CN101830963A - Bufogenin compound and application thereof in preparing anti-tumor medicaments - Google Patents
Bufogenin compound and application thereof in preparing anti-tumor medicaments Download PDFInfo
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- CN101830963A CN101830963A CN200910047288A CN200910047288A CN101830963A CN 101830963 A CN101830963 A CN 101830963A CN 200910047288 A CN200910047288 A CN 200910047288A CN 200910047288 A CN200910047288 A CN 200910047288A CN 101830963 A CN101830963 A CN 101830963A
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Abstract
The invention relates to a bufogenin compound and an application thereof in preparing anti-tumor medicaments. The bufogenin compound comprises cinobufagin and derivatives thereof, contains pharmaceutically acceptable salts thereof, has a chemical structural formula which is shown in the specification, wherein groups R1, R2, R3 and R4 are respectively selected from hydrogen, halogens, C1-C6straight chain or branch chain saturated or unsaturated alkyls, C3-C7 ring alkyls, benzyls, aromatic groups or 5-7-tuple heterocyclic groups. Proved by in-vitro cellular experiments, the compound can remarkably inhibit the proliferation of liver cancer and lung cancer cells and accordingly can be used for preparing medicaments for inhibiting tumor growth.
Description
Technical field
The present invention relates to medical technical field, is a kind of toad lactone compound and the application in the preparation antitumor drug thereof.Said toad lactone compound is meant Cinobufagin alcohol and derivative thereof, comprises its pharmacy acceptable salt.
Background technology
The Bufo animal has kind more than 250, is distributed in all over the world.China has nearly 10 kinds, and main 3 kinds are respectively: bufo West China subspecies, bufo China's subspecies and Bufo melanostictus.Ancient prescription proved recipe widespread use toad draw out pus by applying a plaster to the affected part detumescence, decide ketone desinsection, cardiac stimulant diuresis.There are preparations such as dried venom of toads analgesia ointment, dried venom of toads injection, HUACHANSU ZHUSHEYE and compound cutis bufonis capsule to be applied to clinical antitumor, analgesia, inducing diuresis to remove edema, enhancing body immunizing power in the market.The assisting therapy that the toad preparation is used for tumour clinically has the advantage for the treatment of both principal and secondary aspect of disease, transfer, the enhance immunity power that can significantly suppress tumour, compare with chemotherapeutics, having can the ameliorate tumor patient suffering, the quality of significantly making the life better, prolong the characteristics of life cycle, also can use simultaneously to heighten the effect of a treatment with chemotherapy drugs in combination.Yet, present toad preparation, all be with crude extract be used as medicine, composition is extremely complicated, except that containing bufotalin, arenobufagin, indoles alkaloid, also contains polytype chemical ingredientss such as amino acid, reducing sugar, steroid class, peptide class.Therefore, in clinical use, the toad preparation has following two main drawbacks: the kill rate to tumour cell is low; Anaphylaxis appears.This all is owing to fail to remove invalid, untoward reaction composition, fails real effective constituent controlled and causes.
With the toad is that the former conventional Chinese medicine material of base has the dried venom of toads, toad skin, dried toad, and its Chemical Composition is quite complicated, can be divided into fat-soluble steroid class (bufotalin class, arenobufagin class), water-soluble indole alkaloids by solvability.The more compound of research comprises Toadpoison Medicine, Gamabufotalin, Bufotalin, Cinobufagin, Respigon etc. at present.
So far do not see that Cinobufagin alcohol and derivative thereof are used to prepare the report that tumor growth suppresses medicine.
Summary of the invention
One of purpose of the present invention provides a class Cinobufagin alcohol derivate; Two of purpose provides the purposes that class Cinobufagin alcohol and derivative or its pharmacy acceptable salt thereof are used for antitumor drug.Cinobufagin alcohol of the present invention and derivatives chemical general structure thereof are as follows:
Wherein: radicals R
1Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
2Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
3Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
4Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical;
Said halogen is selected from fluorine, chlorine, bromine or iodine; Said aromatic base is selected from phenyl, substituted-phenyl, naphthyl or xenyl; Said substituted-phenyl comprises 1～4 substituting group, and this substituting group is selected from halogen, C
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl and C
1-C
4Acyl group; Said 5-7 unit heterocyclic radical is to contain 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen, and/or by the phenyl in the structural formula and close, and/or contain-individual or a plurality of halogen, C of being selected from
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl C
1-C
4The substituting group of acyl group and aromatic base.
Said pharmacy acceptable salt be selected from propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, etc. organic acid and acidic amino acids such as aspartic acid, L-glutamic acid form behind the esters again the salt that forms with mineral alkali, as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt that forms with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc.; Or form behind the esters again and mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid with basic aminoacidss such as Methionin, arginine, ornithine, or with formic acid, acetate, the salt that organic acids such as picric acid, methylsulfonic acid, ethyl sulfonic acid form.
Cell in vitro is learned experiment and is shown, The compounds of this invention can cause kinds of tumor cells Cycle Arrest such as liver cancer, lung cancer, prostate cancer and leukemia, significantly suppress cell proliferation, therefore can be used to prepare inhibition medicine at the kinds of tumors growth that comprises liver cancer.
Description of drawings
Fig. 1 is 60 kinds of toad lactone compounds (4 * 10 of the present invention
-4Mg/ml) to SMMC-7721 cell inhibitory rate figure
Fig. 2 is 60 kinds of toad lactone compounds (4 * 10 of the present invention
-4Mg/ml) to A549 cell inhibitory rate figure
Fig. 3 for the Cinobufagin alcohol among the present invention to SMMC-7721 cell inhibitory rate comparison diagram
Fig. 4 acts on the design sketch of normal cell L02 and 293T for the Cinobufagin alcohol among the present invention
Fig. 5 is the treatment graphic representation of the Cinobufagin alcohol among the present invention to in-vivo tumour
Embodiment
Now in conjunction with the accompanying drawings and embodiments the present invention is described in detail.
The preparation of embodiment 1. Cinobufagin alcohol
(1) preparation of toad lactone extract
Get toad skin 10Kg, use 95% extraction using alcohol 3 times routinely, be 10 times of toad tare weight amounts with the alcohol amount at every turn, and extraction time is 120 minutes, merging filtrate, filtrate decompression is concentrated into 10L, last XAD-4 macroporous resin (ROHM AND HAAS), and elder generation is water and 30% ethanol flush away impurity successively, use 95% ethanol elution again, collect elutriant, decompression and solvent recovery, drying obtains toad lactone extract 125g.
(2) preparation of Cinobufagin alcohol
Get (1) prepared toad lactone extract 75g, separate (Waters Xterra C18, A:0.1% formic acid water through preparation HPLC; B:0.1% formic acid acetonitrile, gradient condition: 5%B～25%B, 30min; 25%B～50%B, 22min; 50%B～95%B, 18min; 95%B, 5min 300nm), is divided into 60 compositions (Fr.1～Fr.60).
Fr.16 reclaims solvent, through HPLC separate (the functionalization chromatographic column, gradient condition is: 95%B～60%B, 40min, wherein A:0.1% formic acid water; B:0.1% formic acid acetonitrile detects wavelength 300nm.), collect wherein main chromatographic peak, reclaim solvent, obtain Compound I 11mg, the HPLC detection level is 99%, physical and chemical determination data and document (Linde H., Hofer P., Meyer K., 1966, Cinobufaginol-Uber Krotengifte.32., HELVETICA CHIMICA ACTA, 49,1243-﹠amp; .) the compound Cinobufagin alcohol of report is consistent substantially, can think that in view of the above Compound I is a Cinobufagin alcohol.
2.60 kinds of toad lactone compounds of embodiment compound is to the cytotoxicity experiment of SMMC-7721 and A549
Cell: SMMC-7721 and A549 tumor cell line are international cell strain, take from east institute of liver and gall surgical department of Second Military Medical University, PLA
Toad lactone compound: embodiment 1 preparation (down together)
Be cell model with SMMC-7721 and A549 respectively, with CCK-8 cell proliferation reagent box (Japanese colleague's chemistry institute product) primary dcreening operation 60 compounds.Experimental design is as follows:
Respectively logarithmic phase SMMC-7721 and A549 cell are adjusted to 5 * 10 with 10% calf serum DMEM substratum
4Individual/ml, set up control group and experimental group separately, 3 every group multiple holes, each 100 μ l is inoculated in 96 orifice plates, places 37 ℃, contains 5%C0
2Incubator in, treat that 24h is adherent after, change 10% calf serum DMEM substratum, 100 μ l, experimental group adds 4 * 10
-4Each compound of mg/ml.Behind the 48h, operate according to CCK-8 test kit step, substratum is removed in suction, each hole adds 0.1% calf serum DMEM substratum, 100 μ l, add CCK-8 reagent 10 μ l again, in 3 blank well, add 0.1% calf serum DMEM substratum, 100 μ l and CCK-8 reagent 10 μ l in addition, place 37 ℃, contain 5%CO
2Incubator hatch 90min, survey 450nm place light absorption value (A value) with multi-functional microplate reader, return to zero the calculating cell proliferation inhibition rate with the blank well that does not add cell.Inhibiting rate=(1-experimental group A value/control group A value) * 100%.The result as shown in Figure 1 and Figure 2.
By Fig. 1, Fig. 2 as seen, Cinobufagin alcohol all has the obvious suppression effect to the propagation of hepatoma cell line SMMC-7721 and lung cancer cell line A549, and its concentration is 4 * 10
-4During mg/ml, the inhibiting rate level (90%) that reached capacity, other small molecules also have certain restraining effect (10-20%) in this concentration.
Cell: the SMMC-7721 tumor cell line, be international cell strain, take from east institute of liver and gall surgical department of Second Military Medical University, PLA
Cinobufagin alcohol: embodiment 1 preparation (down together)
HUACHANSU ZHUSHEYE: Anhui Jinchan Biochemical Co., Ltd.'s (down together)
With SMMC-7721 is cell model, and with the inhibiting rate of CCK-8 cell proliferation reagent box screening different concns Cinobufagin alcohol, experimental design is as follows:
Logarithmic phase SMMC-7721 cell is adjusted to 5 * 10 with 10% calf serum DMEM substratum
4Individual/ml, (HUACHANSU ZHUSHEYE is amounted to crude drug concentration and is respectively 0.5 * 10 to set up control group separately
-3G/ml, 1 * 10
-3G/ml, 2 * 10
-3G/ml, 4 * 10
-3G/ml, 8 * 10
-3G/ml, 16 * 10
-3G/ml, A1-A6 in the corresponding diagram 3) and experimental group (Cinobufagin alcohol 0.25 * 10
-4Mg/ml, 0.5 * 10
-4Mg/ml, 1.0 * 10
-4Mg/ml, 2.0 * 10
-4Mg/ml, 3.0 * 10
-4Mg/ml, 4.0 * 10
-4Mg/ml, amounting to crude drug concentration is 0.375 * 10
-3G/ml, 0.75 * 10
-3G/ml, 1.5 * 10
-3G/ml, 3 * 10
-3G/ml, 4.5 * 10
-3G/ml, 6 * 10
-3G/ml, B1-B6 in the corresponding diagram 3), 3 every group multiple holes, each 100 μ l is inoculated in 96 orifice plates, places 37 ℃, contains 5%CO
2Incubator in, treat that 24h is adherent after, change 10% calf serum DMEM substratum, 100 μ l, two groups all add medicine by predetermined scheme.Behind the 48h, operate according to CCK-8 test kit step, substratum is removed in suction, each hole adds 0.1% calf serum DMEM substratum, 100 μ l, add CCK-8 reagent 10 μ l again, in 3 blank well, add 0.1% calf serum DMEM substratum, 100 μ l and CCK-8 reagent 10 μ l in addition, place 37 ℃, contain 5%CO
2Incubator hatch 90min, survey 450nm place light absorption value (A value) with multi-functional microplate reader, return to zero the calculating cell proliferation inhibition rate with the blank well that does not add cell.Inhibiting rate=(1-experimental group A value/control group A value) * 100%.The result as shown in Figure 3.
As seen from Figure 3, Cinobufagin alcohol 4 * 10
-4The level that reached capacity during mg/ml (90%), amounting to crude drug concentration is 8 * 10
-4G/ml; And for reaching identical curative effect, HUACHANSU ZHUSHEYE then needs 160 * 10
-4G/ml (according to the crude drug concentration conversion), both concentration differences are apart from very big.
Embodiment 4. Cinobufagin alcohol are to the toxic action of non-tumor cell system
Cell: L02 and 293T are international cell strain, take from east institute of liver and gall surgical department of Second Military Medical University, PLA
Cinobufagin alcohol: embodiment 1 preparation (down together)
Whether have non-specific cytotoxicity for getting rid of Cinobufagin alcohol, selecting non-tumor cell is that L02 and 293T detect, and experimental design is as follows:
Respectively logarithmic phase normal hepatocytes epithelial cell L02 and human embryo kidney (HEK) epithelial cell 293T are adjusted to 5 * 10 with 10% calf serum DMEM substratum
4Individual/ml, set up control group and experimental group separately, 3 every group multiple holes, each 100 μ l is inoculated in 96 orifice plates, places 37 ℃, contains 5%CO
2Incubator in, treat that 24h is adherent after, change 10% calf serum DMEM substratum, 100 μ l, experimental group adds medicine makes that final concentration is 1 * 10
-4Mg/ml, 2 * 10
-4Mg/ml, 3 * 10
-4Mg/ml, 4 * 10
-4Mg/ml.Behind the 48h, operate according to CCK-8 test kit step, substratum is removed in suction, each hole adds 0.1% calf serum DMEM substratum, 100 μ l, add CCK-8 reagent 10 μ l again, in 3 blank well, add 0.1% calf serum DMEM substratum, 100 μ l and CCK-8 reagent 10 μ l in addition, place 37 ℃, contain 5%CO
2Incubator hatch 90min, survey 450nm place light absorption value (A value) with multi-functional microplate reader, return to zero the calculating cell proliferation inhibition rate with the blank well that does not add cell.Inhibiting rate=(1-experimental group A value/control group A value) * 100%.The result is (A is the L02 cell, and B is the 293T cell) as shown in Figure 4.
As seen from Figure 4, be among L02 and the 293T at non-tumor cell, the proliferation function of Cinobufagin alcohol pair cell is not obvious, and does not have specific dose-effect relationship, suppresses the effect basically identical when lower concentration and high density.The inhibiting rate of maximum concentration only can reach 20%, illustrates that it is not (if toxic action, then should survival rate reduces along with increasing of concentration) that non-specific toxic action causes to the inhibition of tumour cell.
Embodiment 5. Cinobufagin alcohol are to the restraining effect of tumour
Animal: the Nude mouse is provided by the The 2nd Army Medical College animal center; The SMMC-7721 tumor cell line is international cell strain, takes from east institute of liver and gall surgical department of Second Military Medical University, PLA
Cinobufagin alcohol: embodiment 1 preparation (down together)
For detecting Cinobufagin alcohol anti-tumor activity in animal body, selecting the Nude mouse is model, does positive reference with HUACHANSU ZHUSHEYE, observes its treatment tumor effect.Experimental design is as follows:
Get 8 all Nude mouse, 6 about 25 grams of counterpoise, male, subcutaneous injection hepatoma cell line SMMC-7721 cell 2 * 10
6Individual, the successful lotus knurl in 3 week backs is divided into 2 groups, 3 of control groups, 3 of experimental group at random.Experimental group is pressed 0.5mg*kg
-1* d
-1Continuous intratumor injection Cinobufagin alcohol, the continuous intratumor injection equivalent of control group physiological saline observed for 4 weeks.The result as shown in Figure 5.
As seen from Figure 5, compare with control group, the experimental group gross tumor volume significantly dwindles, and carries out statistical analysis with paired t-test, and P＜0.05 shows that Cinobufagin alcohol has the obvious treatment effect to liver cancer.
Claims (2)
1. toad lactone compound and pharmacy acceptable salt thereof, chemical structure of general formula is as follows:
Wherein: radicals R
1Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
2Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
3Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical, R
4Represent hydrogen, halogen, C
1-C
6Saturated or the unsaturated alkyl of straight or branched, C
3-C
7Cyclic hydrocarbon radical, benzyl, aromatic base or 5-7 unit heterocyclic radical;
Said halogen is selected from fluorine, chlorine, bromine or iodine; Said aromatic base is selected from phenyl, substituted-phenyl, naphthyl or xenyl; Said substituted-phenyl comprises 1～4 substituting group, and this substituting group is selected from halogen, C
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl and C
1-C
4Acyl group; Said 5-7 unit heterocyclic radical is to contain 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen, and/or by the phenyl in the structural formula and close, and/or contain one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl C
1-C
4The substituting group of acyl group and aromatic base;
Said pharmacy acceptable salt be selected from propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, etc. organic acid and acidic amino acids such as aspartic acid, L-glutamic acid form behind the esters again the salt that forms with mineral alkali, as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt that forms with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc.; Or form behind the esters again and mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid with basic aminoacidss such as Methionin, arginine, ornithine, or with formic acid, acetate, the salt that organic acids such as picric acid, methylsulfonic acid, ethyl sulfonic acid form.
2. described toad lactone compound of claim 1 and pharmacy acceptable salt thereof the application in the preparation antitumor drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000091A (en) * | 2010-10-29 | 2011-04-06 | 中国人民解放军第二军医大学 | Bufarenogin, and application of derivatives and pharmaceutically acceptable salts thereof |
| CN102203112A (en) * | 2010-01-15 | 2011-09-28 | 苏州润新生物科技有限公司 | Certain chemical entities, compositions, and methods |
| CN103006670A (en) * | 2012-09-29 | 2013-04-03 | 暨南大学 | Total unsaturated toad lactone, and preparation method and use thereof |
-
2009
- 2009-03-10 CN CN200910047288A patent/CN101830963A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102203112A (en) * | 2010-01-15 | 2011-09-28 | 苏州润新生物科技有限公司 | Certain chemical entities, compositions, and methods |
| CN102203112B (en) * | 2010-01-15 | 2014-05-07 | 苏州润新生物科技有限公司 | Certain chemical entities, compositions, and methods |
| CN102000091A (en) * | 2010-10-29 | 2011-04-06 | 中国人民解放军第二军医大学 | Bufarenogin, and application of derivatives and pharmaceutically acceptable salts thereof |
| CN102000091B (en) * | 2010-10-29 | 2011-12-21 | 中国人民解放军第二军医大学 | Application of bufarenogin,its derivatives and pharmaceutically acceptable salts thereof |
| CN103006670A (en) * | 2012-09-29 | 2013-04-03 | 暨南大学 | Total unsaturated toad lactone, and preparation method and use thereof |
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Application publication date: 20100915 |