CN101906118A - Method for synthesizing mitochondria targeted spinning scavenger MitoPBNs (spinning probe) - Google Patents
Method for synthesizing mitochondria targeted spinning scavenger MitoPBNs (spinning probe) Download PDFInfo
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- CN101906118A CN101906118A CN2010101646959A CN201010164695A CN101906118A CN 101906118 A CN101906118 A CN 101906118A CN 2010101646959 A CN2010101646959 A CN 2010101646959A CN 201010164695 A CN201010164695 A CN 201010164695A CN 101906118 A CN101906118 A CN 101906118A
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Abstract
The invention discloses a method for preparing a mitochondria targeted spinning scavenger MitoPBNs (spinning probe). The structural formula of the MitoPBN is shown in a formula (I). A synthesis flow is shown in the formula (II), and comprises the following steps of: performing elimination reaction on 4-hydroxybenzaldehyde and dibromo-straight-chain paraffin under alkali condition to prepare a compound 3; reacting the compound 3 with triphenylphosphine to prepare the compound 4; in ethanol, mixing the compound 4, 2-nitro-2-methylpropane, a 4A molecular sieve and zinc powder in a solvent, adding dropwise a glacial acetic acid, stirring and reacting the mixed solution at room temperature, placing the mixed solution in a refrigerator for refrigeration, and performing separation and purification to prepare the spinning probe MitoPBN; and performing liposome packing treatment. The method has the characteristics of relatively fewer synthesis steps, low raw material cost, readily available raw materials and relatively higher product purity. The probe for scavenging free radical signals can enter cell mitochondria.
Description
Technical field
The present invention relates to a kind of simple and practical preparation method of MitoPBN series compound, the present invention has that synthesis step is shorter, and raw material is cheap and easy to get, the characteristics that product purity is higher relatively.Its function can enter cell mitochondrial to the probe of Mulberry Extract signal, by the survey of picking up to the probe binding substances, and the change information of the reduction of observation analysis cellular oxidation in early days microenvironment, but and early intervention.Thereby can realize to the early warning of diseased region with to the early prevention and treatment of disease.
Background technology
Ceaselessly produce in the body and contain oxygen and nitrogenous free radical material (ROS and RNS), they are playing the part of very important role in vital movement.Free radical constantly produces in the physiological conditions lower body, also constantly is eliminated, and number of free radical is remained among the running balance.When some factor causes this dysequilibrium, relevant diseases will appear in body, as cancer, inflammation, aging etc.The harm of free radical mainly is the damage biomacromolecule.(1) damage of radical pair DNA: studies have shown that, DNA hydrogen splitting of chain in the cell that free radical causes, base degraded and main chain untwist.These damages may be nonvolatil, also can be repaired, but the dna mutation rate after repairing are much larger than the mutation rate of normal DNA.(2) damage of radical pair biomacromolecule: mainly, cause structure and spatial conformational change, cause peptide splitting of chain, polymerization, change connection by the modified amino acid residue.(3) other macromolecular toxic actions of radical pair: have and studies have shown that free radical can damage biological polyoses, hyaluronic acid. unsaturated fatty acids etc.Oxyradical can make monose generation autoxidation, causes a series of seizures of disease.
The spin trapping agent generates the characteristic of stabilized radical, oneself because of itself and the combined with radical of high reaction activity
Just detecting free radical, exhibited one's skill to the full in the scientific research of exploration free radical and biomechanism thereof since the appearance.In recent decades, the spin trapping agent has been obtained rapidly development, so far bibliographical information be used to spin the compound of catching reached hundreds of more than.On the other hand, because the spin trapping agent has the effect of certain removing free radical,, it has extraordinary prospect so being used for the treatment of the disease that radical damage causes.Nitrone compound reduce and the prevention living things system in free radical cause aspect the damage therapeutic action nineteen ninety by OliverC., Starke-Read P., StadmanE., Liu G., Carncy J., Floyd R.Natl.Acad.USA (1990) 87,5144-5147 prove.
Traditional theory thinks that the topmost generation of free radical place is positioned at plastosome in the body, because plastosome is the supplier of cellular energy.Electronegative in the mitochondrial membrane, film is outer positively charged, so positively charged organic molecule can enter in the mitochondrial membrane under the driving of electrical forces.Based on this theory, Martin D.Brand etc. with season phosphonium salt link together with spin trapping agent PBN, be positioned in the mitochondrial membrane in order to target, intervene free radical situation wherein.See document for details: Speroxide Activates Uncoupling Proteins by Generating Carbon-centeredRadicals and initiating Lipid Peroxidation-studies using amitochondria-targeted spin trap derived from α-phenyl-N-tert-butylnitron.2003; 278 (49): its synthetic route of 48534-48545. is suc as formula shown in (I).
Formula (I)
This route need be used iodo compound, and there is the raw material costliness in metal hydride, severe reaction conditions, and preparation procedure is loaded down with trivial details, and productive rate is not high, the shortcoming that product purity is not high, these have all seriously limited the research in this field.And there is not liposome-treated can have detection and an intervention to redox microenvironment in the born of the same parents as yet.
Summary of the invention
The purpose of this invention is to provide a kind of easy, the with low cost highly purified method for preparing MitoPBN.
The method that the invention provides the Mitochondrially targeted localized spin trapping agent MitoPBN of preparation can be used as the preparation of spin probe, the steps include:
1) p-Hydroxybenzaldehyde and two bromo straight-chain paraffins are reacted under alkaline condition, obtain the compound of formula structure
2) compound and the triphenyl phosphorus with the formula structure reacts the season phosphonium salt that obtains the formula structure in solvent.
3) in solvent, under the condition of ice bath, season phosphonium salt, 2 nitros-2 alkyl propane and the zinc powder of formula structure are mixed by 1/3/10 equivalence ratio, add the 4A molecular sieve again, drip glacial acetic acid then, glacial acetic acid and season phosphonium salt equivalence ratio be 5/1, be added dropwise to complete in 1 hour, add the back and continue under ice bath, to stir 6 hours, place 4 degrees centigrade of refrigerators to deposit then, separate after post.
The described alkali of step 1) is organic bases or mineral alkali, and organic bases is diethylamine, triethylamine, pyridine, diisopropylamine, 2, tetrabutyl ammonium fluoride; Described mineral alkali is yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus or sodium hydride.
The described reaction times of step 1) is 10 minutes-two weeks.
Step 2) Fan Ying solvent is ethanol, methyl alcohol, benzene, toluene or acetone, and the reaction times is 10 minutes-two weeks.
The described refrigerator shelf-time of step 3) is 1 hour-two week.
The spin probe that the described target compound of step 4) is prepared into the 20-500 nanometer with liposome-treated is used for the detection and the intervention of redox microenvironment in the pair cell.
Cost of material of the present invention is cheap, the reaction conditions gentleness, and reactions steps is shorter, and purification of intermediate is easy, and the product purity height can be applicable to diseased region early warning and early intervention.Present method is easy to realize a large amount of synthetic, can realize commercialization production.
Description of drawings
Fig. 1 is the proton nmr spectra of 4-(4-bromination of n-butane oxygen base) phenyl aldehyde;
Fig. 2 is the proton nmr spectra of (4-(4-butoxy) phenyl aldehyde) triphenylphosphine bromine salt;
Fig. 3 is the proton nmr spectra of MitoPBN.
Embodiment
Embodiment MitoPBN's is synthetic
1) 4-(4-bromine butoxy) phenyl aldehyde is synthetic: add p-Hydroxybenzaldehyde 2.0 grams (16.4mmol) in the 250mL reaction flask, 4.5 gram (32.8mmol, 2eq) Anhydrous potassium carbonate, 2.5mL 1,4-dibromobutane and 50 milliliters of DMF react after 12 hours, reaction solution is poured in the 150mL frozen water, with ethyl acetate extraction (50mL * 4), merge organic phase, once with the 100mL washing.Organic phase with anhydrous magnesium sulfate drying after, filter, underpressure distillation must concentrate crude product.Crude product separates purification (eluent: ethyl acetate/petroleum ether=1/3) with silica gel column chromatography.Get product 3.1g, productive rate 73%.
1H?NMR(400MHz，CDCl
3)：δ9.84(s，1H)，7.78(d，J＝5.6Hz，2H)，6.95(d，J＝3.2Hz，2H)，4.04(t，2H)，3.46(t，2H)，2.01-2.05(m，2H)，1.93-1.97(m，2H)。
2) season phosphonium salt A's is synthetic:
In the 100mL reaction flask, add 4-(4-bromine butoxy) 2.6 grams (10mmol), (30mmol, 3eq), the 50mL acetonitrile refluxed 12 hours triphenyl phosphorus 7.3g.Then with the reaction solution evaporate to dryness, add the dissolving of 5mL methylene dichloride, impouring 50mL ethyl acetate immediately, the adularescent precipitation is separated out, filter thick product.With the thick product of silica gel chromatography (eluent: methylene dichloride/acetone/methanol=10/2/1), get pure season phosphonium salt A 4.3 grams, productive rate 82.6%.
1H?NMR(400MHz，CDCl
3)：δ9.82(s，1H)，7.81-7.85(m，6H)，7.74-7.77(m，5H)，7.63-7.67(m，6H)，6.91(d，J＝2.6Hz，2H)，4.19(t，J＝4.2Hz，2H)，3.95(t，J＝8.4Hz，2H)，2.22-2.27(m，2H)，1.82-1.89(m，2H)。
3) MitoPBN's is synthetic: add season phosphonium salt A 0.5 gram (1mmol) in the 50mL reaction flask, activated zinc powder 0.65 gram (10mmol, 10eq), 2-nitro-2-methylpropane 0.3 gram (3mmol, 3eq), 4A molecular sieve 1 gram, dehydrated alcohol 10mL.Add 5mL ethanol in the dropping funnel, 0.3 gram glacial acetic acid under ice bath, adds to the drips of solution in the dropping funnel in the reaction flask in 1 hour.Ice bath reacted 12 hours down, was transferred to 4 ℃ of refrigerator cold-storages then 7 days.Filter, filter residue 5mL absolute ethanol washing, concentrating under reduced pressure filtrate gets crude product.Crude product silica gel chromatography (eluent: methylene dichloride/acetone/methanol=10/2/1), get pure MitoPBN0.27 gram, productive rate 48%.
1H?NMR(400MHz，CDCl
3)：δ8.24(d，J＝3.8Hz，1H)，7.80-7.84(m，6H)，7.75-7.76(m，3H)，7.64-7.68(m，6H)，7.49(s，1H)，6.84(d，J＝3.8Hz，2H)，4.15(t，J＝4.4Hz，2H)，3.91(t，J＝11.2Hz，2H)，2.22-2.27(m，2H)，1.8-1.88(m，2H)，1.60(s，9H)。
Claims (7)
1. synthetic method for preparing MitoPBN (spin probe) series compound of structure is characterized in that may further comprise the steps:
1) p-Hydroxybenzaldehyde and two bromo straight-chain paraffins are reacted under alkaline condition, obtain the compound of formula (I) structure,
Wherein: n is the integer between 2 to 18.
2) compound and the triphenyl phosphorus of formula (I) structure reacted the formula that obtains (III) structure in solvent season phosphonium salt,
Wherein: n is the integer between 2 to 18.
3) in solvent, under the condition of ice bath, season phosphonium salt, 2 nitros-2 alkyl propane and the zinc powder of formula (II) structure are mixed by 1/3/10 equivalence ratio, add the 4A molecular sieve, drip glacial acetic acid then, glacial acetic acid and season phosphonium salt equivalence ratio be 5: 1, be added dropwise to complete in 1 hour, add the back and continue under ice bath, to stir 6 hours, place 4 degrees centigrade of refrigerators to deposit then, separate with chromatographic column again, get target product.
2. method according to claim 2 is characterized in that the described alkali of step 1) is organic bases or mineral alkali, and organic bases is diethylamine, triethylamine, pyridine, diisopropylamine, 2, tetrabutyl ammonium fluoride; Described mineral alkali is yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus or sodium hydride.
3. method according to claim 2 is characterized in that the described reaction times of step 1) is 10 minutes-two weeks.
4. method according to claim 2 is characterized in that step 2) reaction solvent be ethanol, methyl alcohol, acetonitrile, benzene, toluene or acetone.
5. method according to claim 2 is characterized in that step 2) the described reaction times is 10 minutes-two weeks.
6. method according to claim 2 is characterized in that the described refrigerator shelf-time of step 3) is 1 hour-two week.
7. method according to claim 2, it is characterized in that step 4) the spin probe target compound through liposome-treated, make particle diameter accomplish 20 to 500 nanometers, be used to enter cell and catch the spin signal, change cellular oxidation reduction microenvironment.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104804029A (en) * | 2014-01-23 | 2015-07-29 | 中国科学院烟台海岸带研究所 | Fluorine-boron pyrrole compound and applications thereof |
| CN106432312A (en) * | 2016-09-22 | 2017-02-22 | 武汉大学 | Mitochondria target fluorescence probe, as well as preparation method and application thereof |
| CN106562929A (en) * | 2016-03-01 | 2017-04-19 | 常州莱道斯生物医药科技有限公司 | Method for preparing novel lipidosome-coated spinning targeted nanoparticle L-MPBN medicinal compound |
| CN107510848A (en) * | 2016-06-15 | 2017-12-26 | 常州莱道斯生物医药科技有限公司 | Applications of the Mitochondrially targeted preparation MitoPBN in diabetes are prevented and treated |
| CN110151700A (en) * | 2019-06-06 | 2019-08-23 | 复旦大学 | Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament |
-
2010
- 2010-05-05 CN CN2010101646959A patent/CN101906118A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| LINSEY ROBERTSON， ET AL.: "Synthesis of N-arylpyridinium salts bearing a nitrone spin trap as potential mitochondria-targeted antioxidants", 《TETRAHEDRON》 * |
| MICAEL HARDY， ET AL.: "Mito-DEPMPO synthesized from a novel NH2-reactive DEPMPO spin trap: a new and improved trap for the detection of superoxide", 《CHEM. COMM.》 * |
| MICHAEL P. MURPHY， ET AL.: "Superoxide Activates Uncoupling Proteins by Generating Carbon-centered Radicals and Initiating Lipid Peroxidation", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104804029A (en) * | 2014-01-23 | 2015-07-29 | 中国科学院烟台海岸带研究所 | Fluorine-boron pyrrole compound and applications thereof |
| CN106562929A (en) * | 2016-03-01 | 2017-04-19 | 常州莱道斯生物医药科技有限公司 | Method for preparing novel lipidosome-coated spinning targeted nanoparticle L-MPBN medicinal compound |
| CN107510848A (en) * | 2016-06-15 | 2017-12-26 | 常州莱道斯生物医药科技有限公司 | Applications of the Mitochondrially targeted preparation MitoPBN in diabetes are prevented and treated |
| CN106432312A (en) * | 2016-09-22 | 2017-02-22 | 武汉大学 | Mitochondria target fluorescence probe, as well as preparation method and application thereof |
| CN106432312B (en) * | 2016-09-22 | 2019-01-29 | 武汉大学 | A kind of Mitochondrially targeted fluorescence probe and its preparation method and application |
| CN110151700A (en) * | 2019-06-06 | 2019-08-23 | 复旦大学 | Nano-MitoPBN is preparing the application in anti-oxidant and treatment diabetes medicament |
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