CN106397439A - Spin-labeling luotonin A compound as well as preparation method and application thereof - Google Patents
Spin-labeling luotonin A compound as well as preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
Abstract
The invention discloses a spin-labeling luotonin A compound of formula (I) as shown in the specification, as well as a preparation method and application of the compound. In-vitro antitumor activity screening results show that compared with luotonin A, the spin-labeling luotonin A compound disclosed by the invention is relatively intense in inhibition activity on human lung adenocarcinoma cells (A549), human breast cancer cell lines (MDA-MB-468), human ovarian neoplasm cells (SKOV3) and human colon cancer cell lines (HCT 116), and has good application prospects.
Description
Technical field
The present invention relates to a kind of peaceful alkali A compound of spin labeling camel, and the preparation method of this compound and its
Prepare the purposes in antineoplastic.Belong to field of medicaments.
Background technology
Camel peaceful alkali A is 1997 from medicinal plants in China camel wormwood artemisia (Peganum nigellastrum Bunge.)
A kind of natural quinazoline alkaloid isolated.The concern to camel peaceful alkali A for the researcher, is primarily due to find camel
Peaceful alkali A has similar chemical constitution with the camptothecine with active anticancer, and in vitro to mouse tumor cell P388 cell
There is inhibitory action (IC in system501.8 μ g/mL), and demonstrate it have similar camptothecine suppression topoisomerase I activity ((1)
Molecules,2011,16,4861-4883).Based on this, researcher, with camel peaceful alkali A as pilot model, is in recent years
Unite and carried out fully synthetic, structure optimization and the antitumor activity evaluation research ((1) of camel peaceful alkali A and its derivative
Org.Biomol.Chem.,2007,5,2486–2490；(2)Bioorganic&Medicinal Chemistry,2007,15,
4237–4246；(3)Tetrahedron Letters,2011,52,1592–1596；(4)Tetrahedron Letters
2004,45,6721–6723；(5) TetrahedronLetters, 1998,39,9097-9098).Although research work in recent years
Person has done substantial amounts of research work in the derivative synthesis of the peaceful alkali of camel and antitumor structure-activity relationship, but camel peaceful alkali A is as one
Individual antitumor guide's molecule, still suffers from that antitumor activity is low and the narrow problem of activity profile, or even through, after derivative and structural modification, spreading out
Biological antitumor activity cannot be effectively improved or completely lose.And do not have one effectively to modify and optimize plan so far yet
Slightly to improve the antitumous effect of this quasi-molecule.
Content of the invention
It is an object of the invention to provide a kind of new peaceful alkali cpd of spin labeling camel, meanwhile, the present invention's is another
Purpose is preparation method and its purposes in antineoplastic providing this compound.
A kind of new peaceful alkali cpd of spin labeling camel of the present invention has the chemical constitution shown in formula 1, is designated as
Spin labeling camel peaceful alkali A compound：
In recent years, many experiments confirm that stable nitrogen-oxygen free radical has clear and definite antitumor activity, in vivo and in vitro to many
Plant tumour and there is selective inhibitory, chemotherapy and radiation effect can be increased and reduce its side effect, it is encouraging that answering
Can prevent and delay the generation of tumour for a long time with stable nitrogen-oxygen free radical and non-evident effect it is considered to be most clinical should
Field ((1) J.Heterocyclic Chem.2005,42,437～449 with potentiality；(2)FreeRadic.Biol.&
Med.2007,42,1632～1650.).Particularly stable nitrogen-oxygen free radical is marked in antineoplastic molecule to improve it
Pharmacodynamic profiles become its optimization design antineoplastic a kind of Critical policies (Pure＆Appl.Chem.1990,62,289～
294.).The thio-tepa of stable nitrogen-oxygen free radical mark (or referred to as spin labeling), nitroso ureas, mustargen, cis-platinum class alkylating agent
(Acta Pharm.Sin.1988,23,792～798)；Podophyllotoxin analogues ((1) Anticancer Drug Des.1993,
8,193～202；(2) Europ.J.Med.Chem.2014,75,282～288), 5-fluor-uracil (SCI,
1992,13,1561～1563.), adriamycin (SCI, 2000,21,884～887), rotenone
(Bioorg.Med.Chem.Lett.2012,22,920～923) and CA-4 (Bioorg.Med.Chem.2013,21,1248
～1256) etc. by a large amount of derivative synthesis, its pharmacologically active evaluation shows antibumor molecules：Some stable nitrogen-oxygen free radicals can be rapid
Pass through cell membrane and blood-brain barrier, be connected with some cancer therapy drugs as carrier, drug delivery can be promoted through carefully preferential
After birth is it is easy to accumulate in tumor tissues, so that the active anticancer of its medicine keeps even increasing, enables parent drug more preferably
Play antitumor activity.
Accordingly, in order to improve the antitumor activity of camel peaceful alkali A, the antitumor structure-activity relationship with existing camel peaceful alkali A is
Clue, the present invention on the basis of retaining the biocompatibility that has of camel peaceful alkali A guide structure and quasi-medicated property, by fully synthetic
Devise a kind of spin labeling camel peaceful alkali A compound of " being fitted together to " type, show that the present invention's is this through further evaluation experimental
Compound is to human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-468), Proliferation of Human Ovarian Cell (SKOV3) and people
4 kinds of tumor cell lines of the thin strain of colon cancer (HCT 116) have preferable inhibitory activity.
Preparation method of the present invention is carried out by following chemical equation：
Spin labeling camel peaceful alkali cpd preparation method as shown in reaction equation 2, will phthalic anhydride 1 and benzylamine molten
In appropriate glacial acetic acid, it is heated to reflux obtaining intermediate 2, then intermediate 2 is dissolved in appropriate dimethylbenzene, inert gas
Under protection between 60～70 DEG C under be slowly added to methylpyridinium iodide magnesium in aforementioned liquids, then reactant liquor is gradually heated to 165
DEG C～180 DEG C of back flow reaction 2 hours, reaction removes most of solvent under reduced pressure after terminating at this temperature, is subsequently cooled to room temperature,
It is added thereto to bulk petroleum ether and obtains turbid solution, passed through suction filtered through kieselguhr, collect all filtrates, filtrate is placed in the air
Chromatographed with alkali alumina again after 24 hours, concentrated after obtain product 3, then add 20～30 milliliters in product 3
Glacial acetic acid makes it dissolve, and is subsequently adding 10% palladium carbon, after stirring protects reaction system in the inert gas of 4 atmospheric pressure
Fully reacted under shield, faint yellow intermediate products 4 will be concentrated to give after reactant liquor separation of solid and liquid, intermediate 4 is dissolved in 50 millis
In methyl alcohol/acetonitrile=14/1 (volume ratio) rising, then sequentially add sodium acid carbonate (15eq), Disodium tungstate (Na2WO4) dihydrate
(0.55eq), it is eventually adding the hydrogen peroxide solution of 30% (volume ratio), this muddy reactant liquor is sufficiently stirred for reacting, instead at normal temperatures
A small amount of water quenching should be added after terminating to go out reaction, remove solvent, add appropriate water and the sulfuric acid solution of 1N to be extracted, be associated with
Machine phase, after magnesium sulfate dry filter, obtains yellow product 5 after reduced pressure concentration, slow in intermediate 5 under condition of ice bath,
The concentrated sulfuric acid will be added and stir, stirring under condition of ice bath will be placed on reaction 20 minutes in 60 DEG C of oil bath, so after 30 minutes
It is placed on afterwards in ice bath again, fuming nitric aicd is added dropwise in above-mentioned solution, after completion of dropping, stir under condition of ice bath
Reaction is stirred overnight under normal temperature after 30 minutes again, next day, this Chinese red reactant liquor is heated to 100 DEG C and reacts 20 minutes, then
Be placed in ice bath, the sodium hydroxide solution of 10% (mass ratio) be slowly added thereto regulation pH value to 8 about, with chloroform by its
Extracted, merged organic phase, filtered after being dried with magnesium sulfate, reduced pressure concentration is obtained yellow solid 6, intermediate 6 is used methyl alcohol molten
Solution, then add 10% dry palladium carbon wherein, stir, with pressurized with hydrogen to 1 atmospheric pressure, stirring reaction 6 hours, reaction
Filter after end, reduced pressure concentration filtrate obtains yellow solid 7, then intermediate 7 is dissolved in methyl alcohol, is subsequently adding copper acetate acetic acid
Copper (0.128eq), stirring reaction 3 hours under normal temperature, reaction is quenched reaction with chloroform after terminating, and obtains solid residue after concentration, with
Petrol ether/ethyl acetate obtains flaxen solid pure product 8 for eluant, eluent through column chromatography, compound 9 is first dissolved in the two of drying
In the middle of chloromethanes, add the DMF of catalytic amount, then oxalyl chloride is dissolved in 30～50 milliliters of dry methylene chloride, ice bath bar
Slowly to be instilled in above-mentioned reactant liquor under part, reactant liquor reduced pressure concentration was obtained solid crystal, by it after 1.5 hours by reaction
Be re-dissolved in dry methylene chloride, and be slowly dropped into containing intermediate 8 (1.5eq) under condition of ice bath, sodium acid carbonate (4.5eq)
30～50 milliliters of dry methylene chloride solution in react, reaction adds water quenching to go out reaction after terminating, and is reacted with chloroform extraction
Liquid, merges organic phase, obtains solid residue with reduced pressure concentration after magnesium sulfate dry filter, with chloroform/methanol for eluant, eluent through post layer
Analysis purifying obtains yellow solid product 10, product 10 (3.6mmol) is dissolved in toluene (50mL) and water (0.2mL), Ran Houyi
Secondary addition potassium carbonate (7.2mmol), lithium bromide (7.2mmol), TBAB (0.4mmol), propargyl bromide (5.7mmol), then will be anti-
80 DEG C should be warming up to fully react, react the solid residue of reactant liquor reduced pressure concentration after terminating, with chloroform/methanol as eluant, eluent
Purify through column chromatography and obtain crocus solid product 11, triphenylphosphine oxide (2.75eq) is dissolved in 30～50 milliliters dichloromethane is dried
In alkane, under condition of ice bath, trifluoromethanesulfanhydride anhydride (1.38eq) is dissolved in 30～50 milliliters of dry methylene chloride, then will be molten
The dichloromethane having trifluoromethanesulfanhydride anhydride lentamente drips the dichloromethane solution entering dissolved with triphenylphosphine oxide, in zero degrees celsius
Lower stirring reaction 30 minutes, intermediate 11 is dissolved in 30～50 milliliters of dry methylene chloride, is delayed under condition of ice bath
Slowly it is added drop-wise to dissolved with the dichloromethane solution of trifluoromethanesulfanhydride anhydride, stirring is simultaneously fully reacted, add 10% (body after completion of the reaction
Long-pending ratio) sodium bicarbonate aqueous solution reaction is quenched, after reduced pressure concentration solid residue, with chloroform/methanol for eluant, eluent through post layer
Analysis purifying obtains crocus target compound 12.
Show through anti tumor activity in vitro the selection result, the spin labeling white horse with a black mane compared with camel peaceful alkali A, synthesized by the present invention
The peaceful alkali A compound of camel is to human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-468), Proliferation of Human Ovarian Cell
And the thin strain of human colon carcinoma (HCT 116) shows stronger inhibitory activity (SKOV3).Therefore, the compound of present invention synthesis can
For preparing anti-tumor drug.The peaceful alkali A compound structure of spin labeling camel of the present invention is novel, product purity is high,
Stronger inhibitory action is shown to tumour cell, there is good application prospect.
Below by way of specific embodiment, the above of the present invention is described in further detail.But should not be by this
It is interpreted as the limit to the present invention.
Specific embodiment
First, the preparation method of the peaceful alkali cpd of spin labeling camel of the present invention
The following is the optimal preparation method of the peaceful alkali cpd of spin labeling camel of the present invention：
1) synthesis of intermediate 2：Phthalic anhydride (1.69eq) is placed in appropriate glacial acetic acid, then by benzylamine
(2.3eq) slowly it is added thereto.After this mixture heating reflux reaction 5 hours, hot reactant liquor is directly poured into frozen water
In, a large amount of precipitations occur, with cold water, filter cake is rinsed several times after suction filtration, obtain compound 2 after drying (with reference to Chemistry A
European Journal,2009,15(47):12960-12962), referring to formula 6.
2) synthesis of intermediate 3：First, whole reaction unit is evacuated, and is replaced 3～5 times with argon gas, then will
Methylpyridinium iodide magnesium (6eq) is squeezed in round-bottomed flask with syringe, is heated to 90 degrees Celsius, and decompression pumps solvent ether, directly
To the no longer bubbling of the liquid in round-bottomed flask, recover normal pressure and be down to 60 degrees Celsius.Then by intermediate 2 (1eq)
It is dissolved in appropriate dimethylbenzene, it is lentamente squeezed in reaction bulb with syringe, keep reactant liquor to obtain temperature and take the photograph 60～70
Between family name's degree.After injection finishes, after reactant liquor is heated to 165 degrees Celsius of back flow reaction 2 hours, decompression at this temperature boils off
Half solvent；Then reaction temperature is risen to 180 degrees Celsius in back flow reaction 2 hours, reaction is reduced pressure after terminating at this temperature
Most of solvent is evaporated off, is subsequently cooled to room temperature, be added thereto to bulk petroleum ether and obtain turbid solution, taken out by diatomite
Filter, and rinse filter cake several times with petroleum ether, collect all filtrates, after filtrate is placed in the air 24 hours, solution assumes purple
Rowland color.This purple organic solvent is chromatographed with alkali alumina, is collected the organic solvent after all chromatographies, decompression again
Obtain final products after concentration, be in colorless oil in the state of heat, white solid crystal 3 (reference Chemistry A after cooling
European Journal,2009,15(47):12960-12962), referring to formula 7.
3) synthesis of intermediate 4：Intermediate 3 (621mg) is placed in the liner of autoclave, adds appropriate glacial acetic acid to make it
Dissolving, is subsequently adding 10% dry palladium carbon (56.5mg), seals autoclave, use hydrogen by inside reaction system after stirring
Displacement 3～5 times, finally will be flushed with hydrogen gas till 4 atmospheric pressure in system.After reaction 5 hours, by this reacting liquid filtering, filter
Cake is rinsed with dichloromethane, will be soluble in water after filtrate reduced in volume, then uses 10% sodium hydroxide solution regulation pH value to 9
Left and right, with chloroform extraction 3 times, combining extraction liquid, after magnesium sulfate dry filter, obtains light yellow product 4 (ginseng after reduced pressure concentration
Examine Australian Journal ofChemistry, 1983,36 (2):397-401), referring to formula 8.
4) synthesis of intermediate 5：Intermediate 4 (18.8eq) is dissolved in appropriate methyl alcohol/acetonitrile=14/1, then successively
Add sodium acid carbonate (15eq), Disodium tungstate (Na2WO4) dihydrate (0.55eq), be eventually adding 30% hydrogen peroxide solution (62eq), this is muddy
Reactant liquor stirring reaction two days at normal temperatures, reaction adds a small amount of water quenching to go out reaction after terminating.Decompression boils off solvent, adds appropriate
Water and the sulfuric acid solution of 1N extracted, merge organic phase, after magnesium sulfate dry filter, obtain yellow after reduced pressure concentration and produce
Product 5 (with reference to Australian Journal ofChemistry, 1983,36 (2):397-401), referring to formula 9.
5) synthesis of intermediate 6：Intermediate 5 (7.07mmol) is placed in round-bottomed flask, by dense sulphur under condition of ice bath
Sour (13.5mL) is slowly dropped into wherein and stirs, and now solution is in bronzing.Will after about stirring half an hour under condition of ice bath
It is placed in 60 degrees Celsius of oil bath and reacts 20 minutes, is then placed in ice bath again.Treat that it is cooled to zero degrees celsius, will send out
Cigarette nitric acid (19.1mmol) is added dropwise in above-mentioned solution, and after completion of dropping, under condition of ice bath, stirring reaction is after 30 minutes
It is stirred overnight under normal temperature again.Next day, this Chinese red reactant liquor is heated to 100 degrees Celsius and reacts 20 minutes, be subsequently placed in ice bath
In, 10% sodium hydroxide solution is slowly added thereto regulation pH value to 8 about.Extracted with chloroform, be associated with
Machine phase, is filtered after being dried with magnesium sulfate, and reduced pressure concentration obtains yellow solid 6 (with reference to (1) Australian Journal
ofChemistry,1983,36(2):397-401；(2)Bioconjugate Chemistry,2013,24(6):1110-
1117), referring to formula 10.
6) synthesis of intermediate 7：Intermediate 6 (6.38mmol) is placed in autoclave liner and with proper amount of methanol dissolving,
Add 10% dry palladium carbon (150mg), stir, with hydrogen, autoclave is replaced 3～5 times, finally use pressurized with hydrogen
To 1 atmospheric pressure, stirring reaction 6 hours.Reaction is filtered after terminating, and reduced pressure concentration filtrate obtains yellow solid 7 (reference
Organic&Biomolecular Chemistry,2013,11(25):4147-4153.), referring to formula 11.
7) synthesis of intermediate 8：Intermediate 7 (6.38eq) is dissolved in appropriate methyl alcohol, is subsequently adding copper acetate
(0.128eq), stirring reaction 3 hours under normal temperature.Reaction is quenched reaction with chloroform after terminating, and obtains solid residue after reduced pressure concentration,
Flaxen solid pure product 8 (reference (1) Organic＆ is obtained for eluant, eluent through column chromatography with petrol ether/ethyl acetate
Biomolecular Chemistry,2013,11(25):4147-4153；(2)Journal of the American
Chemical Society,1975,97(5):1273-1274), referring to formula 12.
8) synthesis of intermediate 10：Compound 9 (3eq) is first dissolved in, in the middle of the dichloromethane of drying, adding catalytic amount
DMF, then oxalyl chloride (9eq) is dissolved in appropriate dry methylene chloride, with constant pressure funnel dropwise by it under condition of ice bath
Enter in above-mentioned reactant liquor.Reactant liquor reduced pressure concentration was obtained solid crystal after 1.5 hours by reaction, was re-dissolved in dry methylene chloride
In, and it is dropwise instilled containing intermediate 8 (1.5eq) under condition of ice bath, the dry methylene chloride of sodium acid carbonate (4.5eq) is molten
In liquid.TLC monitors reaction process, and reaction adds water quenching to go out reaction after terminating, and uses chloroform extraction reactant liquor, merging organic phase,
Solid residue is obtained with reduced pressure concentration after magnesium sulfate dry filter, is purified through column chromatography for eluant, eluent with chloroform/methanol and obtain yellow
Solid product 10, referring to formula 13.
9) synthesis of intermediate 11：Intermediate 10 (3.6mmol) is dissolved in toluene (50mL) and water (0.2mL), then
Sequentially add potassium carbonate (7.2mmol), lithium bromide (7.2mmol), TBAB (0.4mmol), propargyl bromide (5.7mmol), then will
Reaction is warming up to 80 degrees Celsius, reacts 2 hours.React the solid residue of reactant liquor reduced pressure concentration after terminating, with chloroform/methanol
Purify through column chromatography for eluant, eluent and obtain crocus solid product 11, referring to formula 14.
10) synthesis of the peaceful alkali of the camel of spin labeling 12：Triphenylphosphine oxide (2.75eq) is dissolved in dry dichloromethane
In, under condition of ice bath, trifluoromethanesulfanhydride anhydride (1.38eq) is dissolved in appropriate dry methylene chloride and lentamente dropping enters
Above-mentioned solution, stirring reaction 30 minutes under zero degrees celsius.Intermediate 11 (0.92eq) is dissolved in appropriate dry methylene chloride
In, it is slowly added dropwise under condition of ice bath in the above-mentioned solution of entrance.TLC monitors reaction process, adds 10% after completion of the reaction
Sodium bicarbonate aqueous solution reaction is quenched.Obtain solid residue after reduced pressure concentration, purified through column chromatography for eluant, eluent with chloroform/methanol
Obtain crocus target compound 12.
IR(KBr):3438,2982,1678,1628,1609,1576,1487,1468,1442,1385,1367(NO·),
1239,776,694,638cm-1；MS-ESI m/z:399.2[M+2H]+；ESR:G=2.0079.
2nd, the test method of antitumor activity of the peaceful alkali of spin labeling camel and result
The pharmacological evaluation of the present invention adopts Sulforhodamine B (sulforhodamine B, SRB) colorimetric method.Tumour cell
From the RPMI-1640 culture medium of 10% hyclone (FBS), by tumor cell inoculation in 96 orifice plates, each hole is cultivated for culture
3-5 × 103 cell, adds the solution title compound to be tested of variable concentrations.After culture 72 hours, every hole adds precooling
Solution of trichloroacetic acid (50%, w/v) fixes cell, fixes 30 minutes in refrigerator.After drying under 96 orifice plate room temperatures, every hole adds
The SRB dye liquor (1% peracetic acid formulation, purchased from Sigma Chemical company) of 0.04% (w/v), dyeing outwelled dye after 30 minutes
Liquid, is rinsed 4 times with acetic acid, removes unconjugated dyestuff, and room temperature is dried.With 100 μ L non-buffered Tris-base alkali lye dissolvings and carefully
The protein bound dyestuff of born of the same parents, horizontal shaker vibrates 20 minutes, absorbs light ELIASA (Bio-Tek company of the U.S. using ELx800
Produce, operate software Gen5) measure absorption value at 515nm.All tests set 3 parallel groups or in triplicate.Spin labeling white horse with a black mane
The cytotoxic activity test result of the peaceful alkali (12) of camel is shown in Table 1.
The peaceful alkali A of table 1 spin labeling camel (12) and the cytotoxic activity result of the test of camel peaceful alkali A
Note：(1) screening technique：Sulforhodamine B colorimetric method；(2) action time：72 hours.
4 tumor cell line in vitro cytotoxic effect test results are shown：Compared with camel peaceful alkali A, synthesized by the present invention
Spin labeling camel peaceful alkali A compound more than 16 times are improve to the inhibitory activity of human lung adenocarcinoma cell (A549)；To human milk
The inhibitory activity of adenocarcinoma cell strain (MDA-MB-468) improves more than 7 times, the inhibitory activity to Proliferation of Human Ovarian Cell (SKOV3)
Improve more than 2 times；To human colon carcinoma, the inhibitory activity of thin strain (HCT 116) improves nearly 14 times, based on above-mentioned active testing, enters
This optimisation strategy by the present invention for the one step explanation, is remarkably improved the antitumor activity of camel peaceful alkali A, for developing further
High activity spin labeling camel peaceful alkali A derivative provides theoretical foundation.And compound of the present invention shows and preferably should
Use prospect.
Claims (8)
1. the spin labeling camel peaceful alkali A compound as shown in formula (I)
.
2. the spin labeling camel peaceful alkali A compounds process for production thereof described in claim 1 it is characterised in that as react formula (II) institute
Show,
Phthalic anhydride 1 and benzylamine will be dissolved in appropriate glacial acetic acid, be heated to reflux obtaining intermediate 2, then by centre
Body 2 is dissolved in appropriate dimethylbenzene, under inert gas shielding between 60～70 DEG C under be slowly added to methyl in aforementioned liquids
Magnesium iodide, then reactant liquor is gradually heated to 165 DEG C～180 DEG C back flow reaction 2 hours, reaction is reduced pressure after terminating at this temperature
Most of solvent is evaporated off, is subsequently cooled to room temperature, be added thereto to bulk petroleum ether and obtain turbid solution, taken out by diatomite
Filter, collect all filtrates, chromatographed with alkali alumina again after filtrate is placed in the air 24 hours, concentrated after produced
Thing 3, then add 20～30 milliliters of glacial acetic acid so that it is dissolved in product 3, it is subsequently adding 10% palladium carbon, after stirring
Reaction system is fully reacted under the inert gas shielding of 4 atmospheric pressure, is concentrated to give after reactant liquor separation of solid and liquid
Faint yellow intermediate products 4, intermediate 4 are dissolved in 50 milliliters of methyl alcohol/acetonitrile=14/1 (volume ratio), then sequentially add carbon
Sour hydrogen sodium (15eq), Disodium tungstate (Na2WO4) dihydrate (0.55eq), it is eventually adding the hydrogen peroxide solution of 30% (volume ratio), this muddiness reaction
Liquid is sufficiently stirred for reacting at normal temperatures, and reaction adds a small amount of water quenching to go out reaction after terminating, and removes solvent, the appropriate water of addition and 1N
Sulfuric acid solution extracted, merge organic phase, after magnesium sulfate dry filter, obtain yellow product 5 after reduced pressure concentration, in ice
Slow in intermediate 5 under the conditions of bath, the concentrated sulfuric acid will be added and stir, stirring under condition of ice bath will be placed on 60 after 30 minutes
DEG C oil bath in react 20 minutes, be then placed on again in ice bath, fuming nitric aicd be added dropwise in above-mentioned solution, dropping
After finishing, under condition of ice bath, stirring reaction is stirred overnight under normal temperature after 30 minutes again, next day, this Chinese red reactant liquor is heated
React 20 minutes to 100 DEG C, be subsequently placed in ice bath, the sodium hydroxide solution of 10% (mass ratio) is slowly added thereto regulation
PH value, to 8 about, is extracted with chloroform, merges organic phase, filters after being dried with magnesium sulfate, and it is solid that reduced pressure concentration obtains yellow
Body 6, intermediate 6 methyl alcohol is dissolved, then adds 10% dry palladium carbon wherein, stir, with pressurized with hydrogen to 1 air
Pressure, stirring reaction 6 hours, reaction is filtered after terminating, and reduced pressure concentration filtrate obtains yellow solid 7, then intermediate 7 is dissolved in methyl alcohol
In, it is subsequently adding copper acetate copper acetate (0.128eq), stirring reaction 3 hours under normal temperature, reaction is quenched instead with chloroform after terminating
Should, obtain solid residue after concentration, flaxen solid pure product 8 is obtained for eluant, eluent through column chromatography with petrol ether/ethyl acetate, will
Compound 9 is first dissolved in adding the DMF of catalytic amount in the middle of the dichloromethane of drying, then oxalyl chloride is dissolved in 30～50 milliliters
In dry methylene chloride, slowly to be instilled in above-mentioned reactant liquor under condition of ice bath, reactant liquor was subtracted after 1.5 hours by reaction
Pressure is concentrated to give solid crystal, is re-dissolved in dry methylene chloride, and is slowly dropped into containing intermediate 8 under condition of ice bath
(1.5eq), react in 30～50 milliliters of dry methylene chloride solution of sodium acid carbonate (4.5eq), reaction adds water quenching after terminating
Go out reaction, and use chloroform extraction reactant liquor, merge organic phase, solid residue is obtained with reduced pressure concentration after magnesium sulfate dry filter, with
Chloroform/methanol is that eluant, eluent obtains yellow solid product 10 through column chromatography purifying, and product 10 (3.6mmol) is dissolved in toluene
(50mL), and in water (0.2mL), potassium carbonate (7.2mmol), lithium bromide (7.2mmol), TBAB are then sequentially added
(0.4mmol) then reaction is warming up to 80 DEG C and fully reacts, reactant liquor is reduced pressure after terminating by reaction by, propargyl bromide (5.7mmol)
The solid residue concentrating, is purified through column chromatography for eluant, eluent with chloroform/methanol and obtains crocus solid product 11, by triphenyl oxygen
Phosphine (2.75eq) is dissolved in 30～50 milliliters of dry methylene chloride, is dissolved in trifluoromethanesulfanhydride anhydride (1.38eq) under condition of ice bath
In 30～50 milliliters of dry methylene chloride, then the dichloromethane dissolved with trifluoromethanesulfanhydride anhydride is lentamente dripped entrance dissolved with three
The dichloromethane solution of phenyl phosphine oxide, stirring reaction 30 minutes under zero degrees celsius, intermediate 11 is dissolved in 30～50 milliliters
In dry methylene chloride, in the dichloromethane solution being slowly dropped to trifluoromethanesulfanhydride anhydride under condition of ice bath, stirring is simultaneously
Fully react, add the sodium bicarbonate aqueous solution of 10% (volume ratio) that reaction is quenched after completion of the reaction, after reduced pressure concentration, obtain solid
Residue, is purified through column chromatography for eluant, eluent with chloroform/methanol and obtains crocus target compound 12.
3. method according to claim 2 is it is characterised in that silica gel for chromatography post adopts the column chromatography of 200～300 mesh to use
Silica gel.
4. the peaceful alkali A compound of spin labeling camel according to claim 1 is used for preparing antineoplastic.
5. the peaceful alkali A compound of spin labeling camel according to claim 1 is in the medicine of preparation treatment human lung adenocarcinoma
Application.
6. the peaceful alkali A compound of spin labeling camel according to claim 1 is in the medicine of preparation treatment human breast carcinoma
Application.
7. the peaceful alkali A compound of spin labeling camel according to claim 1 is in the medicine of preparation treatment Proliferation of Human Ovarian Cell
In application.
8. the peaceful alkali A compound of spin labeling camel according to claim 1 is in the thin medicine of preparation treatment human colon carcinoma
Application.
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|---|---|---|---|---|
| CN102249987A (en) * | 2011-05-06 | 2011-11-23 | 兰州大学 | Combretastatin compound and preparation method and application thereof |
| CN103351383A (en) * | 2013-07-29 | 2013-10-16 | 中国人民解放军第四军医大学 | 5-fluorouracil nitroxyl-free-radical anti-tumor drug |
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|---|---|---|---|---|
| CN102249987A (en) * | 2011-05-06 | 2011-11-23 | 兰州大学 | Combretastatin compound and preparation method and application thereof |
| CN103351383A (en) * | 2013-07-29 | 2013-10-16 | 中国人民解放军第四军医大学 | 5-fluorouracil nitroxyl-free-radical anti-tumor drug |
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| EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,: "Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| XUAN TIAN ET AL.: "Antitumor and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners", 《LIFE SCIENCES》 * |
| 张自义等: "稳定氮氧自由基TMPO和TMPRO的合成与应用", 《有机化学》 * |
| 陈晓等: "2,2,6,6-四甲基-3-烯哌啶氮氧自由基鱼藤酮肟酯体外抗肿瘤作用", 《兰州大学学报(医学版)》 * |
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