CN105566304B - Sulfur-bearing uridine anticancer compound and its intermediate and preparation method - Google Patents
Sulfur-bearing uridine anticancer compound and its intermediate and preparation method Download PDFInfo
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Abstract
The present invention relates to intermediates and preparation method that a kind of pair of UVA light has 4- sulphur -5- (2- vinyl halides base) the uridine compound and this compound with anticancer activity compared with strong sensitivity.The method includes following reactions: iodination reaction, halogenating reaction, protects the hydroxyl in saccharide ring, and sulphur replaces oxygen, and sloughs O blocking group, can obtain 4- sulphur -5- (2- vinyl halides base) uridine.The disadvantages of present invention has the reaction time short, and yield is high, the high advantage of product purity, avoids the time consumption and energy consumption of prior synthesizing method, low yield.Advantage is provided further to develop sulfur-bearing nucleoside medicine.
Description
Technical field
The present invention relates to a kind of medical compounds and preparation method thereof, especially a kind of pair of UVA light to have compared with strong sensitivity
The intermediate and preparation method of 4- sulphur -5- (2- vinyl halides base) uridine compound and this compound with anticancer activity.
Background technique
At present in terms for the treatment of of cancer, chemotherapy, radiotherapy and operative treatment are not ideal treatment means, chemotherapy and radiation
It is big to the lethality of normal cell, the high recurrence rate of operative treatment, so the treatment method for researching and solving these drawbacks has become
Urgent need.Therefore the proposition of photodynamic therapy provides new way for research new anticancer drug.
Photodynamic therapy is a kind of combination photosensitizer, light source and oxygen molecule, is treated by photodynamics reaction pernicious
The novel therapies of tumour.Its process is that photosensitizer is first injected patient's diseased region, then uses the illness of specific band laser irradiation
Region excites photosensitizer.Energy transmission to the oxygen of surrounding, is generated highly active singlet oxygen by the photosensitizer of excitation state,
Oxidation reaction occurs for singlet oxygen and adjacent large biological molecule, generates cytotoxic effect, and then leads to cell damage or even dead
It dies.It is compared with the traditional method, photodynamic therapy avoids wound caused by operation by optical fiber, endoscope and other interventional techniques
Wound and pain.Simultaneously as photosensitizer is only absorbed and retained by sick cell, no general toxicity, effect light wave cannot be normal
Tissue resorption, so treatment guarantees that normal tissue cell is not damaged just for pathological tissues.
Currently, the research of photosensitive drug has obtained very big progress, on the basis of first generation photosensitizer hematoporphyrin derivative
On develop second generation 5-ALA (5-ALA) drug.Third generation drug is the lucid asparagus acyl group with the crosslinking of various substances
Chlorin (Npe6) and phthalein blueness class.Some are still in the zooscopy stage to these drugs, and some has entered clinical investigation phase.
But photosensitive drug used in existing photodynamic therapy drains that slow, the residence time is long in skin, is also easy to produce skin light poison
Reaction, needs to be protected from light 20 days or more during treatment.Drug can be more especially in liver,kidney,spleen throughout whole body with vein simultaneously, influences
The normal physiological metabolism of body.For the disadvantages mentioned above for overcoming photosensitive drug, scientists are still finding new photosensitive drug.
In the bioactivity of nucleoside derivates, the structure of base plays conclusive effect.Therefore, to nucleoside base
Carrying out structure of modification is the effective means for finding new lead compound.N DNA does not include sulphur, since Lipsett is from large intestine bar
After bacterium isolates 4- thiouracil nucleotide, the concern of sulfur-bearing base and thionucleoside attraction people.Compared with normal DNA,
There is sulfur-bearing base DNA unique property, especially the pyrimidine ring series compound containing sulfydryl to have anticancer activity and be immunized
Humidification, this is because thiopyrimidine base is in terms of lipophilicity, than tradition compared with traditional pyridimine nucleosides compound
Pyrimidine nucleoside tool improve.
At present in thionucleoside, 6- imuran, Ismipur and 6- thioguanine (6-TG) are treating cancer and inflammation
The important drugs of venereal disease disease, wherein 6- imuran is the choice drug for treating leukemia of children.Thionucleoside is in addition to having weight
Outside the medical value wanted, also there is certain side effect, research finds that the patient skin lesion probability for taking such drug is big.This
It is because 6-TG is very strong UVA chromophore, this has very big difference compared with other DNA bases.DNA base is in far-ultraviolet region
(UVB, 290nm-340) has UV absorption, and 6-TG maximum absorption wave a length of 340 belongs near ultraviolet region (320-400).6-TG
Meeting enzyme becomes 6-TG nucleosides and replaces original DNA of 0.01-0.03% after into cell DNA, so that the DNA in skin is to UVA
The sensibility of light enhances, and causes cell to cooperate with toxicity after then 6-TG is in conjunction with UVA.Its reason may be that 6-TG can cause DNA
With the oxidation of protein, then cross-coupling reaction occurs for DNA break, to cause DNA lesion.By to this base analog
DNA damage and the research of the biochemical characteristic of reparation, discovery 6-TG have the function of postponing cytotoxic.But its side effect is strong, is killing
Also normal cell can be killed while dead cancer cell, very strong toxicity is gone out to cells show, so it is necessary to finding new light
Sensitizing drug.
Summary of the invention
The purpose of the present invention is to provide a kind of pair of UVA light the sulfur-bearing uridine with anticancer activity compared with strong sensitivity
Close the intermediate and preparation method of object and this compound.
In order to achieve the purpose that foregoing invention, sulfur-bearing uridine anticancer drug provided by the invention is that (2- is halogenated by 4- sulphur -5-
Vinyl) uridine, the chemical general formula (I) of 4- sulphur -5- (2- vinyl halides base) uridine are as follows:
R1Represent the blocking group or H of hydroxyl O；
R2Represent OR1Or OH；
X represents halogen.
Sulfur-bearing uridine anticancer compound intermediate of the invention is the intermediate of 4- sulphur -5- (2- vinyl halides base) uridine,
It is characterized in that, the chemical general formula (I) of intermediate are as follows:
R1Represent the blocking group or H of hydroxyl O；
R2Represent OR1；
X represents halogen, carboxyl or ester group.
The synthetic method of compound described in chemical general formula (I), specific synthesis include the following steps:
Step A specifically: under the conditions of 110 DEG C, uridine and iodine pass through in the dilute nitric acid solution of 0.212mol/L
Thin-layered chromatography monitors response situation, solvent CH2Cl2:CH3OH=7:1.It is molten to collect lower layer for product petroleum ether extraction
Liquid.The white solid of precipitation is collected after standing.
Step B specifically: add argon gas to protect anhydrous Isosorbide-5-Nitrae-dioxane, be heated to 70 DEG C, sequentially add palladium acetate, three
Phenylphosphine and triethylamine are stirred to solution and become peony.The product that step A is added passes through thin layer color with acrylate reactions
Spectrometry monitors response situation, solvent CH2Cl2:CH3OH=7:1.Filtrate is collected by filtration, standing there are a large amount of solids into filtrate
It is precipitated.It is recrystallized with dehydrated alcohol, obtains white fluffy solid.
Step C includes: step C1, is hydrolyzed with step B product with sodium hydroxide solution and reacts synthesis (E) -5- (2- carboxylic
Vinyl)-uridine；And step C2 with (E) -5- (2- carboxyl vinyl)-uridine carries out halogenation synthesis (E) -5- (2- is halogenated
Vinyl) uridine.
Step C1 specifically: (E) -5- (2- acrylate)-uridine solution is added dropwise in sodium hydroxide solution, instead
Concentrated hydrochloric acid is added dropwise under condition of ice bath after answering completely, until pH is 1, suction filtration obtains white solid after standing.
Step C2 specifically: take (E) -5- (2- propylene carboxyl)-uridine under the conditions of 100 DEG C with Anhydrous potassium carbonate and halogenated
Reagent reaction, revolving remove half solvent, are placed in refrigerator overnight, obtain product after suction filtration.
Step D specifically: take step C product under condition of ice bath with anhydrous pyridine and acetic acid anhydride reactant.Pass through thin layer
Chromatography monitors response situation.Solvent is removed under reduced pressure, obtains sticky mass, is recrystallized to give with dehydrated alcohol greyish white
Color solid.
Step E specifically: take D step products to be dissolved in Isosorbide-5-Nitrae-dioxane, under the conditions of 105 DEG C with P2S5Reaction, with rich layer
Chromatography detects response situation, solvent PE:EA=1:1.Solvent is removed under reduced pressure, obtains brown-red solid.With PE:
EA=2:1 makees eluant, eluent, and post separation obtains yellow solid.
Step F specifically: it takes E step products to react in methanolic ammonia solution, response situation is detected by thin-layered chromatography,
Solvent is CHCl2:CH3OH=7:1.Solvent is removed under reduced pressure, obtains yellow solid, uses CHCl2:CH3OH=7:1 column
Separation, obtains product.
The present invention also protects above-described compound preparing the application in anticancer drug.
The advantages and positive effects of the present invention are: tumour cell can be enhanced to penetrating in the compound of the present invention and its derivative
The sensitivity of line, in conjunction with UVA after for treat cutaneum carcinoma effect more preferable.The compound and its derivative can enter tumour cell
DNA in, irradiated by UVA and the DNA of cell for having the function that damage increases without limitation that interacts.The ultraviolet light of low dosage
After in conjunction with the compound, cancer cell can be effectively killed, and do not poison to normal cell.Therefore treating cancer especially
Have broad application prospects in terms of cutaneum carcinoma.
In addition, application synthetic method of the present invention has the reaction time short, yield is high, and the high feature of product purity avoids
The disadvantages of time consumption and energy consumption of prior synthesizing method, low yield.Advantageous item is provided further to develop sulfur-bearing nucleoside medicine
Part.
Detailed description of the invention
Fig. 1 is human melanoma cell survival rate schematic diagram under different ultraviolet lights.
Specific embodiment
Elaborate below to the embodiment of the present invention: the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
The present invention relates to the synthetic methods of 4- sulphur -5- (2- vinyl halides base) uridine and intermediate.The feature of this compound
It is its structure are as follows:
R1Represent the blocking group or H of hydroxyl O；
R2 represents OR1Or OH；
X represents halogen, carboxyl or ester group.
Under preferred embodiment, the blocking group of specific hydroxyl O includes alkanoyl and aroyl (such as acyl group, especially acetyl
Base, benzoyl), three substituted arylmethyl groups (trityl dimethoxy) and silylation (such as trialkylsilane, especially three
Methyl-monosilane)；Halogen is bromine or iodine.
In addition, this compound can indicate tautomerism, present discovery may include all tautomers
Form and mixture.This compound belongs to sulfur-bearing nucleosides treating cancer drug, can be used for the relevant disease for the treatment of cancer.
The synthesis path of sulfur-bearing uridine anticancer compound of the present invention is as follows:
The specific synthesis step of this compound are as follows:
Uridine is carried out 5 iodination reactions by A. iodination reaction in acid condition；
B.5 position substitution reaction replaces iodine with acrylate, obtains (E) -5- (2- acrylate)-uridine；
C. halogen substitution reaction reacts synthesis (E) -5- (2- halogenated hydrocarbons)-with halogenating agent with the product that second step obtains
Uridine；
D. the hydroxyl in saccharide ring is protected, (E) -5- (2- halogenated hydrocarbons)-uridine is protected via O blocking group shown in logical formula (I)
Shield；
E. sulphur replaces oxygen, and the compound after using blocking group shown in general formula to protect is reacted with phosphorus pentasulfide, is obtained
4- sulphur -5- (2- vinyl halides base) uridine and the like；
F. O blocking group shown in logical formula (I) is sloughed, it is molten that products therefrom in step 5 is dissolved in the ammonia methanol prepared
Liquid can obtain 4- sulphur -5- (2- vinyl halides base) uridine.
The step A, specifically: under the conditions of 110 DEG C, the dilute nitric acid solution of uridine and iodine in 0.212mol/L
In pass through thin-layered chromatography monitor response situation, solvent CH2Cl2:CH3OH=7:1.Product petroleum ether extraction, under collection
Layer solution.The white solid of precipitation is collected after standing.
The step B, specifically: add argon gas to protect anhydrous Isosorbide-5-Nitrae-dioxane, is heated to 70 DEG C, sequentially adds vinegar
Sour palladium, triphenylphosphine and triethylamine are stirred to solution and become peony.The product of step A is added, with acrylate reactions, leads to
Cross thin-layered chromatography monitoring response situation, solvent CH2Cl2:CH3OH=7:1.Filtrate is collected by filtration, standing has into filtrate
A large amount of solids are precipitated.It is recrystallized with dehydrated alcohol, obtains white fluffy solid.
The step C, further includes: C1 step, reacts synthesis (E) -5- with sodium hydroxide solution with step B product
(2- carboxyl vinyl)-uridine；C2 step carries out halogenation synthesis (E) -5- (2- halogen with (E) -5- (2- carboxyl vinyl)-uridine
For vinyl) uridine.
The C1 step, specifically: (E) -5- (2- is acrylate-based)-uridine solution is added dropwise to sodium hydroxide
In solution, concentrated hydrochloric acid is added dropwise under condition of ice bath after fully reacting, until PH is 1, suction filtration obtains white solid after standing.
The C2 step, specifically: take (E) -5- (2- propylene carboxyl)-uridine under the conditions of 100 DEG C with Carbon Dioxide
Potassium and halogenating agent reaction, revolving remove half solvent, are placed in refrigerator overnight, obtain product after suction filtration.
The D step, specifically: take step C product under condition of ice bath with anhydrous pyridine and acetic acid anhydride reactant.It is logical
Cross thin-layered chromatography monitoring response situation.Solvent is removed under reduced pressure, obtains thick solid, is recrystallized with dehydrated alcohol
To pale solid.
The E step, specifically: take D step products to be dissolved in Isosorbide-5-Nitrae-dioxane, under the conditions of 105 DEG C with P2S5Instead
It answers, detects response situation, solvent PE:EA=1:1 with rich layer chromatography.Solvent is removed under reduced pressure, obtains brownish red
Solid.Eluant, eluent is made with PE:EA=2:1, post separation obtains yellow solid.
The F-step, specifically: it takes E step products to react in methanolic ammonia solution, is detected by thin-layered chromatography anti-
Answer situation, solvent CHCl2:CH3OH=7:1.Solvent is removed under reduced pressure, obtains yellow solid, uses CHCl2:CH3OH
=7:1 post separation, obtains product.
Embodiment 1:(E) -4- sulphur -5- (2- bromo vinyl)-uridine and intermediate and synthetic method, include the following steps,
In following steps, the ratio of solvent or eluant, eluent is volume ratio:
(1) the iodo- uridine of 5- is synthesized by uridine
It takes uridine (13.06g, 53.50mmol) to be dissolved in 252ml dust technology, is heated to 110 DEG C, be added (10.09g,
39.92mmol) iodine monitors response situation, solvent CH by thin-layered chromatography2Cl2:CH3OH=7:1, reaction about 4
Raw material point disappears after hour, illustrates fully reacting, stops reaction.It is used 30ml petroleum ether extraction 3 times after standing cooling, collects lower layer
Solution, upper solution are extracted with 30ml deionized water, merge the lower layer's solution extracted twice.Standing has white solid precipitation, sets
A large amount of white solids are obtained, as 5-I- uridine (14.30g, 38.64mmol), yield is overnight in refrigerator upper layer
72.22%.M.p.206-209 DEG C (m.p.208-210 DEG C of literature value)；
1H NMR(500MHz,DMSO-d6) δ 11.69 (s, 1H ,-NH), 8.48 (s, 1H, 6-H), 5.72 (d, J=4.6Hz,
1H, 1 '-H), the 5.43 (- OH of s, 1H, 2 '), the 5.27 (- OH of s, 1H, 3 '), the 5.08 (- OH of s, 1H, 5 '), 4.03 (d, J=4.1Hz,
1H, 2 '-H), the 3.98 (- H of t, J=4.4Hz, 1H, 3 '), 3.90-the 3.82 (- H of m, 1H, 4 '), 3.68 (d, J=11.6Hz, 1H,
5 '-H), the 3.57 (- H of d, J=11.7Hz, 1H, 5 ') .13C NMR (125MHz, DMSO-d6)δ160.99(C-4),150.59(C-
2),145.52(C-6),87.98(C-5),85.10(C-1’),70.47(C-4’),69.77(C-3’),61.27(C-2’),
40.65(C-5’).
(2) (E) -5- (2- methyl acrylate base)-uridine is synthesized by 5- ioduria glycosides
Take anhydrous Isosorbide-5-Nitrae-dioxane 360ml in 500ml three-necked flask, argon gas added to protect, be heated to 70 DEG C, successively plus
Enter palladium acetate (0.31g, 1.38mmol), triphenylphosphine (0.72g, 2.75mmol), triethylamine 5ml, stir about 30 minutes until
Solution becomes peony.It is added 5-I uridine (10.18g, 27.52mmol), methyl acrylate (7.11g, 82.56mmol,
7.11ml), response situation, solvent CH are monitored by thin-layered chromatography2Cl2:CH3OH=7:1, it is former after reaction about 20 hours
Shots disappear, and illustrate fully reacting, stop reaction.Filtrate is collected in filtering, is stood, and has a large amount of solids to be precipitated in filtrate, after
Filter.Solid is obtained by filtration to be recrystallized with dehydrated alcohol, obtains white fluffy solid (6.57g, 20.01mmol).Yield is
72.71%.m.p.194-197℃.
1H NMR(400MHz,DMSO-d6) δ 11.67 (s, 1H ,-NH), 8.51 (s, 1H, 6-H), 7.35 (d, J=
12.0Hz, 1H ,-HC=CH), 6.85 (d, J=12.0Hz, 1H ,-HC=CH), the 5.77 (- H of d, J=4.0Hz, 1H, 1 '), 5.46
(- the OH of d, J=4.0Hz, 1H, 2 '), the 5.30 (- OH of t, J=4.0Hz, 1H, 3 '), the 5.08 (- OH of d, J=4.0Hz, 1H, 5 '),
The 4.08 (- H of dd, J=12.0,4.0Hz, 1H, 2 '), the 4.01 (- H of dd, J=12.0,4.0Hz, 1H, 3 '), 3.87 (dd, J=
4.0Hz,4.0Hz,1H,4’-H),3.68(s,3H,-OCH3),3.57(s,2H,5’-H).13C NMR(125MHz,DMSO-d6)δ
167.61 (C-1 "), 162.14 (C-4), 149.91 (C-2), 144.43 (C-6), 138.36 (C-HC=CH), 116.73 (C-HC
=CH), 108.67 (C-5), 89.13 (C-1 '), 85.13 (C-4 '), 74.37 (C-2 '), 69.48 (C-3 '), 60.66 (C-
5’),51.75(-OCH3).HRMS:[M+H]+328.0927calculated for C13H16N2O8；found 329.0972.UV-
Vis(in CH3CN)λmax/nm:301.IR(fim)-1: 3336.0 (OH), 1730.0 (C=O), 1624.2 (C=C), 1436,
1382.0(NH).
(3) (E) -5- (2- carboxyl vinyl)-uridine is synthesized by (E) -5- (2- methyl acrylate base)-uridine
Taking (E) -5- (2- methyl acrylate base),-uridine (6.00g, 18.29mmol) is in 250ml round-bottomed flask, dropwise
73ml 2M sodium hydroxide solution is added, after being stirred at room temperature 3 hours, concentrated hydrochloric acid is added dropwise under condition of ice bath, is examined with PH test paper
It surveys, until PH is 1, there are a large amount of white precipitates to generate at this time.Half an hour is stood, is filtered, obtained solid is washed with water, and obtains white
Solid (5.31g, 16.89mmol).Yield is 92.34%.m.p.269-270℃.1H NMR(400MHz,DMSO-d6)δ8.43
(s, 1H, 6-H), 7.18 (d, J=12.0Hz, 1H ,-HC=CH), 6.74 (d, J=12.0Hz, 1H ,-HC=CH), 5.78 (d, J
=4.0Hz, 1H, 1 '-H), the 4.09 (- H of t, J=4.0Hz, 1H, 2 '), the 4.04 (- H of t, J=4.0Hz, 1H, 3 '), 3.89 (d, J=
- the H of 4.0Hz, 1H, 4 '), the 3.70 (- H of m, J=4.0Hz, 1H, 5 '), the 3.61 (- H of dd, J=8.0Hz, 1H, 5 ')13C NMR
(125MHz,DMSO-d6)δ169.52(-COOH),162.28(C-4),150.08(C-2),142.67(C-6),135.36(C-
), HC=CH 121.27 (C-HC=CH), 109.40 (C-5), 88.93 (C-1 '), 85.28 (C-4 '), 74.41 (C-2 '),
69.72(C-3’),60.78(C-5’).HRMS:[M+Na]+337.0570calculated for C12H14N2O8；found
337.0632.UV-Vis(in CH3CN)λmax/nm:302.IR(fim)-1:3648(COOH),3324.6(OH),1682.0(C
=O), 1607.2 (C=C), 1454.8,1416.5 (NH)
(4) (E) -5- (2- bromo vinyl)-uridine is synthesized by (E) -5- (2- carboxyl vinyl)-uridine
It takes (E) -5- (2- propylene carboxyl)-uridine (4.50g, 14.31mmol) to be placed in 500ml three-necked flask, is added
120ml water heats 100 DEG C of stirrings.Anhydrous potassium carbonate 1.20g is added.NBS1.3g is taken to be dissolved in 22.5ml acetone and 22.5ml water
In, and mixed liquor is added dropwise in flask, at least 135min is added dropwise.Stirring 3 hours, stops reaction, and revolving removes half
Solvent is placed in refrigerator, overnight.There are a large amount of needle-shaped brown crystals to be precipitated, filters, obtain product (2.70g, 7.73mmol).It receives
Rate is 50.54%.m.p.170-172℃.1H NMR(400MHz,DMSO-d6)δ11.57(s,1H,-NH),8.16(s,1H,6-
), H 7.24 (d, J=8.0Hz, 1H ,-HC=CH), 6.82 (d, J=12Hz, 1H ,-HC=CH), 5.76 (d, J=4.0Hz, 1H,
1 '-H), 5.23-5.09 (m, 3H, 2 '-OH, 3 '-OH, 5 '-OH), the 4.05 (- H of t, J=4.0Hz, 1H, 2 '), 4.00 (t, J=
- the H of 4.0Hz, 1H, 3 '), the 3.86 (- H of dd, J=8.0,4.0Hz, 1H, 4 '), the 3.71 (- H of dd, J=12.0,8.0Hz, 1H, 5 '),
The 3.59 (- H of dd, J=12.0,8.0Hz, 1H, 5 ')13C NMR(125MHz,DMSO-d6)δ162.13(C-4),149.99(C-
2), 139.96 (C-6), 130.16 (C-HC=CH), 110.14 (C-HC=CH), 107.03 (C-5), 88.83 (C-1 '),
85.14(C-4’),74.23(C-2’),69.72(C-3’),60.88(C-5’).HRMS:[M+Na]+
370.9855calculated for C11H13BrN2O6Na；found 372.9815.UV-Vis(in CH3CN)λmax/nm:
251,295.IR(fim)-1: 3358 (OH), 1698.0 (C=O), 1467.8,1384.5 (NH)
(5) (E) -2 ', 3 ', 5 '-O- triacetyl -5- (2- vinyl bromide is synthesized by (E) -5- (2- bromo vinyl)-uridine
Base)-uridine
Take (E) -5- (2- bromo vinyl)-uridine (2.50g, 7.16mmol) in 100ml three-necked flask, under condition of ice bath
Anhydrous pyridine 21.00ml, acetic anhydride (4.81ml, 50.77mmol) is added.Response situation, reaction are monitored by thin-layered chromatography
After about 5 hours, raw material point disappears, and illustrates fully reacting, stops reaction.Solvent is removed under reduced pressure, obtains thick solid,
It is recrystallized with dehydrated alcohol, obtains pale solid (2.87g, 6.03mmol).Yield 84.25%.m.p.191-193℃.1H
NMR(400MHz,DMSO-d6) δ 11.74 (s, 1H ,-NH), 7.93 (s, 1H, 6-H), 7.30 (d, J=12.0Hz, 1H ,-HC=
), CH 6.87 (d, J=12.0Hz, 1H ,-HC=CH), the 5.92 (- H of d, J=4.0Hz, 1H, 1 '), 5.45 (dd, J=4.0Hz,
- the H of 8.0Hz, 1H, 2 '), 5.35-the 5.33 (- H of m, 1H, 3 '), the 4.34 (- H of t, J=8.0Hz, 1H, 4 '), 4.28-4.23 (m, 2H,
5’-H),2.08–2.05(m,9H,3×-CH3).13C NMR(125MHz,DMSO-d6)δ170.52,169.79,169.77(3
×-C=O), 162.01 (C-4), 149.65 (C-2), 140.38 (C-6), 129.77 (C-HC=CH), 111.02 (C-HC=
CH),107.97(C-5),88.35(C-1’),79.52(C-4’),72.50(C-2’),69.91(C-3’),63.37(C-5’),
20.99,20.73,19.02(3×-CH3).HRMS:[M+Na]+497.0172calculated for C17H19BrN2O9Na；
found 397.0171,500.0186.UV-Vis(in CH3CN)λmax/nm:257,297.IR(fim)-1: 1751.5 (C=
O),1463.2,1373.7(NH).
(6) by (E) -2 ', 3 ', 5 '-O- triacetyl -5- (2- bromo vinyl)-uridine synthesize (E) -4- sulphur -2 ', 3 ',
5 '-O- triacetyl -5- (2- bromo vinyl)-uridines
(E) -2 ', 3 ', 5 '-O- triacetyl -5- (2- bromo vinyl)-uridine (2.29g, 4.81mmol) is taken, is dissolved in
193m11,4- dioxane are heated to 105 DEG C.P is added2S5(2.15g, 9.62mmol) starts to react, and is examined with rich layer chromatography
Response situation is surveyed, solvent PE:EA=1:1, raw material point disappears after reaction 4 hours, stops reaction.It is removed under reduced pressure molten
Agent obtains brown-red solid.Make eluant, eluent with PE:EA=2:1, post separation obtain yellow solid (0.73g,
1.49mmol).Yield is 31.05%.m.p.200-202℃.1H NMR(400MHz,DMSO-d6)δ13.06(s,1H,-NH),
7.96 (s, 1H, 6-H), 7.21 (d, J=12.0Hz, 1H ,-HC=CH), 7.09 (d, J=8.0Hz, 1H ,-HC=CH), 5.89
(- the H of d, J=4.0Hz, 1H, 1 '), the 5.57 (- H of dd, J=8.0,4.0Hz, 1H, 2 '), the 5.38 (- H of t, J=6.0Hz, 1H, 3 '),
4.38–4.33(m,1H,4’-H),4.31–4.26(m,2H,5’-H),2.08–2.03(m,9H,3×-CH3).13C NMR
(125MHz,DMSO-d6) δ 188.77 (- C=S), 170.49,169.75,169.74 (3 ×-C=O), 147.23 (C-2),
135.59 (C-6), 131.26 (C-HC=CH), 119.02 (C-HC=CH), 107.83 (C-5), 89.53 (C-1 '), 79.93
(C-4’),72.60(C-2’),69.82(C-3’),63.24(C-5’),20.97-20.70(3×-CH3).HRMS:[M+Na]+
512.9943calculated for C17H19BrN2NaO8SNa；found 512.9950.UV-Vis(in CH3CN)λmax/
nm:346.IR(fim)-1: 1701.7 (C=O), 1621.9 (C=C), 1454.5,1376.0 (NH)
(7) by (E) -4- sulphur -2 ', 3 ', 5 '-O- triacetyl -5- (2- bromo vinyl)-uridines synthesize (E) -4- sulphur -5-
(2- bromo vinyl)-uridine
Take (E) -4- sulphur -2 ', 3 ', 5 '-O- triacetyl -5- (2- bromo vinyl)-uridines (0.60g, 1.22mmol), ammonia
Methanol solution 120ml, is stirred at room temperature, and detects response situation, solvent CHCl by thin-layered chromatography2:CH3OH=7:1, about 4
Stop reaction after hour.Solvent is removed under reduced pressure, obtains yellow solid, uses CHCl2:CH3OH=7:1 post separation, is produced
Product (0.15g, 0.42mmol).Yield is 34.58%.m.p.170-172℃.1H NMR(400MHz,DMSO-d6)δ12.91(s,
1H ,-NH), 8.42 (s, 1H, 6-H), 7.25 (d, J=8.0Hz, 1H ,-HC=CH), 6.93 (d, J=8.0Hz, 1H ,-HC=
), CH the 5.71 (- H of d, J=4.0Hz, 1H, 1 '), 4.11-the 4.10 (- H of m, 1H, 2 '), 4.04-the 4.02 (- H of m, 1H, 3 '), 3.90-
The 3.89 (- H of m, 1H, 4 '), the 3.78 (- H of dd, J=12.0,4.0Hz, 1H, 5 '), 3.62 (dd, J=12.0,8.0Hz, 1H, 5 '-
H).13C NMR(125MHz,DMSO-d6) δ 188.06 (- C=S), 147.49 (C-2), 134.88 (C-6), 131.68 (C-HC=
), CH 118.23 (C-HC=CH), 106.50 (C-5), 90.00 (s, 3H, C-1 '), 84.89 (C-4 '), 74.57 (C-2 '),
68.98(C-3’),60.07(C-5’).HRMS:[M+Na]+386.9626calculated for C11H13BrN2O5SNa；
found388.9610.UV-Vis(in CH3CN)λmax/nm:230,279,351.IR(fim)-1:3405.2(OH),1684.4
(C=O), 1603.9 (C=C), 1459.1,1391.1 (NH)
Embodiment 2: the outer human melanoma's A375 cell activity of test body
1, to the inhibiting effect of human melanoma cell A375
The A375 cell (human melanoma cell) of logarithmic growth phase, with the DMEM for containing 10% fetal calf serum and antibiotic
It is 10 × 10 that culture solution, which adjusts cell concentration,5Two flat tissue culture plates in 96 holes, every 100 μ L (about 10 of hole is added in/mL4It is a thin
Born of the same parents), 37 DEG C are put into, is cultivated 24 hours in 5% carbon dioxide incubator.Next day will contain (E) -4- sulphur -5- (2- bromo vinyl) -
96 hole of experimental group is added in uridine (4-SBVU) and the culture solution for compareing testing drug (E) -5- (2- bromo vinyl)-uridine (BVU)
In plate, every kind of pharmaceutical composition sets three parallel holes.Every pore volume is 100 μ L, appropriate amount of drug solution is added, so that drug is finally dense
Degree is 100 μM/L, only adds culture solution in 96 orifice plate of blank control group, drug is not added.Two plates are placed on 37 DEG C, 5% carbon dioxide
It is cultivated 48 hours in incubator.
2, MTT experiment (MTT method)
Every hole is added 20 μ L MTT solution (5mg/mL) and continues to cultivate 3 hours after culture, takes out 96 orifice plates, discards hole
Interior whole supernatant, and gently dips in the Liquid Residue in dry 96 orifice plate with clean paper handkerchief, should not crystal in destroying pores.Every hole is added
100 μ L DMSO dissolve 30 minutes, then with the light absorption value at microplate reader measurement wavelength 570nm, i.e. OD value.Record experiment knot
Fruit handles data, obtains cell survival rate %=(OD experiment/OD control) × 100%.
Drug used in illumination comparative experiments is 100 μM/L (E) -5- (2- bromo vinyl)-uridine, (E) -4- sulphur -5- (2- bromine
Vinyl)-uridine, (E) -2 ', 3 ', 5 '-O- triacetyl -5- (2- bromo vinyl)-uridine, (E) -4- sulphur -2 ', 3 ', 5 '-O-
Triacetyl -5- (2- bromo vinyl)-uridine, light group 96 orifice plate of ultraviolet light do not have to purple under control group the same terms
Outer light irradiation culture, uv agent amount 15KJ/m2, its OD value is measured respectively, calculates cell survival rate.Experimental result such as Fig. 1
It is shown.
As can be seen from Figure 1: 1) in blank assay, when being added without two kinds of drugs of BVU and 4-SBVU, ultraviolet lighting is used only
There is certain lethal effect to cancer cell；2) in the case where not using ultraviolet irradiation, when two kinds of drug concentrations are identical, 4-SBVU
The cancer cell survival rate of effect is obviously lower than the survival rate of BVU, illustrates that the thio rear anticancer activity of nucleosides is remarkably reinforced；3) using purple
In the case where external exposure, when two kinds of drug concentrations are identical, the obvious survival rate than BVU of cancer cell survival rate of 4-SBVU effect
It is low, illustrate anti-compared to what corresponding nucleosides and ultraviolet light acted synergistically to anticancer activity after ultraviolet light synergistic effect after nucleosides is thio
It is carcinous to be remarkably reinforced；4) in the case where being separately added into same drug effect, obviously than not having to ultraviolet irradiation under ultraviolet irradiation condition
When cancer cell survival rate it is low, illustrate that the synergistic effect of ultraviolet light is conducive to make drug to enhance the lethal effect of cancer cell.
Claims (2)
1. a kind of synthetic method of sulfur-bearing uridine anticancer compound, the sulfur-bearing uridine anticancer compound is that (2- is halogenated by 4- sulphur -5-
Vinyl) uridine, which is characterized in that the chemical general formula (I) of 4- sulphur -5- (2- vinyl halides base) uridine are as follows:
R1Represent H；
R2Represent OH；
X represents halogen bromine；
The sulfur-bearing uridine anticancer compound, synthetic method include the following steps:
Uridine is carried out 5 iodination reactions by A. iodination reaction in acid condition；
B.5 position substitution reaction replaces iodine with acrylate, obtains (E) -5- (2- is acrylate-based)-uridine；
C. halogenating reaction reacts synthesis (E) -5- (2- vinyl halides base) uridine with the product obtained in step B with halogenating agent；
D. the hydroxyl in saccharide ring is protected, (E) -5- (2- vinyl halides base) uridine is protected by oxygen blocking group；
E. sulphur replaces oxygen, and the compound after using oxygen blocking group to protect is reacted with phosphorus pentasulfide；
F. oxygen blocking group is sloughed, products therefrom in step E is dissolved in into the methanolic ammonia solution prepared, 4- sulphur -5- (2- halogen can be obtained
For vinyl) uridine；
The step C further comprises:
C1. it is hydrolyzed with step B products therefrom with sodium hydroxide solution and reacts synthesis (E) -5- (2- carboxyl vinyl)-uridine；
C2. halogenation synthesis (E) -5- (2- vinyl halides base) uridine is carried out with (E) -5- (2- carboxyl vinyl)-uridine；
The step C1 specifically: (E) -5- (2- acrylate)-uridine solution is added dropwise in sodium hydroxide solution,
Concentrated hydrochloric acid is added dropwise under condition of ice bath after fully reacting, until pH is 1, suction filtration obtains white solid after standing；Described
Step C2, specifically: take (E) -5- (2- carboxyl vinyl)-uridine anti-with Anhydrous potassium carbonate and halogenating agent under the conditions of 100 DEG C
It answers, revolving removes half solvent, is placed in refrigerator overnight, obtains product after suction filtration；
The step A specifically: under the conditions of 110 DEG C, uridine and iodine are anti-in the dilute nitric acid solution of 0.212mol/L
It answers, response situation, solvent CH is monitored by thin-layered chromatography2Cl2:CH3OH=7:1；Product petroleum ether extraction is collected
Lower layer's solution；The white solid of precipitation is collected after standing；
The step B specifically: add argon gas to protect anhydrous Isosorbide-5-Nitrae-dioxane, be heated to 70 DEG C, sequentially add palladium acetate, three
Phenylphosphine and triethylamine are stirred to solution and become peony；The product that step A is added passes through thin layer color with acrylate reactions
Spectrometry monitors response situation, solvent CH2Cl2:CH3OH=7:1；Filtrate is collected by filtration, standing there are a large amount of solids into filtrate
It is precipitated；It is recrystallized with dehydrated alcohol, obtains white fluffy solid；
The step D specifically: take step C product under condition of ice bath with anhydrous pyridine and acetic acid anhydride reactant；By thin
Layer chromatography monitors response situation；Solvent is removed under reduced pressure, obtains sticky mass, is recrystallized to give ash with dehydrated alcohol
White solid；
The E step specifically: take D step products to be dissolved in Isosorbide-5-Nitrae-dioxane, under the conditions of 105 DEG C with P2S5Reaction, use are thin
Layer chromatography detects response situation, solvent PE:EA=1:1；Solvent is removed under reduced pressure, obtains brown-red solid；With
PE:EA=2:1 makees eluant, eluent, and post separation obtains yellow solid；
The F-step specifically: it takes E step products to react in methanolic ammonia solution, response situation is detected by thin-layered chromatography,
Solvent is CHCl2:CH3OH=7:1；Solvent is removed under reduced pressure, obtains yellow solid, uses CHCl2:CH3OH=7:1 column
Separation, obtains product.
2. sulfur-bearing uridine anticancer compound 4- sulphur -5- (2- vinyl halides base) uridine described in claim 1 is preparing anticarcinogen
Application in object.
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| Synthesis and Antiviral Activity of (E)-5-(2-Bromovinyl)uracil and (E)+ (2-Bromovinyl) uridine;Erik De Clercq,et al.;《Journal of Medicinal Chemistry》;19861231;第29卷(第2期);213-217 |
| 溴呋啶及其类似物的合成新方法研究;李培源等;《有机化学》;20151231;第35卷;910-916 |
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