CN105566304A - Sulfur-containing uridine anticancer compound and intermediate and preparation method thereof - Google Patents
Sulfur-containing uridine anticancer compound and intermediate and preparation method thereof Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
The invention relates to a 4-sulfur-5-(2-halogenated vinyl)uridine compound which has the higher sensibility to UVA light and the anticancer activity and an intermediate and preparation method of the compound. The method comprises the following steps that an iodination reaction is performed, a halogenating reaction is performed, hydroxyl on a sugar ring is protected, oxygen is replaced by sulfur, an O protection group is removed, and then 4-sulfur-5-(2-halogenated vinyl)uridine is obtained. The method has the advantages of being short in reaction time and high in yield and product purity, and the defects that in a traditional synthesis method, time and energy are consumed, and the yield is low are overcome. Beneficial conditions are supplied for further developing sulfur-containing nucleoside drugs.
Description
Technical field
The present invention relates to a kind of medical compounds and preparation method thereof, particularly a kind of have compared with 4-sulphur-5-(2-vinyl halides base) the uridine compound with antitumour activity of strong sensitivity and the intermediate of this compound and preparation method UVA light.
Background technology
At present in cancer therapy, chemotherapy, radiotherapy and operative treatment are not desirable treatment meanss, and chemotherapy and radiation is large to Normocellular lethality, and the recurrence rate of operative treatment is high, so the methods for the treatment of researching and solving these drawbacks becomes active demand.Therefore the proposition of photodynamic therapy, for research new type anticancer medicine provides new way.
Photodynamic therapy be one in conjunction with photosensitizers, light source and oxygen molecule, reacted the novel therapies for the treatment of malignant tumour by photodynamics.Its process is, first photosensitizers is injected patient's diseased region, then by specific band laser radiation affected areas, photosensitizers is excited.The photosensitizers of excited state to the oxygen of surrounding, generates transmission ofenergy active very strong singlet oxygen, singlet oxygen and adjacent biomacromolecule generation oxidizing reaction, produces cytotoxic effect, and then cause cell damage and even death.Compared with traditional method, photodynamic therapy, by optical fiber, endoscope and other interventional techniques, avoids the wound and misery of performing the operation and causing.Meanwhile, only absorbed by sick cell and retain due to photosensitizers, without general toxicity, effect light wave can not be absorbed by healthy tissues, so treatment only ensures normal tissue cell not damaged for pathological tissues.
At present, the research of photosensitive drug has obtained very large progress, and the basis of first-generation photosensitizer hematoporphyrin derivative develops s-generation 5-ALA (5-ALA) medicine.Third generation medicine is the blue or green class of the Radix Asparagi acyl group chlorin (Npe6) crosslinked with various material and phthalein.These medicines some be still in the zooscopy stage, what have enters clinical investigation phase.But the photosensitive drug used in existing photodynamic therapy is drained slowly in skin, the residence time is long, easily produce skin phototoxic reaction, treatments period needs lucifuge more than 20 days.Medicine can be especially more in liver,kidney,spleen throughout whole body with vein simultaneously, affects the normal physiological metabolism of body.For overcoming the above-mentioned shortcoming of photosensitive drug, scientists is still finding new photosensitive drug.
In the biological activity of nucleoside derivates, the structure of its base plays conclusive effect.Therefore, carrying out structure of modification to nucleoside base is the effective means finding new lead compound.N DNA does not comprise sulphur, and after Lipsett isolates 4-thiouracil Nucleotide from intestinal bacteria, sulfur-bearing base and thionucleoside attract the concern of people.Compared with normal DNA, sulfur-bearing base DNA has unique character, especially the pyrimidine ring series compound containing sulfydryl has antitumour activity and immuno-potentiation, this is because with traditional pyrimidine nucleosides Compound Phase ratio, thiopyrimidine base, in lipotropy, improves than traditional pyrimidine nucleoside tool.
In current thionucleoside, 6-azathioprine, Ismipur and 6-Tioguanine (6-TG) are the important drugs of Therapeutic cancer and inflammatory conditions, and wherein 6-azathioprine is the choice drug for the treatment of leukemia of children.Thionucleoside, except having important pharmaceutical use, also has certain side effect, and research finds that the patient skin pathology probability taking such medicine is large.This is because 6-TG is very strong UVA chromophoric group, this has very large difference compared with other DNA bases.DNA base has uv-absorbing at extreme ultraviolet (UVB, 290nm-340), and 6-TG maximum absorption wavelength is 340, belongs near ultraviolet region (320-400).6-TG nucleosides can be become and replace original DNA of 0.01-0.03% by enzyme after 6-TG enters cell DNA, the DNA in skin is strengthened the susceptibility of UVA light, so 6-TG and UVA causes cell to work in coordination with toxicity after combining.Its reason may be the oxidation that 6-TG can cause DNA and protein, then DNA break generation cross-coupling reaction, thus causes DNA pathology.By to the DNA damage of this base analog and the biochemical characteristic research of reparation, find that 6-TG has the effect postponing cytotoxic.But its side effect is strong, also can kill normal cell, go out very strong toxicity to cells show, so the photosensitive drug that necessary searching is new while killing cancer cells.
Summary of the invention
The object of the present invention is to provide a kind of have UVA light compared with strong sensitivity, there is the sulfur-bearing uridine compound of antitumour activity and the intermediate of this compound and preparation method.
In order to reach the object of foregoing invention, sulfur-bearing uridine cancer therapy drug provided by the invention, be 4-sulphur-5-(2-vinyl halides base) uridine, the chemical general formula (I) of 4-sulphur-5-(2-vinyl halides base) uridine is:
R
1the blocking group of representation hydroxy O or H;
R
2represent OR
1or OH;
X represents halogen.
Sulfur-bearing uridine anticancer compound intermediate of the present 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 is:
R
1the blocking group of representation hydroxy O or H;
R
2represent OR
1;
X represents halogen, carboxyl or ester group.
The synthetic method of the compound described in chemical general formula (I), concrete synthesis comprises the steps:
Steps A is specially: under 110 DEG C of conditions, and uridine and iodine monitor response situation by tlc in the dilute nitric acid solution of 0.212mol/L, and developping agent is CH
2cl
2: CH
3oH=7:1.Product petroleum ether extraction, collects lower floor's solution.The white solid of separating out is collected after leaving standstill.
Step B is specially: anhydrous Isosorbide-5-Nitrae-dioxane is added argon shield, is heated to 70 DEG C, add palladium, triphenylphosphine and triethylamine successively, be stirred to solution and become scarlet.Add the product of steps A, with acrylate reactions, monitor response situation by tlc, developping agent is CH
2cl
2: CH
3oH=7:1.Collecting by filtration filtrate, leaves standstill and has a large amount of solid to separate out to filtrate.Use dehydrated alcohol recrystallization, obtain white fluffy solid.
Step C comprises: step C1, to be hydrolyzed Reactive Synthesis (E)-5-(2-carboxyl vinyl)-uridine with step B product and sodium hydroxide solution; And step C2 (E)-5-(2-carboxyl vinyl)-uridine carries out halogenating reaction synthesis (E)-5-(2-vinyl halides base) uridine.
Step C1 is specially: dropwise joined in sodium hydroxide solution by (E)-5-(2-acrylate)-uridine solution, dropwise adds concentrated hydrochloric acid after reacting completely under condition of ice bath, until pH is 1, after leaving standstill, suction filtration obtains white solid.
Step C2 is specially: get (E)-5-(2-propylene carboxyl)-uridine and react with Anhydrous potassium carbonate and halogenating agent under 100 DEG C of conditions, revolves and steams removing half solvent, be placed in refrigerator overnight, obtain product after suction filtration.
Step D is specially: get step C product and react with anhydrous pyridine and acetic anhydride under condition of ice bath.Response situation is monitored by tlc.Except desolventizing under reduced pressure, obtain sticky mass, obtain pale solid with dehydrated alcohol recrystallization.
Step e is specially: get D step products and be dissolved in Isosorbide-5-Nitrae-dioxane, with P under 105 DEG C of conditions
2s
5reaction, by rich layer chromatography detection reaction situation, developping agent is PE:EA=1:1.Except desolventizing under reduced pressure, obtain brown-red solid.Make eluent with PE:EA=2:1, post is separated and obtains yellow solid.
Step F is specially: get E step products and react in methanolic ammonia solution, and by tlc detection reaction situation, developping agent is CHCl
2: CH
3oH=7:1.Except desolventizing under reduced pressure, obtain yellow solid, use CHCl
2: CH
3oH=7:1 post is separated, and obtains product.
The present invention also protects above-described compound preparing the application in cancer therapy drug.
Advantage of the present invention and positively effect are: compound of the present invention and derivative thereof can strengthen the sensitivity of tumour cell to ray, are used for the treatment of skin carcinoma better effects if with UVA after being combined.This compound and derivative thereof can enter in the DNA of tumour cell, are irradiated and interact to reach the effect of the DNA damaging the cell increased without limitation by UVA.After the UV-light of low dosage is combined with this compound, effectively can kills cancer cells, and normal cell is not poisoned.Therefore have broad application prospects in Therapeutic cancer especially skin carcinoma.
In addition, applying synthetic method of the present invention, to have the reaction times short, and productive rate is high, the feature that product purity is high, avoids the time consumption and energy consumption of prior synthesizing method, the shortcomings such as low yield.Favourable condition is provided for developing sulfur-bearing nucleoside medicine further.
Accompanying drawing explanation
Fig. 1 is human melanoma cell survival rate schematic diagram under different UV-irradiation.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented under premised on technical solution of the present invention, give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The present invention relates to the synthetic method of 4-sulphur-5-(2-vinyl halides base) uridine and intermediate.The feature of this compound is that its structure is:
R
1the blocking group of representation hydroxy O or H;
R2 represents OR
1or OH;
X represents halogen, carboxyl or ester group.
Under optimal way, the blocking group of specific hydroxyl O comprises alkyloyl and aroyl (as acyl group, particularly ethanoyl, benzoyl), three substituted arylmethyl groups (trityl dimethoxy) and silylation (as trialkyl silane, particularly trimethyl silane); Halogen is bromine or iodine.
In addition, this compound can represent tautomerism, and present discovery can comprise all tautomeric forms and mixture.This compound belongs to sulfur-bearing nucleosides Therapeutic cancer medicine, can be used for the disease that Therapeutic cancer is relevant.
The synthesis path of sulfur-bearing uridine anticancer compound of the present invention is as follows:
The concrete synthesis step of this compound is:
A. iodination reaction, carries out 5 iodination reactions in acid condition by uridine;
B.5 position substitution reaction, replaces iodine with acrylate, obtains (E)-5-(2-acrylate)-uridine;
C. halogen substiuted reaction, the product obtained with second step and halogenating agent Reactive Synthesis (E)-5-(2-halohydrocarbon)-uridine;
D. protect the hydroxyl on sugared ring, (E)-5-(2-halohydrocarbon)-uridine is protected via O blocking group general formula (I) Suo Shi;
E. sulphur replaces oxygen, and the compound after protecting using blocking group shown in general formula and thiophosphoric anhydride react, and obtain 4-sulphur-5-(2-vinyl halides base) uridine and analogue thereof;
F. slough the O blocking group shown in general formula (I), products therefrom in step 5 is dissolved in the methanolic ammonia solution prepared, 4-sulphur-5-(2-vinyl halides base) uridine can be obtained.
Described step A, is specially: under 110 DEG C of conditions, and uridine and iodine monitor response situation by tlc in the dilute nitric acid solution of 0.212mol/L, and developping agent is CH
2cl
2: CH
3oH=7:1.Product petroleum ether extraction, collects lower floor's solution.The white solid of separating out is collected after leaving standstill.
Described step B, is specially: anhydrous Isosorbide-5-Nitrae-dioxane is added argon shield, is heated to 70 DEG C, add palladium, triphenylphosphine and triethylamine successively, be stirred to solution and become scarlet.Add the product of steps A, with acrylate reactions, monitor response situation by tlc, developping agent is CH
2cl
2: CH
3oH=7:1.Collecting by filtration filtrate, leaves standstill and has a large amount of solid to separate out to filtrate.Use dehydrated alcohol recrystallization, obtain white fluffy solid.
Described step C, comprises further: C1 step, with step B product and sodium hydroxide solution Reactive Synthesis (E)-5-(2-carboxyl vinyl)-uridine; C2 step, carries out halogenating reaction synthesis (E)-5-(2-vinyl halides base) uridine with (E)-5-(2-carboxyl vinyl)-uridine.
Described C1 step, be specially: (E)-5-(2-is acrylate-based)-uridine solution is dropwise joined in sodium hydroxide solution, under condition of ice bath, dropwise add concentrated hydrochloric acid after reacting completely, until PH is 1, after leaving standstill, suction filtration obtains white solid.
Described C2 step, is specially: get (E)-5-(2-propylene carboxyl)-uridine and react with Anhydrous potassium carbonate and halogenating agent under 100 DEG C of conditions, revolves and steams removing half solvent, be placed in refrigerator overnight, obtain product after suction filtration.
Described D step, is specially: get step C product and react with anhydrous pyridine and acetic anhydride under condition of ice bath.Response situation is monitored by tlc.Except desolventizing under reduced pressure, obtain thick solid, obtain pale solid with dehydrated alcohol recrystallization.
Described E step, is specially: get D step products and be dissolved in Isosorbide-5-Nitrae-dioxane, with P under 105 DEG C of conditions
2s
5reaction, by rich layer chromatography detection reaction situation, developping agent is PE:EA=1:1.Except desolventizing under reduced pressure, obtain brown-red solid.Make eluent with PE:EA=2:1, post is separated and obtains yellow solid.
Described F step, is specially: get E step products and react in methanolic ammonia solution, and by tlc detection reaction situation, developping agent is CHCl
2: CH
3oH=7:1.Except desolventizing under reduced pressure, obtain yellow solid, use CHCl
2: CH
3oH=7:1 post is separated, and obtains product.
Embodiment 1:(E)-4-sulphur-5-(2-bromo vinyl)-uridine and intermediate and synthetic method, comprise the steps, in following steps, the ratio of developping agent or eluent is volume ratio:
(1) the iodo-uridine of 5-is synthesized by uridine
Get uridine (13.06g, 53.50mmol) to be dissolved in 252ml dust technology, be heated to 110 DEG C, add (10.09g, 39.92mmol) iodine, monitor response situation by tlc, developping agent is CH
2cl
2: CH
3oH=7:1, react raw material point after about 4 hours and disappear, explanation reacts completely, stopped reaction.Use 30ml petroleum ether extraction 3 times after leaving standstill cooling, collect lower floor's solution, upper solution 30ml deionized water extraction, merges lower floor's solution of twice extraction.Leave standstill adularescent solid to separate out, be placed in refrigerator upper strata, spend the night, obtain a large amount of white solid, be 5-I-uridine (14.30g, 38.64mmol), yield is 72.22%.M.p.206-209 DEG C (literature value m.p.208-210 DEG C);
1HNMR(500MHz,DMSO-d
6)δ11.69(s,1H,-NH),8.48(s,1H,6-H),5.72(d,J＝4.6Hz,1H,1’-H),5.43(s,1H,2’-OH),5.27(s,1H,3’-OH),5.08(s,1H,5’-OH),4.03(d,J＝4.1Hz,1H,2’-H),3.98(t,J＝4.4Hz,1H,3’-H),3.90–3.82(m,1H,4’-H),3.68(d,J＝11.6Hz,1H,5’-H),3.57(d,J＝11.7Hz,1H,5’-H).13CNMR(125MHz,DMSO-d
6)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
Get anhydrous Isosorbide-5-Nitrae-dioxane 360ml in 500ml there-necked flask, add argon shield, be heated to 70 DEG C; add palladium (0.31g, 1.38mmol) successively, triphenylphosphine (0.72g; 2.75mmol), triethylamine 5ml, stir about 30 minutes is until solution becomes scarlet.Add 5-I uridine (10.18g, 27.52mmol), methyl acrylate (7.11g, 82.56mmol, 7.11ml), monitors response situation by tlc, and developping agent is CH
2cl
2: CH
3oH=7:1, react raw material point after about 20 hours and disappear, explanation reacts completely, stopped reaction.Filter, collect filtrate, leave standstill, have a large amount of solid to separate out in filtrate, refilter.Filtration obtains solid dehydrated alcohol recrystallization, obtains white fluffy solid (6.57g, 20.01mmol).Yield is 72.71%.m.p.194-197℃.
1HNMR(400MHz,DMSO-d
6)δ11.67(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),5.77(d,J＝4.0Hz,1H,1’-H),5.46(d,J＝4.0Hz,1H,2’-OH),5.30(t,J＝4.0Hz,1H,3’-OH),5.08(d,J＝4.0Hz,1H,5’-OH),4.08(dd,J＝12.0,4.0Hz,1H,2’-H),4.01(dd,J＝12.0,4.0Hz,1H,3’-H),3.87(dd,J＝4.0Hz,4.0Hz,1H,4’-H),3.68(s,3H,-OCH
3),3.57(s,2H,5’-H).
13CNMR(125MHz,DMSO-d
6)δ167.61(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(-OCH
3).HRMS:[M+H]
+328.0927calculatedforC
13H
16N
2O
8；found329.0972.UV-Vis(inCH
3CN)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
Get (E)-5-(2-methyl acrylate base)-uridine (6.00g, 18.29mmol) in 250ml round-bottomed flask, dropwise add 73ml2M sodium hydroxide solution, stirring at room temperature is after 3 hours, dropwise concentrated hydrochloric acid is added under condition of ice bath, use PH detection paper, until PH is 1, now have a large amount of white precipitate to generate.Leave standstill half an hour, suction filtration, gained solids washed with water, obtains white solid (5.31g, 16.89mmol).Yield is 92.34%.m.p.269-270℃.
1HNMR(400MHz,DMSO-d
6)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),4.09(t,J＝4.0Hz,1H,2’-H),4.04(t,J＝4.0Hz,1H,3’-H),3.89(d,J＝4.0Hz,1H,4’-H),3.70(m,J＝4.0Hz,1H,5’-H),3.61(dd,J＝8.0Hz,1H,5’-H).
13CNMR(125MHz,DMSO-d
6)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]
+337.0570calculatedforC
12H
14N
2O
8；found337.0632.UV-Vis(inCH
3CN)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
Get (E)-5-(2-propylene carboxyl)-uridine (4.50g, 14.31mmol) and be placed in 500ml there-necked flask, add 120ml water and heat 100 DEG C of stirrings.Add Anhydrous potassium carbonate 1.20g.Get NBS1.3g to be dissolved in in 22.5ml water in 22.5ml acetone, and drop in flask by mixed solution, at least 135min dropwises.Stir 3 hours, stopped reaction, revolve and steam removing half solvent, be placed in refrigerator, spend the night.Have a large amount of needle-like brown crystal to separate out, suction filtration, obtains product (2.70g, 7.73mmol).Yield is 50.54%.m.p.170-172℃.
1HNMR(400MHz,DMSO-d
6)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),4.05(t,J＝4.0Hz,1H,2’-H),4.00(t,J＝4.0Hz,1H,3’-H),3.86(dd,J＝8.0,4.0Hz,1H,4’-H),3.71(dd,J＝12.0,8.0Hz,1H,5’-H),3.59(dd,J＝12.0,8.0Hz,1H,5’-H).
13CNMR(125MHz,DMSO-d
6)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]
+370.9855calculatedforC
11H
13BrN
2O
6Na；found372.9815.UV-Vis(inCH
3CN)λmax/nm:251,295.IR(fim)
-1:3358(OH),1698.0(C＝O),1467.8,1384.5(NH).
(5) (E)-2 ' is synthesized by (E)-5-(2-bromo vinyl)-uridine, 3 ', 5 '-O-triacetyl-5-(2-bromo vinyl)-uridine
Get (E)-5-(2-bromo vinyl)-uridine (2.50g, 7.16mmol) in 100ml there-necked flask, add anhydrous pyridine 21.00ml under condition of ice bath, acetic anhydride (4.81ml, 50.77mmol).Monitor response situation by tlc, react after about 5 hours, raw material point disappears, and explanation reacts completely, stopped reaction.Except desolventizing under reduced pressure, obtain thick solid, use dehydrated alcohol recrystallization, obtain pale solid (2.87g, 6.03mmol).Productive rate 84.25%.m.p.191-193℃。
1HNMR(400MHz,DMSO-d
6)δ11.74(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),5.92(d,J＝4.0Hz,1H,1’-H),5.45(dd,J＝4.0Hz,8.0Hz,1H,2’-H),5.35–5.33(m,1H,3’-H),4.34(t,J＝8.0Hz,1H,4’-H),4.28–4.23(m,2H,5’-H),2.08–2.05(m,9H,3×-CH
3).
13CNMR(125MHz,DMSO-d
6)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×-CH
3).HRMS:[M+Na]
+497.0172calculatedforC
17H
19BrN
2O
9Na；found397.0171,500.0186.UV-Vis(inCH
3CN)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 synthesis (E)-4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-bromo vinyl)-uridine
Get (E)-2 ', 3 ', 5 '-O-triacetyl-5-(2-bromo vinyl)-uridine (2.29g, 4.81mmol), is dissolved in 193m11,4-dioxane, is heated to 105 DEG C.Add P
2s
5(2.15g, 9.62mmol), starts reaction, and by rich layer chromatography detection reaction situation, developping agent is PE:EA=1:1, reacts raw material point after 4 hours and disappears, stopped reaction.Except desolventizing under reduced pressure, obtain brown-red solid.Make eluent with PE:EA=2:1, post is separated and obtains yellow solid (0.73g, 1.49mmol).Yield is 31.05%.m.p.200-202℃.
1HNMR(400MHz,DMSO-d
6)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(d,J＝4.0Hz,1H,1’-H),5.57(dd,J＝8.0,4.0Hz,1H,2’-H),5.38(t,J＝6.0Hz,1H,3’-H),4.38–4.33(m,1H,4’-H),4.31–4.26(m,2H,5’-H),2.08–2.03(m,9H,3×-CH
3).
13CNMR(125MHz,DMSO-d
6)δ188.77(-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×-CH
3).HRMS:[M+Na]
+512.9943calculatedforC
17H
19BrN
2NaO
8SNa；found512.9950.UV-Vis(inCH
3CN)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)-uridine synthesis (E)-4-sulphur-5-(2-bromo vinyl)-uridine
Get (E)-4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-bromo vinyl)-uridine (0.60g; 1.22mmol), methanolic ammonia solution 120ml, stirring at room temperature; by tlc detection reaction situation, developping agent is CHCl
2: CH
3oH=7:1, stopped reaction after about 4 hours.Except desolventizing under reduced pressure, obtain yellow solid, use CHCl
2: CH
3oH=7:1 post is separated, and obtains product (0.15g, 0.42mmol).Yield is 34.58%.m.p.170-172℃.
1HNMR(400MHz,DMSO-d
6)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),5.71(d,J＝4.0Hz,1H,1’-H),4.11–4.10(m,1H,2’-H),4.04–4.02(m,1H,3’-H),3.90–3.89(m,1H,4’-H),3.78(dd,J＝12.0,4.0Hz,1H,5’-H),3.62(dd,J＝12.0,8.0Hz,1H,5’-H).
13CNMR(125MHz,DMSO-d
6)δ188.06(-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]
+386.9626calculatedforC
11H
13BrN
2O
5SNa；found388.9610.UV-Vis(inCH
3CN)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 A375 cytoactive of test body
1, to the restraining effect of human melanoma cell A375
The A375 cell (human melanoma cell) of taking the logarithm vegetative period, regulates cell concn to be 10 × 10 with the DMEM nutrient solution containing 10% foetal calf serum and antibiotic
5/ mL, adds two 96 flat Tissue Culture Plates in hole, every hole 100 μ L (about 10
4individual cell), put into 37 DEG C, cultivate 24 hours in 5% CO2gas incubator.Next day, add in experimental group 96 orifice plate by the nutrient solution containing (E)-4-sulphur-5-(2-bromo vinyl)-uridine (4-SBVU) and contrast testing drug (E)-5-(2-bromo vinyl)-uridine (BVU), often kind of drug regimen establishes three parallel holes.Every pore volume is 100 μ L, adds appropriate amount of drug solution, makes medicine ultimate density be 100 μMs/L, only adds nutrient solution, do not add medicine in blank group 96 orifice plate.Two plates are placed on 37 DEG C, cultivate 48 hours in 5% CO2gas incubator.
2, MTT experiment (MTT method)
Cultivation terminates rear every hole and adds 20 μ LMTT solution (5mg/mL) and continue cultivation 3 hours, takes out 96 orifice plates, discards whole supernatant liquor in hole, and dip in the debris in dry 96 orifice plates gently with clean paper handkerchief, not crystal in destroying pores.Every hole adds 100 μ LDMSO, dissolves 30 minutes, then measures the light absorption value at wavelength 570nm place by microplate reader, i.e. OD value.Record experimental result, processing data, obtains cell survival rate %=(OD experiment/OD contrasts) × 100%.
Illumination contrast experiment medicine used is 100 μMs/L (E)-5-(2-bromo vinyl)-uridine; (E)-4-sulphur-5-(2-bromo 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 UV-irradiation 96 orifice plate; cultivate without UV-irradiation under control group the same terms, UV-light dosage is 15KJ/m
2, measure its OD value respectively, calculate cell survival rate.Experimental result as shown in Figure 1.
As can be seen from Figure 1: 1) in blank assay, when not adding BVU and 4-SBVU two kinds of medicines, ultraviolet lighting is only used to have certain lethal effect to cancer cells; 2), when not using uv irradiating, when two kinds of drug levels are identical, the cancer cell survival rate of 4-SBVU effect is obviously low than the survival rate of BVU, and after nucleosides sulfo-is described, antitumour activity obviously strengthens; 3) when using uv irradiating, when two kinds of drug levels are identical, the cancer cell survival rate of 4-SBVU effect is obviously low than the survival rate of BVU, and after acting synergistically to ultraviolet after nucleosides sulfo-is described, antitumour activity obviously strengthens compared to corresponding nucleosides and the synergistic cancer resistance of ultraviolet; 4), when adding same drug effect respectively, obviously than low without the survival rate of cancer cells during uv irradiating under ultraviolet irradiation condition, illustrate that the synergy of UV-light is conducive to medicine is strengthened the lethal effect of cancer cells.
Claims (10)
1. a sulfur-bearing uridine anticancer compound, be 4-sulphur-5-(2-vinyl halides base) uridine, it is characterized in that, the chemical general formula (I) of 4-sulphur-5-(2-vinyl halides base) uridine is:
R
1the blocking group of representation hydroxy O or H;
R
2represent OR
1or OH;
X represents halogen.
2. an intermediate for sulfur-bearing uridine anticancer compound, be the intermediate of 4-sulphur-5-(2-vinyl halides base) uridine, it is characterized in that, the chemical general formula (I) of described intermediate is:
R
1the blocking group of representation hydroxy O or H;
R
2represent OR
1;
X represents halogen, carboxyl or ester group.
3. prepare a synthetic method for sulfur-bearing uridine anticancer compound, comprise the steps:
A. iodination reaction, carries out 5 iodination reactions in acid condition by uridine;
B.5 position substitution reaction, replaces iodine with acrylate, obtains (E)-5-(2-is acrylate-based)-uridine;
C. halogenating reaction, with the product obtained in step B and halogenating agent Reactive Synthesis (E)-5-(2-vinyl halides base) uridine;
D. protect the hydroxyl on sugared ring, (E)-5-(2-vinyl halides base) uridine is protected via O blocking group general formula (I) Suo Shi;
E. sulphur replaces oxygen, and the compound after protecting using blocking group shown in logical formula I and thiophosphoric anhydride react, and obtain 4-sulphur-5-(2-vinyl halides base) uridine and analogue thereof;
F. slough the hydroxyl O blocking group shown in general formula (I), products therefrom in step e is dissolved in the methanolic ammonia solution prepared, 4-sulphur-5-(2-vinyl halides base) uridine can be obtained.
4. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, is characterized in that: described step C comprises further:
C1. to be hydrolyzed Reactive Synthesis (E)-5-(2-carboxyl vinyl)-uridine with step B products therefrom and sodium hydroxide solution;
C2. (E)-5-(2-carboxyl vinyl)-uridine is used to carry out halogenating reaction synthesis (E)-5-(2-vinyl halides base) uridine;
Described step C1 is specially: dropwise joined in sodium hydroxide solution by (E)-5-(2-acrylate)-uridine solution, under condition of ice bath, dropwise concentrated hydrochloric acid is added after reacting completely, until pH is 1, after leaving standstill, suction filtration obtains white solid; Described step C2, is specially: get (E)-5-(2-propylene carboxyl)-uridine and react with Anhydrous potassium carbonate and halogenating agent under 100 DEG C of conditions, revolves and steams removing half solvent, be placed in refrigerator overnight, obtain product after suction filtration.
5. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, described steps A is specially: under 110 DEG C of conditions, uridine and iodine react in the dilute nitric acid solution of 0.212mol/L, monitor response situation by tlc, and developping agent is CH
2cl
2: CH
3oH=7:1; Product petroleum ether extraction, collects lower floor's solution; The white solid of separating out is collected after leaving standstill.
6. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, described step B is specially: anhydrous Isosorbide-5-Nitrae-dioxane is added argon shield, is heated to 70 DEG C, add palladium, triphenylphosphine and triethylamine successively, be stirred to solution and become scarlet; Add the product of steps A, with acrylate reactions, monitor response situation by tlc, developping agent is CH
2cl
2: CH
3oH=7:1; Collecting by filtration filtrate, leaves standstill and has a large amount of solid to separate out to filtrate; Use dehydrated alcohol recrystallization, obtain white fluffy solid.
7. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, described step D is specially: get step C product and react with anhydrous pyridine and acetic anhydride under condition of ice bath; Response situation is monitored by tlc; Except desolventizing under reduced pressure, obtain sticky mass, obtain pale solid with dehydrated alcohol recrystallization.
8. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, described E step is specially: get D step products and be dissolved in Isosorbide-5-Nitrae-dioxane, with P under 105 DEG C of conditions
2s
5reaction, by rich layer chromatography detection reaction situation, developping agent is PE:EA=1:1; Except desolventizing under reduced pressure, obtain brown-red solid; Make eluent with PE:EA=2:1, post is separated and obtains yellow solid.
9. a kind of synthetic method preparing sulfur-bearing uridine anticancer compound according to claim 3, described F step is specially: get E step products and react in methanolic ammonia solution, and by tlc detection reaction situation, developping agent is CHCl
2: CH
3oH=7:1; Except desolventizing under reduced pressure, obtain yellow solid, use CHCl
2: CH
3oH=7:1 post is separated, and obtains product.
10. the compound in claim 1 or 2 described in arbitrary claim is preparing the application in cancer therapy drug.
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| CN101862345A (en) * | 2000-10-18 | 2010-10-20 | 法玛塞特公司 | The modified nucleosides that is used for the treatment of viral infection and abnormal cell proliferation |
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