CN1473855A - Sulfuric galactosan and use of its derivative - Google Patents
Sulfuric galactosan and use of its derivative Download PDFInfo
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- CN1473855A CN1473855A CNA031389740A CN03138974A CN1473855A CN 1473855 A CN1473855 A CN 1473855A CN A031389740 A CNA031389740 A CN A031389740A CN 03138974 A CN03138974 A CN 03138974A CN 1473855 A CN1473855 A CN 1473855A
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Abstract
Sulfuric galactosan and its derivative is used in preparing antiviral preparation, antitumor preparation, antioxidant, immunity regulator and bacteriostat. Sulfuric galactosan, test shows, possesses powerful bioactivity closely related with its molecular weight, structure, sulfur content and position. It is possible that the spatial structure of the polysaccharide plays important role in the bioactivity considering that many of the acceptor distinguishing reactions are based on the spatial structure. The present invention obtains oligose with proper polymerization degree and specially chemically modified derivative, which can be absorbed by body to enter the destination tissue to take role with high safety.
Description
Technical field
The present invention relates to the application of a kind of galactan sulfate and derivative thereof.
Background technology
Galactan sulfate derives from the sulfuric acid colloid polysaccharide that extracts in some red algae cell walls.This polysaccharide is widely used in fields such as food, light industry at present.Because undegradable polysaccharide viscosity is big, the diffusion difficulty, is difficult to be absorbed by body, bioavailability is low; And its toxicity is big, does not reach the experimental animal that just can cause death under the situation of effective dose, thereby has seriously limited its application.Galactan sulfate and derivative thereof that at present existing polysaccharide degradeds form have many biological activitys, for example treat stomach ulcer and ulcerative colitis, anticoagulation etc., but they range of application still not extensive.
Summary of the invention
The purpose of this invention is to provide a kind of activated galactan sulfate and derivative thereof, it can overcome the above-mentioned shortcoming of prior art.
Galactan sulfate and derivative thereof are used to prepare antiviral agent;
Galactan sulfate and derivative thereof are used to prepare antineoplastic agent;
Galactan sulfate and derivative thereof are used to prepare antioxidant;
Galactan sulfate and derivative thereof are used to prepare immunomodulator;
Galactan sulfate and derivative thereof are used to prepare fungistat.
The present invention's acquisition galactan sulfate of degrading, and adopt the method for chemically modified to obtain its derivative, and proof by experiment, it has very strong biological activity and multiple use.Because the biologic activity of galactan sulfate is equipped with substantial connection with the content and the presence bit of its molecular weight, structure and sulphur, possible reason is that the space structure of polysaccharide has vital role for its biological activity, and many acceptor recognition reactions are all based on space structure.The galactan sulfate of high-polymerization degree is difficult to be absorbed by body, can't enter into the purpose tissue.Thereby the present invention can be fast absorbed by body and enters into the purpose tissue and play a role, and in use safe.
Description of drawings and embodiment
Accompanying drawing 1 is sulfuric acid semi-lactosi and derivant structure figure thereof
Accompanying drawing 2 is the active synoptic diagram of sulfuric acid semi-lactosi anti-HIV-1
Accompanying drawing 3 is the inhibiting rate synoptic diagram of sulfuric acid semi-lactosi to HIV-1
Accompanying drawing 4 is the active synoptic diagram of sulfuric acid galactose derivate anti-HIV-1
Accompanying drawing 5 is the inhibiting rate synoptic diagram of sulfuric acid galactose derivate to HIV-1
Accompanying drawing 6 is the tumour inhibiting rate contrast figure of galactan sulfate and derivative thereof
Accompanying drawing 7 is galactan sulfate and derivative lipid peroxidation effect synoptic diagram thereof
Accompanying drawing 8 is that galactan sulfate and derivative thereof are to H
2O
2The restraining effect synoptic diagram of the haemolysis that causes
Accompanying drawing 9 is galactan sulfate and derivative thereof the removing effect synoptic diagram to hydroxy radical qiao
Accompanying drawing 10 is that galactan sulfate and derivative thereof are to O
2 -Removing effect synoptic diagram
Several typical OK a karaoke club gum derivatives have been carried out the anti-HIV-1 determination of activity.
Infect MT with virus of AIDS HIV-1
4Cell, reagent concentration 75 μ g/ml behind the 7d, measure supernatant P
24The antigen amount.The result shows, galactan sulfate LW-S-A-1, and LW-S-D-2 and LW-S-C-3 have remarkable inhibiting activity to HIV-1, and the antigen amount only is 1.40-2.04pg/ml in the supernatant, and inhibiting rate is (table 1, Fig. 2,3) between 98.43-98.92%; LW-S-D-2 demonstrates high inhibition activity (inhibiting rate 98.43%), simultaneously, and MT
4The growth of cell is uninfluenced, shows that under experimental concentration, this fraction is to MT
4Cell nontoxicity (table 1); Sulfating product SU-B also has high inhibition activity to HIV-1, and inhibiting rate reaches 98.97% (table 1, Fig. 4,5), is that inhibiting rate is the highest in the reagent.Galactan sulfate has remarkable inhibiting activity to HIV-1, and its average molecular weight range is 3, and 400-10 between 500, has sulfated polysaccharide molecular weight than high antiviral active generally 5, and 000-6 is between 000.Galactan sulfate modified outcome molecular weight size also is influential to its antiviral activity.Wherein, the fraction of molecular weight 7.500 (LW-S-D-2) not only has high HIV-1 to suppress active, to MT
4The cell growth does not produce detrimentally affect, and effect is the most desirable.
Sulfate content plays crucial effect to the sulfated polysaccharide antiviral activity.Experiment finds that sulfate content has remarkable anti-HIV-1 activity in the fraction greater than 19.87%, and up to 38.36% o'clock, antiviral activity was very remarkable; Slough (sulfate content 9.98%) behind the part of sulfuric acid base, its antiviral activity then disappears.Should be pointed out that not to be that sulfate content is high more good more, sulfate content is too high, may be to the host cell toxigenicity, and therefore, sulfate content also has optimum range.
The antiviral activity result of table 1 galactan sulfate and derivative thereof
Embodiment 22.1 anti-tumor in vivo activity
| Title | Concentration μ g/ml | ????OD | Antigen amount (pg/ml) | Tumour inhibiting rate (%) | Molecular weight | SO 4Content (%) | Modifying method |
| HIV-1 aAZT 911 LW-S-A-1 LW-S-D-2 LW-S-C-3 LW-S-D-1 SU-B DS-M-A | ????- ????0.5 ????4.44 ????75 ????75 ????75 ????75 ????75 ????75 | ??2.289 ??0.06 ??1.145 ??0.084 ??0.092 ??0.081 ??2.244 ??0.080 ??2.289 | ????130.21 ????0 ????65.11 ????1.57 ????2.04 ????1.40 ????127.59 ????1.34 ????130.21 | ? ????100 ????50 ????98.79 ????98.43 ????98.92 ????2.20 ????98.97 ????0 | ? ? ? ??10,500 ??7,500 ??3,400 ??2,500 ??8,200 ??4,100 | ? ? ? ??21.02 ??22.10 ??19.81 ??21.73 ??38.36 ??9.98 | ? ? ? 0.1mol/L?H
2SO
4，100℃，3h 0.1mol/L?H
2SO
4，100℃，4h 0.5mol/L?H
2SO
4，100℃， |
The anti-tumor in vivo test selects for use healthy female Kunming mouse to carry out, and 7 every group, tests behind the foster temporarily 3d.Aseptic extraction S180 tumor-bearing mice ascites is used the physiological saline suspension tumor cell, and blood counting chamber counting cells final concentration is 8 * 10
6Individual/ml, press the subcutaneous injection of 0.2ml dosage to the mouse oxter.Galactan sulfate and derivative solution thereof are irritated stomach once every day, by the mouse batheroom scale, irritate stomach dosage and are respectively 200mg/kg, 100mg/kg and 50mg/kg.Intramuscular injection 50mg/kg endoxan (Cy) is to mouse thigh place next day that positive control adopting, and negative control is 0.2ml physiological saline every day.
The anti-tumor in vivo activity of galactan sulfate as shown in Figure 6.After irritating stomach processing 15d, the knurl of negative control group (physiological saline treatment group) mouse heavily increases to 1.248g, and the knurl of positive controls (Cy treatment group) mouse heavily has only 0.184g, and tumour inhibiting rate is 85.3%.When treatment dosage was 100mg/kg, do not derive the galactan sulfate K-II and the galactan sulfate SII-L mouse tumor of slightly deriving were reduced to 0.442g and 0.272g heavily respectively, and tumour inhibiting rate reaches 64.6% and 78.2% respectively.2.2 the mensuration of index of correlation
Behind the experiment 15d, get blood, place the centrifuge tube Trisodium Citrate of final concentration 3.8% (in add) from eyeball of mouse.After mouse is weighed, put to death, accurately take by weighing the weight of knurl piece, liver, spleen and thymus gland, prepare hepatic homogenate liquid by 4 ℃ of homogenate technology, the hemocyte extracting solution then adopts the preparation of alternate freezing and thawing method.The liver homogenate liquid of every laboratory animal and the superoxide-dismutase (SOD) of hemocyte extracting solution and the activity of catalase (CAT) are measured.
Adopt pyrogallol autoxidation method to measure the SOD activity, and calculate enzymic activity.Adopt ultraviolet absorption method to measure the activity of CAT, and the CAT enzyme of calculation sample is lived.
Experimental result sees Table 2.Behind the mouse inoculation oncocyte, intravital SOD and CAT are active to be reduced rapidly, and in this state, intravital free radical can't in time obtain removing and excess accumulation.Oral galactan sulfate then can obviously promote the activity of antioxidase, produces vital role in antitumor activity.SII-L is when treatment dosage is 100mg/kg to the group of slightly deriving, and shows good antioxidant activity, far above control group.The then obvious difference of situation of highly deriving and organizing SII-H (sulphur content is 27.4%) particularly when treatment dosage reaches 200mg/kg, although tumour inhibiting rate is 26.9%, does not show effective anti-oxidant activity.On the other hand, after positive controls was accepted the injection of endoxan, tumour inhibiting rate was very obvious, but activities of antioxidant enzymes is approaching with negative control group in the body, show that endoxan when suppressing tumour, can cause damage to normal physiological function of organism inevitably.
The influence that table 2 galactan sulfate and derivative thereof are lived to antioxidase
SOD???????????????????CAT
Dosage sample hemocyte liver hemocyte liver
(mg/kg)
(U/mgPr)????(U/mg)?????(U/gPr)????(U/g)K-II?????????200??????????3.1????????2.3????????84.6???????128.3
100??????????3.7????????2.6????????100.1??????144.9
50???????????3.1????????2.1????????102.4??????137.2SH-L?????????200??????????2.8????????2.3????????97.8???????143.3
100??????????3.8????????2.5????????114.2??????164.3
50???????????4.2????????2.5????????108.8??????159.8SII-H????????200??????????2.7????????1.6????????86.3???????116.6
100??????????3.0????????1.9????????105.6??????128.1
50 3.0 1.8 103.3 130.6 endoxan, 3.2 2.1 87.6 122.5 control groups (physiological saline), 2.8 1.6 82.5 125.7 embodiment 3
In above-mentioned experiment, verified galactan sulfate can improve the activity of intravital antioxidase SOD of mouse and CAT, thereby helps the antineoplastic immune function of mouse body.In order further to illustrate its anti-oxidant activity, again from anti peroxidation of lipid, removing hydroxy radical qiao, superoxide anion and H
2O
2Etc. the aspect carried out a series of experiment in vitro.3.1 anti peroxidation of lipid experiment
Adopt Fe
2+Bring out lipovitellinin PUFA peroxidation system.The LPO model reaction system that with the lipovitellinin is substrate comprises: the yolk suspension 0.2ml of 1: 25-1: 32 dilutions; Sample solution 0.1ml; 25mmol/LFeSO
47H
2O solution 0.2ml complements to 2.0ml with PBS.Control tube adds 20% trichoroacetic acid(TCA) (TCA) solution 0.5ml in advance.Above-mentioned test tube is placed 37 ℃ of water-baths 15min that vibrates simultaneously, after the taking-up, in this developmental tube, add 20%TCA 0.Sml, after leaving standstill 10min, with control tube in the centrifugal 10min of 3500r/min, get the 2.0ml supernatant liquor, add 0.8% thiobarbituricacid (TBA) solution 1.0ml respectively, jump a queue and in 100 ℃ of water-baths, react 15min, take out cooling.With blank pipe (PBS solution) zeroing, survey light absorption value down in 532nm with 721 type spectrophotometers.
The present invention can obviously suppress Fe
2+The lipovitellinin peroxidation phenomenon of bringing out when sample SII-L is 8mg/ml in concentration, reaches 40.8% (Fig. 7) to the inhibiting rate of lipid peroxidation.3.2 to H
2O
2Scavenging(action)
With the new freshly-slaughtered poultry blood of Alsever ' s liquid collection,,, make 2% cell suspending liquid with physiological saline washing 3 times with 2000r/min centrifugal collecting precipitation red corpuscle.
Get red cell suspension 1ml, (concentration is respectively 6.4,3.2,1.6,0.8,0.4,0.2,0.1mg/ml) and 0.3mlH to add the galactan sulfate of 0.1ml different concns and derivative sample thereof
2O
2(concentration is 24mmol/L), behind the reaction 1h, with 3 times of physiological saline dilutions, the centrifugal 10min of 2000r/min collects supernatant liquor, measures light absorption value in the 415nm place in 37 ℃ of incubators.Not add H
2O
2The red corpuscle normal group be blank zeroing, with H
2O
2Add red corpuscle and be mixed into control group, test group is made comparisons with control group, and calculates the erythrocyte hemolysis inhibiting rate.
Experimental result shows that this product can obviously suppress by H
2O
2The erythrocyte hemolysis phenomenon that causes, the haemolysis inhibiting rate presents the positive correlation phenomenon with sample concentration, occurs the highest inhibiting rate 86.2% (Fig. 8) during for 6.4mg/ml in sample SII-L concentration.3.3 scavenging(action) to OH
Contain 1.0ml 0.6mol/L FeSO in the 3ml reaction solution
4, 0.75ml 8mmol/L sodium salicylate and 0.5ml different concns galactan sulfate and derivative sample thereof, add 0.75ml 24mmol/L H at last
2O
2, start reaction, in 37 ℃ of reaction 1h, survey the light absorption value at 510nm place, calculate the clearance rate (%) of OH.
Experiment shows that this product can be to H
2O
2+ Fe
2+The hydroxy radical qiao that brings out generation produces tangible scavenging(action), and removes effect and present tangible positive correlation phenomenon with the concentration of sample, and wherein the Hydroxyl Radical Scavenging of sample K-I is particularly evident, and the highest clearance rate reaches 88.1% (Fig. 9).Calculate O 3.4 adopt pyrogallol autoxidation method
2 -Scavenging(action)
Get 2.4ml Tris-HCl damping fluid (pH8.2), the galactan sulfate and the derivative sample thereof that add the 0.1ml different concns, the pyrogallol 0.3ml that adds 7mmol/L behind the mixing, behind mixing during 4min with the HCl number stopped reaction of 10mol/L, survey light absorption value down in 325nm.
The present invention has to a certain degree restraining effect to the superoxide anion that is formed by the pyrogallol autoxidation.The antioxidant effect of sample SII-L is fairly obvious.When concentration is 6.4mg/ml, the coloured intermediate product that produces owing to the pyrogallol autoxidation is reached 62.5% (Figure 10) at the inhibiting rate of the photoabsorption of 325nm place formation.
The detection of embodiment 44.1 macrophage immunity functions
After mouse is accepted the last administration, get the abdominal cavity of every experiment mice of chicken red blood cell (CRBC) suspension injection of 0.5ml 5% hematocrit, put to death behind the 6h, injection Hank ' s solution is to the abdominal cavity, after gently rubbing mouse web portion, draw the peritoneal irrigation drop on slide glass, put into the enamel tray that is lined with wet gauze, in 37 ℃ of incubation 30min.Then, float CRBC and other cells do not engulfed in physiological saline, after drying up, with the fixing 5min of methanol solution, the Giemsa-Wright-PB dye liquor dyeing 3min with 4% dries the back microscopy.Count 100 scavenger cells, calculate phagocytic percentage and phagocytic index.
In order to analyze the anti-tumor in vivo mechanism of action of this product from certain angle, this experiment is also analyzed its anti-immunocompromised activity.The result shows that oral this product can be low at the immune function of mice that suppresses to be caused by endoxan.The phagocytic function of experimental mice scavenger cell is apparently higher than control group, the galactan sulfate SII-L that particularly slightly derives, and phagocytic rate and phagocytic index reach 31.61% and 1.34 (table 3) respectively.
Table 3 galactan sulfate and derivative thereof are to cytophagous immunoregulation effect
Sample dose (mg/kg) phagocytic rate (%) phagocytic index
K-II???????????????100????????????25.19?????????1.25
SII-L??????????????100????????????31.61?????????1.34
Control group (physiological saline) 16.32 0.86
Detection---the microscope count method of normal group 34.55 1.784.2 quantity of leucocyte
Add 2% acetum (adding 1 methylene blue dye liquor) 0.38ml in small test tube,, be blown into white corpuscle diluent bottom, suct a layer diluent again and wash suction pipe for several times, fully mixing with suction pipe draw blood 20 μ l.Draw cell suspension with dropper, charge in the nucleonics of blood counting chamber.Leave standstill 1-2min, treat that cell sinks after, count with low power lens.Count the leukocyte count in 4 big grids, and calculate white corpuscle number in the unit volume, produced very significantly difference (table 4), endoxan can obviously reduce number of WBC in the mouse blood, and sample K-II (galactan sulfate of not deriving) and sample SII-L (galactan sulfate of slightly deriving) can all produce good restitution to female and male mice.
Table 4 sulfuric acid semi-lactosi and derivative thereof are to the influence of quantity of leucocyte
Group white corpuscle number (* 10
5/ ml)
Sample K-II ♂ 45.4 ± 9.7
♀?????????????54.5±14.5
Sample SII-L ♂ 48.6 ± 17.5
♀?????????????61.8±20.4
Control group ♂ 34.6 ± 16.5
♀?????????????18.4±9.5
Normal group ♂ 73.3 ± 14.6
♀?????????????65±14.5
The mensuration of ♀ female mice ♂ male mice 4.3 serum lysozyme vigor
Micrococcus lysodeikticus dry powder is mixed with bacteria suspension with the phosphoric acid buffer of pH6.5, makes A
570=0.3, get 3ml bacterium liquid and 50 μ l test serum mixings, colorimetric under 570nm records A
0Reaction solution places 37 ℃ of temperature to bathe and handles 1h, takes out back ice bath termination reaction, records the A value, calculates antalzyme activity (U/ml).
Experiment shows, this product also has very significant raising (table 5) to the vigor of the humoral immunization factor except the cellular immune function to laboratory animal has tangible immunoregulation effect.Because the immunosuppressive action of endoxan, (accept endoxan stimulates the positive controls mouse, but not using this galactan sulfate and derivative thereof) antalzyme activity in the serum descends greatly, the 23.4-34.9% that only is equivalent to normal experimental mice (injection of not accepting endoxan stimulates), and the present invention can improve activity of lysozyme very significantly, makes the immunocompetence of experimental mice approach the level of normal group mouse.
Table 5 galactan sulfate and derivative thereof are to the influence of serum lysozyme vigor
Group A
0A A
0-A U
LSample KII
0.334 0.142 0.192 81.1
♀ 0.332 0.160 0.172 64.5 sample SII-L
0.334 0.185 0.149 48.3
♀ 0.338 0.155 0.183 70.8 control group
0.323 0.244 0.079 19.4
♀ 0.328 0.228 0.100 26.3 normal group
0.331 0.139 0.192 82.9
♀ 0.336 0.149 0.187 75.34.4 is to the influence of immune organ weight
According to the statistics to relevant organ weights of immunity such as liver, spleen and the thymus gland of normal mouse and immunocompromised model mice, this product can produce positive effect (table 6) to the growth of immune organ.
Table 6 galactan sulfate and derivative thereof are to the influence of immune organ weight
Sample liver weight (g) spleen weight (g) thymic weight (g)
K-II??????????????????1.761??????????????0.269??????????????0.112
SII-L?????????????????1.855??????????????0.250??????????????0.146
Control group (physiological saline) 1.738 0.221 0.128
Normal group 1.817 0.282 0.147
Claims (5)
1. galactan sulfate and derivative thereof are used to prepare antiviral agent;
2. galactan sulfate and derivative thereof are used to prepare antineoplastic agent;
3. galactan sulfate and derivative thereof are used to prepare antioxidant;
4. galactan sulfate and derivative thereof are used to prepare immunomodulator;
5. galactan sulfate and derivative thereof are used to prepare fungistat.
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|---|---|---|---|
| CN 03138974 CN1240722C (en) | 2003-08-04 | 2003-08-04 | Sulfuric galactosan and use of its derivative |
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| CN1240722C CN1240722C (en) | 2006-02-08 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108024947A (en) * | 2015-07-27 | 2018-05-11 | 玫琳凯有限公司 | Topical skin preparations |
| WO2022021315A1 (en) * | 2020-07-30 | 2022-02-03 | 青岛海洋生物医药研究院股份有限公司 | Application of alginic acid derivative against coronavirus and diseases caused by coronavirus |
-
2003
- 2003-08-04 CN CN 03138974 patent/CN1240722C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108024947A (en) * | 2015-07-27 | 2018-05-11 | 玫琳凯有限公司 | Topical skin preparations |
| US10869821B2 (en) | 2015-07-27 | 2020-12-22 | Mary Kay Inc. | Topical skin formulations |
| US11577099B2 (en) | 2015-07-27 | 2023-02-14 | Mary Kay Inc. | Topical skin formulations |
| US11911635B2 (en) | 2015-07-27 | 2024-02-27 | Mary Kay Inc. | Topical skin formulations |
| WO2022021315A1 (en) * | 2020-07-30 | 2022-02-03 | 青岛海洋生物医药研究院股份有限公司 | Application of alginic acid derivative against coronavirus and diseases caused by coronavirus |
| CN114053297A (en) * | 2020-07-30 | 2022-02-18 | 青岛海洋生物医药研究院股份有限公司 | Application of alginic acid derivative in resisting coronavirus and diseases caused by coronavirus |
| CN114053297B (en) * | 2020-07-30 | 2024-02-09 | 青岛海洋生物医药研究院股份有限公司 | Application of alginic acid derivative in resisting coronavirus and diseases caused by alginic acid derivative |
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