0~80~82~96~100~120min, corresponding methanol volume
Concentration 50%-70%-100%-100%-60%-60% methanol, collects 18.5~26.5min
Fraction in time period is No. 3 samples, and the fraction collected in 26.5~32.2min time periods is No. 4 samples, receives
Fraction in the 32.2~42.9min time periods of collection is No. 5 samples, collects evaporating in 42.9~51.9min time periods
Being divided into No. 6 samples, the fraction collected in 51.9~67.7min time periods is No. 7 samples, collects 67.7~72.9
Fraction in the min time period is No. 8 samples, and the fraction collected in 72.9~82.8min time periods is No. 9 samples,
The fraction collected in 82.8~87.5min time periods is No. 10 samples;
Wherein said No. 3 samples, No. 4 samples and No. 5 samples, No. 6 samples, No. 7 samples, No. 8 samples, No. 9
With one or two or more kinds in No. 10 samples, there is active anticancer to can be used for preparing in cancer therapy drug.
7. according to the application described in claim 6, it is characterised in that: the bufadienolide of described band amino acid chain
Lactone compound be it is however emphasized that to be protected preferred fraction be the one in 6,7 and No. 8 samples or two kinds with
On there is active anticancer can be used for preparing in cancer therapy drug.
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CN101829123A (en) * | 2009-03-11 | 2010-09-15 | 中国科学院大连化学物理研究所 | Application of |
CN102101879A (en) * | 2009-12-16 | 2011-06-22 | 中国科学院大连化学物理研究所 | Arenobufagin space isomer compound and preparation and application thereof |
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2015
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JPH05201868A (en) * | 1992-01-27 | 1993-08-10 | Showa Univ | Bufadienolide type differentiation-inducing agent |
CN101177445A (en) * | 2006-11-08 | 2008-05-14 | 山东绿叶制药有限公司 | Novel bufadienolide compound as well as preparation method and uses thereof |
CN101829123A (en) * | 2009-03-11 | 2010-09-15 | 中国科学院大连化学物理研究所 | Application of |
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