CN100387232C - Application of 3-benzyl-5-(2-nitrophenoxymethyl)-gamma-butyrolactone in preparing medicine for inhibiting vascular endothelial senility and apoptosis - Google Patents
Application of 3-benzyl-5-(2-nitrophenoxymethyl)-gamma-butyrolactone in preparing medicine for inhibiting vascular endothelial senility and apoptosis Download PDFInfo
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- CN100387232C CN100387232C CNB2006100432443A CN200610043244A CN100387232C CN 100387232 C CN100387232 C CN 100387232C CN B2006100432443 A CNB2006100432443 A CN B2006100432443A CN 200610043244 A CN200610043244 A CN 200610043244A CN 100387232 C CN100387232 C CN 100387232C
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Abstract
The present invention discloses a new purpose of 3-benzyl group-5-(2-nitrobenzene oxygen methyl)-gamma-butyrolactone, which particularly relates to the application of the 3-benzyl group-5-(2-nitrobenzene oxygen methyl)-gamma-butyrolactone to the preparation of medicine for restricting the senescence and the apoptosis of vascular endothelial cells. When the concentration is 20-60 mg/L, the 3-benzyl group-5-(2-nitrobenzene oxygen methyl)-gamma-butyrolactone can effectively restrict apoptosis, nuclear fragmentation and DNA condensation. The present invention provides a routine of development and application for preparing the medicine for restricting the senescence and the apoptosis of the vascular endothelial cells and treating cardiovascular diseases.
Description
Technical field
The present invention relates to the application of gamma-butyrolactone derivative in vascular endothelial senility and apoptosis; Relate in particular to 3-benzyl-5-(2-nitro the Phenoxymethyl)-application of gamma-butyrolacton in vascular endothelial senility and apoptosis.
Background technology
The gamma-butyrolacton structural formula is:
Molecular formula: C
4H
6O
2
Molecular weight: 86
Character: gamma-butyrolacton is nontoxic transparent oily liquids, dissolves in ethanol, ether, benzene and acetone, can dissolve multiple organic and inorganic compound; Can dissolve each other fully with water; Be that a kind of boiling point height, dissolubility are strong, the solvent of electrical property and good stability.
Butyrolactone derivative has extensive use in the organic synthesis field, be very important intermediate of a class and end-product.The butyrolactone structure is the very important construction unit of a class, all contains this construction unit in many natural products and the synthetic drug.Now, because pharmacology and the medicinal property and the potential economic worth thereof of gamma-butyrolactone derivative, it still is the emphasis of research worker research.But, only limit to of the effect of this analog derivative during the research that the biological activity of butyrolactone derivative is tested is reported at present at aspects such as antitumor, antiulcer, anti-inflammation and sterilization, sedation-analgesia, spasmolytic, inhibition platelet aggregation, inhibition nervus centraliss.And about its in effect aspect vascular endothelial senility and the apoptosis and relevant pharmacological research and application, look into newly through authoritative institution retrieval, do not appear in the newspapers as yet both at home and abroad at present.
Summary of the invention
At the deficiencies in the prior art, the problem to be solved in the present invention provides the new purposes of a kind of butyrolactone derivative 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, i.e. the application of 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton in preparation inhibition vascular endothelial senility and apoptosis medicine.
The gamma-butyrolactone derivative 3-arylmethyl-5-aryloxy methyl-gamma-butyrolacton that the present invention relates to is shown in general formula (I):
Wherein: R
1Represent H, C
1-6Alkyl, C
1-5One of alkoxyl, halogen, nitro, hydroxyl;
R
2Represent H, C
1-5One of alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
R in 3-benzyl-5-of the present invention (2-nitro Phenoxymethyl)-gamma-butyrolacton
1Be nitro, R
2It is phenyl.
The application of 3-benzyl-5-of the present invention (2-nitro Phenoxymethyl)-gamma-butyrolacton in preparation inhibition vascular endothelial senility and apoptosis medicine.
Wherein: (2-nitro Phenoxymethyl)-gamma-butyrolacton concentration is 20～60mg/L effectively to suppress the condensing 3-benzyl-5-of apoptosis, nuclear fragmentationization and DNA.
3-benzyl-5-of the present invention (2-nitro Phenoxymethyl)-gamma-butyrolacton suppress vascular endothelial cell aging with apoptosis in have obvious effect, for the exploitation of novel cardiovascular drugs provides tempting prospect.
In order to understand the action effect of essence of the present invention and chemical compound of the present invention better, below in conjunction with the pharmacological evaluation and the result of 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, further set forth its effect in suppressing vascular endothelial senility and apoptosis.
The preparation of vascular endothelial cell: cultivate vascular endothelial cell with conventional method, choose the good and vascular endothelial cell that be in exponential phase of growth conditions, standby.
Adopt the method for Celluar and Molecular Biology, carry out following experiment, to observe 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton suppressing to remove serum and the vascular endothelial senility of somatomedin and the influence of apoptosis.
1, inverted phase contrast microscope observation of cell morphological change, the i.e. formation of apoptotic body:
Each is organized and adds 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton respectively after vascular endothelial cell is removed serum and somatomedin, handle after 24 hours and 48 hours the formation of the morphological change of direct observation apoptosis of vascular endothelial cell and apoptotic body under the light microscopic.Found that: 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton handles vascular endothelial cell 24 and 48 hours, can obviously suppress the formation of apoptotic body and the morphological change (see figure 1) of apoptosis than matched group.
2, the condensing and karyorrhexis situation of fluorescence microscope nucleus:
Behind each group vascular endothelial cell removal serum and somatomedin, add 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, carry out AO dyeing, when under fluorescence microscope, observing apoptosis of vascular endothelial cell, the condensing and karyorrhexis situation of nucleus DNA.The result shows: the experimental group nucleus DNA is condensing and cracked to reduce (see figure 2) than matched group.
3, detect the activity of cell succinate dehydrogenase with mtt assay, to judge the vascular endothelial cell growth situation:
Vascular endothelial cell is inoculated in 96 well culture plates, through variable concentrations (20,40,60 μ g/ml) after 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is handled, surveyed succinic dehydrogenase activity with mtt assay respectively at 24 hours and 48 hours, calculate survival rate, survivaling cell %=(experimental group 0D value/matched group 0D value) * 100% (is blank group zeroing with not celliferous culture fluid).The result shows: the processed group cell survival rate significantly raises than matched group and is the dose dependent (see figure 7).
The influence of 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton cell growth the results are shown in following table:
4, Tunel dye marker apoptotic cell:
Behind each group vascular endothelial cell removal serum and somatomedin, adding 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton handled after 24 hours, with formalin fixed 25 minutes, 0.2%Triton X-100 handled 5 minutes, every hole adds 50 μ l rTdr Incubating Solutions, hatched SSC cessation reaction, certification mark apoptotic cell under 37 ℃ 1 hour.To following three groups of cell countings, calculate its positive rate (see figure 8) respectively.
The normal group cell did not almost have positive cell in 24 hours with the M199 culture fluid cultivation that contains serum and somatomedin;
Cellular control unit was removed serum and growth factor-2 4 hours, and positive cell is more;
The experimental group cell was handled 24 hours with 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, and positive cell significantly reduces than matched group.
The result shows: 3-benzyl-5-(2-nitro Phenoxymethyl) but-gamma-butyrolacton inhibition apoptosis of vascular endothelial cell (see figure 3).
5, old and feeble relevant beta galactosidase dyeing, to judge the cell ageing situation:
Behind each group vascular endothelial cell removal serum and somatomedin, add 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton and handle after 24 hours, with beta galactose dye liquor dyeing back observation.To 10 visuals field of following three groups of cell picked at random, counting cells sum and positive cell number, the calculating positive rate (see that Fig. 9 annotates:
#Normal group is contrasted in p＜0.05,
*P＜0.05 is according to matched group.)
The normal group cell, the M199 culture fluid that contains serum and somatomedin was cultivated 24 hours, and positive rate is lower;
Cellular control unit, the normal cell positive rate of place to go serum and somatomedin positive rate rises;
The experimental group cell, place to go serum and somatomedin were handled 24 hours with 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, and positive rate descends.
The result shows: 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton has reduced the positive cell ratio, suppresses the vascular endothelial senility (see figure 4).
6,3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton influence that film integrin β 4 is expressed:
To the expression of following three groups of cell membrane integrin β 4 carry out quantitative fluorescence analysis (see that Figure 10 annotates:
#Normal group is contrasted in p＜0.05,
*P＜0.05 is according to matched group).
The normal group cell, the M199 culture fluid that contains serum and somatomedin was cultivated 24 hours, and film integrin β 4 expresses lower;
Cellular control unit, it is expressed and raises behind removal serum and the somatomedin;
The experimental group cell was handled 24 hours with 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton behind removal serum and the somatomedin, and it expresses decline.
The result shows: add 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton and can reduce the expression of film integrin β 4 in removing serum and somatomedin cultured cell, suppress the vascular endothelial senility (see figure 5).
7,3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is to the influence of reactive oxygen species:
Following three groups of cytoactive oxygen levels are carried out quantitative fluorescence analysis (see Figure 11
##Normal group is contrasted in p＜0.01,
* *P＜0.01 is according to matched group .).
The normal group cell, the M199 culture fluid that contains serum and somatomedin was cultivated 24 hours, and reactive oxygen species is expressed lower;
Cellular control unit was removed serum and growth factor-2 4 hours, and reactive oxygen species significantly raises than whole normal group;
The experimental group cell is distinguished but the active oxygen expression decreases not have obviously than matched group.
The result shows: adding 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton can reduce reactive oxygen species but be not remarkable, suppresses the vascular endothelial senility (see figure 6) to a certain extent.
Above-mentioned experimental data statistical procedures:
Experimental data is represented with mean+/-standard error, checks through t: P＜0.05 expression has notable difference.
By above-mentioned experiment and result thereof, can draw as drawing a conclusion:
3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton concentration is when 20-60mg/L, can effectively suppress vascular endothelial senility and apoptosis, indication 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton suppresses in vascular endothelial senility and apoptosis medicine and the treatment cardiovascular disease medicine very big development prospect is arranged in preparation.
Description of drawings
Fig. 1 is normal group shown in the microscopically, matched group and the vascular endothelial cell after 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is handled 24 and 48 hours.
Wherein: A (24 hours), D (48 hours) are normal group; B (24 hours), E (48 hours) are matched group; C (24 hours), F (48 hours) are experimental group for normal group.
Fig. 2 be under the fluorescence microscope shown in normal group, matched group and handle the condensing and karyorrhexis of vascular endothelial cell center after 24 through 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton.
Wherein: A is normal group (24 hours); B is matched group (24 hours); C is experimental group (24 hours).
Fig. 3 is a Tunel dye marker apoptotic cell.
Wherein: A is normal group (24 hours); B is matched group (24 hours); C is experimental group (24 hours).
Fig. 4 is beta galactosidase dyeing, the old and feeble situation of showed cell.
Wherein: A is normal group (24 hours); B is matched group (24 hours); C is experimental group (24 hours).
Fig. 5 is the influence that 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is expressed film integrin β 4.
Wherein: A is normal group (24 hours); B is matched group (24 hours); C is experimental group (24 hours).
Fig. 6 is the influence of 3-benzyl-5 (2-nitro Phenoxymethyl)-gamma-butyrolacton to reactive oxygen species.
Wherein: A is normal group (24 hours); B is matched group (24 hours); C is experimental group (24 hours).
Fig. 7 is the activity that mtt assay detects the cell succinate dehydrogenase, statistics vascular endothelial cell survival rate.
Fig. 8 is a Tunel dyeing statistics cell positive rate.
Fig. 9 is a beta galactosidase dyeing statistics cell positive rate.
Figure 10 is that fluorescence staining shows that film integrin β 4 expresses, statistics film integrin β 4 expressions.
Figure 11 is that fluorescence staining shows reactive oxygen species.
Annotate: above-mentioned positive cell is an apoptotic cell.
The specific embodiment
The preparation of embodiment 13-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton
0.235 gram (10.22 mM) sodium metal is added in 10 milliliters of dehydrated alcohol, treat that the sodium reaction finishes after, begin to stir.Be warming up to 50 ℃, slowly drip ethanol (2 milliliters) solution of 2.503 gram (10.01 mM) diethyl benzyl malonates then.Be cooled to 37 ℃, add ethanol (2 milliliters) solution of 1.953 gram (10.02 mM) 3-(2-nitro-phenoxy)-1,2 epoxy prapanes.55 ℃ of reactions were cooled to below 15 ℃ after 3.5 hours, added 1 milliliter of acetic acid.Decompression steams ethanol, and residue adds 10 ml waters, with chloroform extraction three times (each 20 milliliters).Merge organic facies, use 5% NaHCO
3Solution is given a baby a bath on the third day after its birth time (each 6 milliliters), washes twice (each 6 milliliters), uses anhydrous magnesium sulfate drying, filters concentrating under reduced pressure.Residue adopts silica gel column chromatography to separate (developing solvent is a petrol ether/ethyl acetate=3: 1, volume ratio), obtains cis-and trans-3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton mixture (0.721 gram), yield 22%.
Structural formula is as follows:
Institute's cultured cells is divided into normal group cell, cellular control unit and experimental group cell.The normal group cell is cultivated with the M199 culture fluid that contains serum and somatomedin; Cellular control unit place to go serum and somatomedin are cultivated; The experimental group cell is handled with 3-benzyl-5-(2 nitro the Phenoxymethyl)-gamma-butyrolacton of 20～60mg/L concentration after removing serum and somatomedin.Three groups of cell culture after 24 hours all formaldehyde, 0.5% glutaraldehyde with 2% fix 5 minutes, afterwards be not with the beta galactose dye liquor wash-inferior, add the dye liquor that contains beta galactose and under 37 ℃ of no carbon dioxide conditions, hatched 18-24 hour.PBS cleans the back and observes.To 10 visuals field of above-mentioned three groups of cell picked at random, counting cells sum and positive cell number calculate the positive rate (see figure 9).The result shows that normal group cell positive rate is lower; The cellular control unit positive rate has remarkable rising than normal group; Its positive rate of processed group cell that 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton was handled after 24 hours significantly descends.
3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton has reduced the positive cell ratio, shows that 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton suppresses the vascular endothelial senility (see figure 4).
Embodiment 3
Institute's cultured cells is divided into normal group cell, cellular control unit and experimental group cell.The normal group cell is cultivated with the M199 culture fluid that contains serum and somatomedin; Cellular control unit place to go serum and somatomedin are cultivated; The experimental group cell is handled with 3-benzyl-5-(2-nitro the Phenoxymethyl)-gamma-butyrolacton of 20～60mg/L concentration after removing serum and somatomedin.Three groups of cell culture discarded culture fluid after 24 hours, fixed 15 minutes with 4% paraformaldehyde.After 0.1M PBS cleaning, add the normal serum confining liquid.Abandon confining liquid, add one anti-, abandon one anti-add two anti-, 37 ℃ following 30 minutes, discard two anti-ly, clean the back with 0.1M PBS and observe.Quantitative fluorescence analysis is carried out in expression to above-mentioned three groups of cell membrane integrin β 4.The result shows that normal group cell membrane integrin β 4 expresses lower; Cellular control unit, β 4 expresses and raises; The experimental group cell was handled 24 hours with 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton, and it is expressed significantly and descends.
3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton can reduce the expression of film integrin β 4 in removing serum and somatomedin cultured cell, suppresses the vascular endothelial senility (see figure 5).
Embodiment 4
3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is mixed with 5mg/L, 10mg/L, 20mg/L, 40mg/L, 60mg/L, 80mg/L, the 100mg/L isoconcentration, add respectively with in the vascular endothelial cell of removing serum and somatomedin, handled 24 hours, the variation of a cell of observation in per 4 hours under inverted microscope, the result sees: cellular control unit constantly breaks away from the culture plate bottom surface and floats in the culture fluid, cell forms apoptotic body gradually then, typical apoptosis promptly takes place, 54% cell survival was only arranged after 24 hours, and beta galactosidase staining cell positive rate is up to 36%; 3-benzyl-5-(2-nitro the Phenoxymethyl)-then less generation apoptosis of gamma-butyrolacton processed group cell, nuclear fragmentationization and DNA are condensing all to be suppressed, and the survival rate of this moment is 66～76%, and beta galactosidase staining cell positive rate drops to 21%.Illustrate that 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is under described experimental concentration, all present inhibition apoptosis of vascular endothelial cell and old and feeble phenomenon, particularly 3-benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton is when 20～60mg/L concentration, effectively inhibition apoptosis of vascular endothelial cell and aging.
Claims (2)
1.3-the application of benzyl-5-(2-nitro Phenoxymethyl)-gamma-butyrolacton in preparation inhibition vascular endothelial senility and apoptosis medicine.
2. application as claimed in claim 1 is characterized in that: (2-nitro Phenoxymethyl)-gamma-butyrolacton concentration is 20～60mg/L effectively to suppress the condensing 3-benzyl-5-of apoptosis, nuclear fragmentationization and DNA.
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| CN101095673B (en) * | 2007-07-06 | 2010-05-19 | 山东大学 | Application of 3-benzyl-5-(2-nitrophenoxymethyl)-gamma-butyrolactone |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4130511A (en) * | 1976-05-19 | 1978-12-19 | Ciba-Geigy Corporation | Curable epoxide resin compositions |
| WO1997038057A1 (en) * | 1996-04-05 | 1997-10-16 | Ve.Co S.R.L. | Neutral removers of paint from essentially metallic surfaces |
| US5994597A (en) * | 1998-11-06 | 1999-11-30 | International Business Machines Corporation | Process for recovering high boiling solvents from a photolithographic waste stream comprising less than 10 percent by weight monomeric units |
| CN1724525A (en) * | 2005-06-24 | 2006-01-25 | 山东大学 | Gamma-butyrolactone derivative and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4130511A (en) * | 1976-05-19 | 1978-12-19 | Ciba-Geigy Corporation | Curable epoxide resin compositions |
| WO1997038057A1 (en) * | 1996-04-05 | 1997-10-16 | Ve.Co S.R.L. | Neutral removers of paint from essentially metallic surfaces |
| US5994597A (en) * | 1998-11-06 | 1999-11-30 | International Business Machines Corporation | Process for recovering high boiling solvents from a photolithographic waste stream comprising less than 10 percent by weight monomeric units |
| CN1724525A (en) * | 2005-06-24 | 2006-01-25 | 山东大学 | Gamma-butyrolactone derivative and its preparation method |
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