CN1331836C - C60 trans-succinate with biologic activity and its synthesis - Google Patents
C60 trans-succinate with biologic activity and its synthesis Download PDFInfo
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- CN1331836C CN1331836C CNB2005100237978A CN200510023797A CN1331836C CN 1331836 C CN1331836 C CN 1331836C CN B2005100237978 A CNB2005100237978 A CN B2005100237978A CN 200510023797 A CN200510023797 A CN 200510023797A CN 1331836 C CN1331836 C CN 1331836C
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- derivant
- trans
- succinate
- succinic acid
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Abstract
The present invention belongs to the technical field of an organic inorganic hybrid material, more specifically an inverse succinic acid with bioactivity C60 and a synthetic method of the inverse succinic acid. In the present invention, C60 <2-> negative ions and 1, 2-dibromosuccinic acid sodium react in a tetrahydrofuran solution, and the C60 derivant C60 inverse succinic acid which can be dissolved in a polar solvent is made. Characterization is carried out to a derivant structure by various wave spectrum techniques, and the reaction is indicated to be a high-selectivity addition reaction; the derivant has no toxic side effect on the derivant, which is proved by the bioactivity experiment of the derivant, and the derivant has inhibition effect on colibacillus growth. The derivant shows weak inhibition effect on the growth of hepatoma carcinoma cells under the conditions of the concentrations of 5 mu L and 10 mu L, and the derivant is proved to have application value in terms of the preparation of medicine for inhibiting fungus growth and treating tumours.
Description
Technical field
The invention belongs to inorganic-organic hybrid material technology field, be specifically related to a kind ofly can be dissolved in polar solvent, and the C of biologically active
60Trans-succinate and synthetic method thereof.
Technical background
Since 1993 (S.H.Friedman et al., J.Am.Chem.Soc.1993,115,6506.) such as Friedman synthesize the inhibited water-soluble C of HIV (human immunodeficiency virus) proteolytic enzyme
60Since the derivative, people recognize C
60([60] soccerballene) can biological chemistry and medical aspect have bright prospects.But for a long time because C
60Only be dissolved in the nonpolar and weak polar solvent such as benzene, toluene and dithiocarbonic anhydride water insoluble, tetrahydrofuran (THF) isopolarity solvent, thereby the synthetic C that is dissolved in polar solvent (as water etc.)
60Derivative is C
60In biological chemistry, key in medical applications aspect particularly; While C
60Itself have very big electronegativity, the too high pair cell of electronegativity easily produces the bio-toxicity effect.People make C by chemically modified
60The electronegativity of derivative significantly descends, and reduces their intrinsic bio-toxicities (Zhu Z et al., Biochemistry2003,42,1326; McGovern S.L. et al., J.Med.Chem.2002,45,1712; Chiang, L. Y.etal., J.Chem.Soc., Chem.Commun.1994,2675; Wharton T.et al., Tetrhedron Lett.2001,42 (31), 5159.).The derivative of [60] soccerballene of finding to contain porphyrin ring if any the people is to serum biologically active that self-Immunological diseases patient is arranged (Panagiota S.et al., Tetrahedron 2004,60,2823.); Use water-soluble C
60Derivative is made the artificial lipoid film with similar bioactive film, and usefulness such as Yamakoshi are dissolved in the C of the polyvinylpyrrolidone aqueous solution
60Carried out the hemolytic action experiment, found blood is had no effect; Wilson etc. have done many work in this respect, as (Hungerb ü hler H.et al., J.Am.Chem.Soc.1993,115,3386 such as influence of the phosphatic fullerene derivate of synthetic to the bone tissue growth; Murakami H.et al., J.Am.Chem.Soc.1996,118,4484; Yamakoshi Y.N.et al., J.Chem.Soc.Chem.Commun.1994, (4), 517; Wilson L. J.etal., Bioorg.Med.Chem.2002,10 (6), 1991.).
Summary of the invention
The objective of the invention is to propose a kind of C that can be dissolved in polar solvent, biologically active
60Derivative and synthetic method thereof.
The C that the present invention proposes
60Derivative is at C
60Introduce the C of the generation of polar group carboxyl on the outer spheroid
60Trans-succinate, its structural formula is:
According to C
60Character itself will prepare and is dissolved in the particularly C of water of polar solvent
60Derivative generally has two kinds of methods: the one, and at C
60Introduce polar group on the outer spheroid, the 2nd, make soluble substance comprise C
60Molecule.The present invention passes through at C
60Introduce the polar group carboxyl on the outer spheroid, make C
60Generate the novel derivative---C of water soluble, tetrahydrofuran (THF), acetone isopolarity solvent
60Trans-succinate.The selectivity of this reaction is very high, single additive derivative almost 100%; Productive rate is also higher, can reach about 80%.This all helps carrying out C
60The test of the biological activity test of derivative.Its biological activity test also demonstrates good result, has potential application foreground aspect the property of medicine such as inhibition and elimination fungi, tumour cell.
The C that the present invention proposes
60Anti-succinic carboxylic acid synthetic method is as follows:
Under nitrogen atmosphere, use C
60, potassium, 1-methylnaphthalene and tetrahydrofuran solution, reacted synthetic C 2-3 hour
60 2-Negatively charged ion; Then, add and the isopyknic normal hexane of tetrahydrofuran solution, put into the refrigerator below-10 ℃, time 5-7 days; Take out then, mother liquor is separated, add 1 again, 2-dibromo-succinic acid sodium under 50～70 ℃, refluxes and stirred 5-8 hour; Cool to room temperature, centrifugal, vacuum is taken out and is desolvated; Use washing with acetone, vacuum is drained again, gets brown-black powder, is C
60The trans-succinate derivative; In the above-mentioned reaction, C
60The mol ratio of/potassium is 1: 2, C
60/ 1, the mol ratio of 2-dibromo-succinic acid sodium is 25.1: 50.Through the wave spectrum illness that has not attacked the vital organs of the human body, the structural formula of products therefrom is: C
60(CHCOOH)
2
Among the present invention, 1, the synthetic method of 2-dibromo-succinic acid sodium is as follows: according to classical organic chemical reactions, earlier with FUMARIC ACID TECH GRADE and sodium hydroxide solution reaction, after the salinization itself and liquid bromine reaction can be obtained crude product, promptly obtain high-purity dibromo-succinic acid sodium salt by carbon tetrachloride extraction and recrystallization again.1, the molecular structural formula of 2-dibromo-succinic acid sodium is as follows:
In the above-mentioned synthetic method, should earlier anti-succinic carboxylic acid be converted into sodium salt fully, otherwise the H of carboxylic acid
+To more active, easy elder generation and C
60The negative ion reaction generates hydride, thus the product that can not get expecting.And with the trans-succinate sodium salt directly and C
60React in toluene solution, prove reactionless generation, this may be that the activation energy that reacts is too high relevant.
Showing by the thin plate chromatography, was that single product is C before acidifying
60The trans-succinate disodium salt, this product is water-soluble, is soluble in THF, acetone isopolarity solvent.Show that from the mass spectrum (FD-MS) of compound product C is arranged
60The molecular ion peak 833 of trans-succinate, the absorption peak of infrared spectra mainly contain (KBr compressing tablet): 3437,2924,1731,1709,1631,1606,1550,1528,1440,1428,1181,1121,1084,1037,846,656,578,528, and 434cm
-1Deng.Can show that from data they all have C
60Characteristic peak, C is described
60The molecule basket structure is complete substantially; The v of carboxyl
C=OAt 1731cm
-1The place can be pointed out; And-charateristic avsorption band of OH base is 3437,1636cm
-1The place can be pointed out; The absorption peak of C-O is 1121cm
-1-COO
-Absorption peak 1606,1420cm
-1The place can be pointed out, and showing has a small amount of sodium salt to exist in the final product.Obtain its visible UV spectrum peak in trichloromethane simultaneously: 245,280,328,405,432nm etc.; This also illustrates C in this derivative
60Cage be kept perfectly substantially, but the functional group of being modified influences the displacement to some extent of the position of characteristic peak; δ 5.41 is the methine protons peak in the hydrogen nuclear magnetic resonance spectrogram.
The present invention is to C
60The trans-succinate derivative has carried out biological activity test.We have done it earlier to Normocellular toxicity test, prove to have no side effect.
Earlier with 3g extractum carnis, 10g peptone, 5g NaCl, 20g agar, 1000mL, PH is that 7.4～7.6 distilled water stirs well the even substratum of promptly making; 5mg C
60The trans-succinate derivative adds DMF and water dissolution, and the scraps of paper soak.The solution of DMF and water soaks with the scraps of paper in addition.
Intestinal bacteria and streptococcus aureus are seeded in the 5mL bacterial liquid substratum, cultivate 12 hours for 37 ℃.
Getting bacteria culture medium 15mL adds in the culture dish, as lower floor.Other gets substratum 50mL and adds above-mentioned cultured bacterial liquid substratum 1mL, adds on the lower floor's substratum that has watered, as the upper strata from wherein getting 5mL again.The soaked scraps of paper are placed on above the substratum, cultivate 12 hours for 37 ℃.This compound is to intestinal bacteria and aureus with inhibition and other paired observation result such as table 1.
Table 1 sample is to the biological activity test of fungi
| Intestinal bacteria | Streptococcus aureus | |
| C 60Anti-succinic carboxylic acid | + | - |
| Streptomycin sulphate | + | + |
| DMF+ water | - | - |
(+expression suppresses microorganism growth, and-expression does not suppress microorganism growth)
The solution of DMF and water is to all unrestraint effects of growth of intestinal bacteria and streptococcus aureus, thereby got rid of the effect of solvent; C
60Anti-succinic carboxylic acid has restraining effect to intestinal bacteria growths, but to the growth unrestraint effect of streptococcus aureus.
The present invention also done this compound under different concns to the bioactive test of liver cancer cell: with C
60Anti-succinic carboxylic acid derivative 2mg dissolves in the 2mL deionized water, gets 100 μ L and 400 μ L nutrient solutions are made into 500 μ L, and every hole is got this solution 100,50,10,5 μ L respectively and all is made into 200 μ L, and test is to the restraining effect of liver cancer cell growth.Result such as table 2.
Table 2 sample is to the biological activity test of liver cancer cell
* the data of showing first are the fluorescence absorbancy
Experiment shows, shows liver cancer cell growth is had weak restraining effect under 5 μ L, 10 μ L concentration, do not show restraining effect under other concentration, illustrates that this derivative has snob effect.
Biological activity test shows that this derivative has using value at inhibition fungal growth medicine and medicine for treating tumor object space face.
Embodiment
C
60Synthesizing of trans-succinate derivative
Embodiment 1:
Under nitrogen atmosphere, with 180mg (0.251mmol) C
60, 20mg (0.50mmol) potassium, 1mL 1-methylnaphthalene, 20ml tetrahydrofuran solution, the synthetic C of reaction
60 2-Negatively charged ion after 3 hours, adds normal hexane, puts into the refrigerator below-10 ℃, time 5-7 days; Take out then, after mother liquor is separated, add 80mg (0.50mmol) 1,2-dibromo-succinic acid sodium down, refluxes and stirred 8 hours about 60 ℃.Cooling, centrifugal, vacuum is taken out and is desolvated; Add dilute hydrochloric acid, stir half a day.Centrifugal, vacuum is drained, and uses washing with acetone, and vacuum is drained again, gets the 170mg brown-black powder, is C
60Trans-succinate derivative, productive rate are 81%.
Embodiment 2:
Under nitrogen atmosphere, with 181mg (0.251mmol) C
60, 21mg (0.54mmol) potassium, 1mL 1-methylnaphthalene, 20ml tetrahydrofuran solution, the synthetic C of reaction
60 2-Negatively charged ion after 2 hours, adds normal hexane, puts into the refrigerator below-10 ℃, time 5-7 days; Take out then, after mother liquor is separated, add 79.9mg (0.50mmol) 1,2-dibromo-succinic acid sodium down, refluxes and stirred 5 hours about 50 ℃.Cooling, centrifugal, vacuum is taken out and is desolvated; Add dilute hydrochloric acid, stir half a day.Centrifugal, vacuum is drained, and uses washing with acetone, and vacuum is drained again, gets the 121mg brown-black powder, is C
60Trans-succinate derivative, productive rate are 57%.
Embodiment 3:
Under nitrogen atmosphere, with 179mg (0.249mmol) C
60, 20mg (0.50mmol) potassium, 1mL 1-methylnaphthalene, 20ml tetrahydrofuran solution, the synthetic C of reaction
60 2-Negatively charged ion after 3 hours, adds normal hexane, puts into the refrigerator below-10 ℃, time 5-7 days; Take out then, after mother liquor is separated, add 82mg (0.51mmol) 1,2-dibromo-succinic acid sodium down, refluxes and stirred 8 hours about 70 ℃.Cooling, centrifugal, vacuum is taken out and is desolvated; Add dilute hydrochloric acid, stir half a day.Centrifugal, vacuum is drained, and uses washing with acetone, and vacuum is drained again, gets the 179mg brown-black powder, is C
60Trans-succinate derivative, productive rate are 85%.
Claims (3)
1, a kind of C of biologically active
60Derivative is characterized in that at C
60The C that introduces the polar group carboxyl on the outer spheroid and generate
60Trans-succinate, structural formula is:
2, a kind of C as claimed in claim 1
60The synthetic method of trans-succinate is characterized in that concrete steps are as follows: under nitrogen atmosphere, use C
60, potassium, 1-methylnaphthalene and tetrahydrofuran solution reacted 2-3 hour, synthetic C
60 2-Negatively charged ion; Then, add and the isopyknic normal hexane of tetrahydrofuran solution, put into the refrigerator below-10 ℃, time 5-7 days; Take out then, mother liquor is separated, add 1 again, 2-dibromo-succinic acid sodium under 50～70 ℃, refluxes and stirred 5-8 hour; Cool to room temperature, centrifugal, vacuum is taken out and is desolvated; Use washing with acetone, vacuum is drained again, gets brown-black powder, is C
60The trans-succinate derivative; In the above-mentioned reaction, C
60The mol ratio of/potassium is 1: 2, C
60/ 1, the mol ratio of 2-dibromo-succinic acid sodium is 25.1: 50.
3, C as claimed in claim 1
60The application of trans-succinate in preparation inhibition fungal growth medicine and medicine for treating tumor thing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100237978A CN1331836C (en) | 2005-02-03 | 2005-02-03 | C60 trans-succinate with biologic activity and its synthesis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100237978A CN1331836C (en) | 2005-02-03 | 2005-02-03 | C60 trans-succinate with biologic activity and its synthesis |
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| Publication Number | Publication Date |
|---|---|
| CN1680252A CN1680252A (en) | 2005-10-12 |
| CN1331836C true CN1331836C (en) | 2007-08-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100237978A Expired - Fee Related CN1331836C (en) | 2005-02-03 | 2005-02-03 | C60 trans-succinate with biologic activity and its synthesis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8337494B2 (en) | 2005-07-08 | 2012-12-25 | Plasma Surgical Investments Limited | Plasma-generating device having a plasma chamber |
| US8465487B2 (en) | 2005-07-08 | 2013-06-18 | Plasma Surgical Investments Limited | Plasma-generating device having a throttling portion |
-
2005
- 2005-02-03 CN CNB2005100237978A patent/CN1331836C/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| A new synthon for the incorporation of [60] fullerene inmacrocycles Rapenne,Gwenael,Diederich,Francois,New J. Chem.,Vol.23 No.12 1999 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8337494B2 (en) | 2005-07-08 | 2012-12-25 | Plasma Surgical Investments Limited | Plasma-generating device having a plasma chamber |
| US8465487B2 (en) | 2005-07-08 | 2013-06-18 | Plasma Surgical Investments Limited | Plasma-generating device having a throttling portion |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1680252A (en) | 2005-10-12 |
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