CN103467549A - Sulfur-bearing uridine anticancer drug, intermediate and synthesis method - Google Patents
Sulfur-bearing uridine anticancer drug, intermediate and synthesis method Download PDFInfo
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Abstract
The invention relates to a synthesis method which comprises the steps of taking uridine as a principal raw material, treating with iodine and dilute nitric acid, obtaining 5-iodine uridine, treating with acetic anhydride to form 2',3',5'-O-trioxide acetyl-5-iodine uridine, allowing 2',3',5'-O-trioxide acetyl-5-iodine uridine to react with 2-(tributyl stannane) furan or thiophene by the action of triphenyl phosphine palladium chloride to form an intermediate, deprotecting by stirring in an ammonia methanol saturated solution at the room temperature by the action of phosphorus pentasulfide, and obtaining 5-(2-furyl or thienyl)-4-sulfur-bearing uridine. The compound has absorption at 363nm, and higher sensitivity to ultraviolet A, can enter inner cells of a tissue and act on cancer cells selectively, and overcomes the disadvantages that a photosensitive reagent for optic treatment at present is not gathered in nuclei and cannot selectively act on the cancer cells. The compound belongs to a novel base sulfur-bearing nucleoside compound, absorption light waves of the compound are in a long wavelength region, and the compound can selectively act on the inner cancer cells of the tissue, has a potential pharmaceutical value, and enters the inner cells of the tissue easily.
Description
Technical field
The present invention relates to a kind of new compound for the treatment of cancer and preparation method thereof, specifically, relate to 5-(2-furyl or thienyl)-4-sulphur uridine and analogue and intermediate and synthetic method, synthetic product UV spectrum has absorption at the 363nm place, to the UVA photaesthesia, be the medicine that is applicable to treat cancer.
Background technology
Malignant tumour is the leading killer who threatens the human life at present, though chemotherapy can reduce cancer mortality, existing anticarcinogen also has larger side effect to normal cell when killing and wounding cancer cells.Radiotherapy can accurately focus on ray on target tissue, but energetic ray also can injure normal cell when kill cancer cell.Operative treatment is still at present to the most effective methods for the treatment of of some tumour, but not is adapted to all treating malignant tumors.For middle and terminal cancer, operative treatment incapability basically is power.Clearly, chemotherapy, radiotherapy and operative treatment have drawback to patient, so we are in the urgent need to a kind of method of better treatment cancer, i.e. and the advantage of comprehensive chemotherapy, radiotherapy: the target position radiation effect of the medicine of chemotherapy and cancer cells effect and radiotherapy.Therefore, find target position accurately and do not injure or injure less Normocellular cancer therapy drug and become important advanced subject.Be now popular photodynamic therapy (
photo
dynamic
therapy, PDT) and the auxiliary cancer drug therapy method of the near-ultraviolet light (UVA) researched and developed be exactly two focuses.
Since two thousand one, the Peter Karran of Britain and doctor Xu Yaozhong carried out a large amount of research and find containing 4-sulphur Thymine deoxyriboside (referred to as: 4-sulphur thymidine) with near-ultraviolet light (UVA) synergy tumoricidal DNA optionally, and kill cancer cell and tissue thereof, propose a kind of auxiliary sulphur thymidine (UVA/4-thiothymidine) methods for the treatment of of cancer treatment method-near-ultraviolet light of novelty for this reason, utilize near-ultraviolet light and 4-sulphur thymidine synergy damage dna and cell thereof.Need continuous repetition DNA in rapid growth process due to cancer cells, cause the enrichment of 4-sulfo-thymidine, therefore, compare with normal tissue cell, it more easily is subject to the impact of near-ultraviolet ray.Research shows, the harmless low dosage near-ultraviolet light of normal tissue cell can kill the cancer cells that contains 4-sulphur thymidine DNA at an easy rate.This near-ultraviolet light/sulfo-thymidine therapy is also a kind of photochemotherapy, its principle is: small molecules photosensitizers (as 4-sulfo-thymidine) enters in the DNA of target cell, by a certain specific wavelength (near ultraviolet, visible or near infrared) momently illumination make their sensitivities, thereby kill cancer cell, optical wavelength used is essential can mate with the optical characteristics of photosensitizers well.Utilize near-ultraviolet light and 4-sulphur thymidine to act synergistically to damage DNA in proliferative cell, visible Fig. 1.
Research shows, to normal cell, harmless low dosage near-ultraviolet light can be at an easy rate kills the proliferative cell of the DNA that contains 4-sulphur thymidine.Visible, 4-sulphur thymidine, in conjunction with the therapy of near-ultraviolet light, has hypotoxicity, the potentiality of highly selective treatment cancer, to skin carcinoma, the cell of bladder cancer has killing effect, be a kind of potential cancer therapy drug, especially skin carcinoma and some other treatment that is subject to the tumour of influence of light received publicity.Although 4-sulphur thymidine can be as a kind of ucleosides new type anticancer medicine, but the near ultraviolet wavelength of 4-sulphur thymidine is at 335nm, poor to the tissue penetration ability, and the light excitation wavelength that the ability of light penetration tissue is subject to photosensitizers is relevant, the ability of the longer penetrate tissue of light wavelength is stronger, easily enters confluent monolayer cells in tissue.Therefore, research and development absorption light wave has been subject to people's attention at the photosensitizers of the new type anticancer medicine of Long wavelength region.
In photodynamic therapy and the auxiliary cancer drug therapy method of the near-ultraviolet light researched and developed, all need " photosensitive drug ".Therefore, develop new antitumor " photosensitive drug " with target, high selectivity be effectively control malignant tumour in the urgent need to.
Summary of the invention
The present invention aims to provide a kind of UV spectrum absorption at the 363nm place, UVA light is had to the compound for the treatment of cancer than strong sensitivity, i.e. intermediate and the synthetic method of sulfur-bearing uridine cancer therapy drug and this medicine (compound).
In order to reach the purpose of the invention described above, sulfur-bearing uridine cancer therapy drug provided by the invention, be 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,-deoxyuridine medicine, is characterized in that, 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,the chemical general formula I of-deoxyuridine is:
Wherein:
R
1represent H;
R
2represent H or OH.
Sulfur-bearing uridine cancer therapy drug intermediate of the present invention is 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,the intermediate of-deoxyuridine medicine, is characterized in that, the chemical general formula I of intermediate is:
Wherein:
R
1represent ethanoyl;
R
2represent OR
1perhaps H.
Sulfur-bearing uridine cancer therapy drug synthetic method of the present invention, i.e. general formula
ithe building-up reactions route of compound is as follows:
General formula (
i) described in the synthetic method of compound, concrete synthetic comprising the steps:
The first step, preparation 5-ioduria glycosides: under the condition of 110 ℃, uridine and iodine are in the salpeter solution of 3 mol/L, tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1), product is colourless to lower floor's solution with petroleum ether extraction, and lower floor's solution left standstill recrystallization obtains sterling
Second step, acetylize: under the condition of 0 ℃, 5-iodo-2
,the protection reagent diacetyl oxide of-deoxyuridine or 5-ioduria glycosides and hydroxyl reacts in pyridine solvent, and ethyl acetate and sherwood oil recrystallization for product, obtain via described R
1the product of protection
The 3rd step; upper thiphene ring or furan nucleus: under the condition that argon shield is 90 ℃; by the second step products therefrom in the dioxane solvent with 2-(tributyl tin alkyl) furans or thiophene, bi triphenyl phosphorus palladium chloride react; tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1); product adds the normal hexane vibration; the solid methylene dichloride obtained: methyl alcohol=1:1 recrystallization obtains sterling
The 4th step, sulphur replaces oxygen: the 3rd step products therefrom is reacted with thiophosphoric anhydride in the dioxane solvent, obtain 4-position sulphur and replace uridine and analogue thereof; Wherein, 1 ~ 1.5 times of equivalent that the consumption of thiophosphoric anhydride is the 3rd step product;
The 5th step, deacetylated: as ammonia to be filled in methanol solution and to prepare the methanol solution that ammonia is saturated, then the 4th step products therefrom is added in the methanol solution that ammonia is saturated and reacted, obtain 5-(2-furyl or thienyl)-4-sulphur uridine and analogue thereof.
5-(2-furyl or thienyl)-the preferred synthetic method of 4-sulphur uridine, comprise the steps:
The first step, preparation 5-ioduria glycosides: under the condition of 110 ℃, uridine and iodine are in the salpeter solution of 3 mol/L, tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1), product is colourless to lower floor's solution with petroleum ether extraction, and lower floor's solution left standstill recrystallization obtains sterling
Second step, acetylize: under the condition of 0 ℃, 5-iodo-2
,the protection reagent diacetyl oxide of-deoxyuridine or 5-ioduria glycosides and hydroxyl reacts in pyridine solvent, and ethyl acetate and sherwood oil recrystallization for product, obtain via described R
1the product of protection
The 3rd step; upper thiphene ring or furan nucleus: under the condition that argon shield is 90 ℃; by the second step products therefrom in the dioxane solvent with 2-(tributyl tin alkyl) furans or thiophene, bi triphenyl phosphorus palladium chloride react; tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1); gained oily product adds the normal hexane vibration; the solid methylene dichloride obtained: methyl alcohol=1:1 recrystallization obtains sterling
The 4th step, sulphur replaces oxygen: the 3rd step products therefrom is reacted with thiophosphoric anhydride in the dioxane solvent, obtain 4-position sulphur and replace uridine and analogue thereof; Wherein, 1 ~ 1.5 times of equivalent that the consumption of thiophosphoric anhydride is the 3rd step products therefrom
The 5th step, deacetylated: as ammonia to be filled in methanol solution and to prepare the methanol solution that ammonia is saturated, then the 4th step products therefrom is added in the methanol solution that ammonia is saturated and reacted, obtain 5-(2-furyl or thienyl)-4-sulphur uridine and analogue thereof.
Wherein, the method that the 4th step is removed impurity is: after reaction, at first under reduced pressure distillation is except desolventizing, and thick product is purified with silica gel column chromatography, the methylene dichloride that eluent is volume ratio 200:1: methyl alcohol, the lower distillation of decompression obtains yellow needle-like crystal except desolventizing.
The method of the 5th step purified product is, remove desolventizing under underpressure distillation, thick product is purified with silica gel column chromatography, and eluent is followed successively by a, methylene dichloride b, methylene dichloride: methyl alcohol=200:1 c, methylene dichloride: methyl alcohol=50:1, then go down to desolventize to obtain yellow needle-like crystal in vacuum.
The UV spectrum of the compounds of this invention and derivative thereof has absorption at the 363nm place, more responsive to UVA light.Therefore the compounds of this invention belongs to sulfur-bearing base novel nucleoside compound, can optionally act on cancer cell, overcomes the difficult problem that the photosensitive drug used in existing optical therapeutic can not optionally act on cancer cell.This compound under UV-irradiation, not only have antitumour activity and also can selectively acting in cancer cell, and toxic side effect is less, it will be the new derivatives for the auxiliary cancer drug therapy of near-ultraviolet light (UVA), further development research and clinical value are higher, application prospect is extensive, especially aspect the treatment skin carcinoma.
In addition, this synthetic method has advantages of that reaction conditions is simple, raw material is easy to get, cost is low, product yield is high, purity is high.Especially in the present invention, adopt diacetyl oxide as acetylation reagent; not only cost of material is cheap, product yield is high, catalyst activity is high, consumption is little, reaction conditions gentle (contrast Acetyl Chloride 98Min.), environmentally friendly; and aftertreatment is simple and easy to realize, thereby greatly improved its industrialized application prospect.
the accompanying drawing explanation
Fig. 1 is photochemotherapy (near-ultraviolet light/4-sulfo-thymidine therapy) schematic diagram; Fig. 2 is 4S5ThioU concentration and cell survival rate figure; Fig. 3 is 4S5ThiodU concentration and cell survival rate figure; Fig. 4 is 4SFurU concentration and cell survival rate figure; Fig. 5 is 4SFurdU concentration and cell survival rate figure.
embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented take technical solution of the present invention under prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The present invention relates to general formula 4-sulphur-5-(2-furyl or thienyl) synthetic method of uridine and derivative thereof.
R
1represent blocking group or the H of O;
R
2represent OR
1perhaps OH.
Under optimal way, specific O blocking group comprises alkyloyl and aroyl (as acyl group, specifically benzoyl), three substituted arylmethyl groups (trityl dimethoxy) and silylation (as trialkyl silane, specifically trimethyl silane).
In addition, compound (I) can mean tautomerism.Present discovery can comprise all tautomeric forms and mixture.Series compound (I) belongs to sulfur-bearing nucleosides treatment cancer drug, can be used for treating the disease that cancer is relevant.
The concrete synthesis step of general formula (I) compound is:
A. iodination reaction is carried out 5 iodination reactions by uridine or deoxyuridine under acidic conditions
B. the hydroxyl on protection sugar ring is protected idoxuridine (thymidine) or 5-ioduria glycosides via blocking group shown in general formula (I)
C. heterocyclic substituted iodine will be used the compound after blocking group shown in general formula (I) is protected to react with tributyl tin alkyl furans or thiophene, the 5-(2-furyl or the thienyl that are protected) uridine and derivative
D. sulphur replaces oxygen by 5-(2-furyl or the thienyl of protection) uridine and derivative react with thiophosphoric anhydride, get final product and to obtain 4-position sulphur replacement 5-(2-furyl or thienyl) uridine and analogue thereof
The protecting group of E. sloughing O as shown in general formula (I) is filled into ammonia in methanol solution and prepares the methanol solution that ammonia is saturated; again products therefrom in step D is added in the methanol solution that ammonia is saturated and reacts, can obtain 4-sulphur-5-(2-furyl or thienyl) uridine and derivative.
Described A step, be specially: under the condition of 110 ℃, uridine and iodine are in the salpeter solution of 3 mol/L, tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1), product is colourless to lower floor's solution with petroleum ether extraction, and lower floor's solution left standstill recrystallization obtains sterling.
Described B step is specially: under the condition of 0 ℃, 5-iodo-2
,the protection reagent of-deoxyuridine or 5-ioduria glycosides and hydroxyl, as diacetyl oxide, Benzyl Chloride, trimethylchlorosilane etc., reacts in pyridine or tetrahydrofuran solvent, and ethyl acetate and sherwood oil recrystallization for product, obtain via described R
1the product of protection.
Described C step; be specially: under the condition that argon shield is 90 ℃; by B walk products therefrom in the dioxane solvent with 2-(tributyl tin alkyl) furans or thiophene, bi triphenyl phosphorus palladium chloride react; tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1); product adds the normal hexane vibration; the solid methylene dichloride obtained: methyl alcohol=1:1 recrystallization obtains sterling.
Described D step is specially: C is walked to products therefrom and react with thiophosphoric anhydride in the dioxane solvent, obtain 4-position sulphur and replace 5-(2-furyl or thienyl) uridine and derivative thereof; Wherein, 1 ~ 1.5 times of equivalent that the consumption of thiophosphoric anhydride is C step products therefrom.
Described E step is specially: ammonia is filled in methanol solution and prepares the methanol solution that ammonia is saturated, then D is walked to products therefrom add in the saturated methanol solution of ammonia and reacted, obtain 5-(2-furyl or thienyl)-4-sulphur uridine and analogue thereof.
Embodiment 1: a kind of 4-sulphur-5-(2-furyl) uridine and its intermediate and synthetic method comprise the steps:
(1) 5-ioduria glycosides is synthetic
1H NMR (400 MHz, DMSO-d
6) (ppm): 11.71(br s,1H, N-H), 8.50(s, 1H, 6-H), 5.74(d, 1H, J = 4.0 Hz, 1’-H), 5.10, 5.29, 5.44(d, t, d, 1H, 1H, and 1H, OH), 4.05 (dd, 1H, J = 4.0 Hz, 8.0Hz, 2’-H), 4.00 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 3’-H), 3.89 (d, 1 H, J =4.0 Hz, 4’-H), 3.54-3.73 (m, 2H, 5’-H); UV-Vis (in CH
3CN), λmax/nm: 280.0, λmax/nm: 243.0。
(2) 2 ', 3 ', 5 '-O-triacetyl-5-ioduria glycosides synthetic
By 5-ioduria glycosides (1.00 g, 2.70 mmol), be dissolved in the anhydrous pyridine of 15 mL, after fully dissolving, it adds diacetyl oxide (3.0 mL, 32 mmol), reaction 5 h (reaction of tlc tracking monitor) under 0 ℃ of condition of ice bath.After reaction stops, under reduced pressure, steam solvent.Thick product ethyl alcohol recrystallization, obtain white solid 2 ', 3 ' after drying, 5 '-O-triacetyl-5-ioduria glycosides 1.23 g, and yield is 92%.M. p. 175-176 ℃, (literature value m. p. 177-178 ℃);
1H NMR(400 MHz, DMSO-d
6) (ppm): 11.83 (br s, 1H, NH), 8.18 (s, 1H,6-H), 5.88(d, J = 4.0 Hz, 1H, 1
，-H), 5.47 (dd, J=8.0 Hz and J = 8.0 Hz, 1H, 2’-H), 5.33~5.35 (m, 1H,3’-H), 4.31~4.36 (m, 1H, 4’-H), 4.21~4.27 (m, 2H, 5’-H), 2.06, 2.07, 2.08(3s, 3H, 3H, 3H, OAc); UV (in CH
3CN): λmin=257.0nm, λmax=226.5nm。
(3) 2 ', 3 ', 5 '-O-triacetyl-5-(2-furyl) uridine is synthetic
By 2 '; 3 '; 5 '-O-triacetyl-5-ioduria glycosides (2 g, 4.02 mmol), be dissolved in anhydrous one or four dioxane of 94ml; argon shield; add tributyl tin alkyl furans (8.70 g, 24.29 mmol), bi triphenyl phosphorus palladium chloride (0.0564 g; 0.08 mmol), reaction 1 hour (reaction of tlc tracking monitor) under 90 ℃ of conditions.After stopped reaction, cooling, diatomite filtration, the yellow oil obtained except desolventizing adds normal hexane 16ml jolting, filters the methylene dichloride of minimum for filter residue: methyl alcohol=1:1 heat of solution, be placed under 4 ℃ and obtain a large amount of pulverulent solids, 1.18 g that weigh after drying to obtain, yield 67.31%.m. p. 193-195℃。
1H NMR (400 MHz, DMSO-d
6) (ppm): 11.83(br s,1H, N-H), 8.06(s, 1H, 6-H), 7.70（s,1H,5
,,-H）,6.91(s,1H,3
,,-H),6.56(s,1H,4
,,H)6.04-6.05(d, 1H, J = 4.0 Hz, 1’-H), 5.48-5.49(d, 1H, J = 4.0 Hz, 2’-H),5.37 (m, 1H, 3’-H),4.31-4.34 (d, 3H, J = 12.0 Hz, 4’-H, 5’-H), 2.10(br s, 9 H, CH
3); UV-Vis (in CH
3CN): λmax/nm: 245.0, λmax/nm:313.5。
(4) 4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-furyl) uridine is synthetic
By 2 '; 3 '; 5 '-O-triacetyl-5-(2-furyl) uridine (1.00 g; 2.32 mmol); be dissolved in anhydrous one or four dioxane of 50 ml; add thiophosphoric anhydride (1.00 g, 4.50 mmol), reaction 4 hours (reaction of tlc tracking monitor) under 105 ℃ of conditions.After stopped reaction, cooling, filter, desolventize, column separating purification obtains yellow solid 0.675g, yield 64.29%.m. p. 189-191℃。
1H NMR (400 MHz, DMSO-d
6)(ppm):13.07(brs,1H,N-H),8.15(s,1H,6-H),7.71（s,1H,5
,,-H）,7.34-7.35(d,1H,J=4Hz,3
,,-H),6.57(s,1H,4
,,H)6.01-6.02(d, 1H, J = 4.0 Hz, 1’-H), 5.53-5.56(t, 1H, J = 4.0 Hz, 2’-H),5.38-5.40 (t, 1H, J=4Hz,3’-H),4.36-4.37 (m, 3H, 4’-H, 5’-H), 2.04-2.08(t,9 H, CH
3); UV-Vis (in CH
3CN): λmax/nm: 234.5, λmax/nm:285, λmax/nm:358.5。
(5) 4-sulphur-5-(2-furyl) uridine is synthetic
By 4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-furyl) uridine (0.36 g, 0.91 mmol) is dissolved in 96 ml ammonia methyl alcohol saturated solutions, stirring at room 5 hours (reaction of tlc tracking monitor).Column separating purification obtains yellow solid 0.1987g, yield 70.96 %.m. p. 211-213℃。
1H NMR (400 MHz, DMSO-d
6) (ppm): 12.91(brs,1H, N-H), 8.61(s,1H, 6-H), 7.61（s,1H,5
，，-H）,7.29-7.30(d,1H,J=4Hz,3
，，-H),6.52(s,1H,4
，，-H)，,5.81 -5.82(d, 1H, J = 4.0 Hz, 1’-H), 4.13-4.15(t, 1H, J = 4.0 Hz, 2’-H),4.02-4.04 (t, 1H, J=4Hz,3’-H),3.94 (s, 1H, 4’-H), 3.71-3.74(d,1 H, J = 12.0 Hz 5’-H) 3.59-3.62(d,1 H, J = 12.0 Hz ,5’-H); UV-Vis (in CH
3CN): λmax/nm: 234.5, λmax/nm:286.5, λmax/nm:362.5。
Embodiment 2: a kind of 4-sulphur-5-(2-thienyl) uridine and its intermediate and synthetic method comprise the steps:
(1) 5-ioduria glycosides is synthetic
1H NMR (400 MHz, DMSO-d
6) (ppm): 11.71(br s,1H, N-H), 8.50(s, 1H, 6-H), 5.74(d, 1H, J = 4.0 Hz, 1’-H), 5.10, 5.29, 5.44(d, t, d, 1H, 1H, and 1H, OH), 4.05 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 2’-H), 4.00 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 3’-H), 3.89 (d, 1 H, J =4.0 Hz, 4’-H), 3.54-3.73 (m, 2H, 5’-H); UV-Vis (in CH
3CN), λmax/nm: 280.0, λmax/nm: 243.0。
(2) 2 ', 3 ', 5 '-O-triacetyl-5-ioduria glycosides synthetic
By 5-ioduria glycosides (1.00 g, 2.70 mmol), be dissolved in the anhydrous pyridine of 15 mL, after fully dissolving, it adds diacetyl oxide (3.0 mL, 32 mmol), reaction 5 h (reaction of tlc tracking monitor) under 0 ℃ of condition of ice bath.After reaction stops, under reduced pressure, steam solvent.Thick product ethyl alcohol recrystallization, obtain white solid 2 ', 3 ' after drying, 5 '-O-triacetyl-5-ioduria glycosides 1.23 g, and yield is 92%.M. p. 175-176 ℃, (literature value m. p. 177-178 ℃);
1H NMR(400 MHz, DMSO-d
6) (ppm): 11.83 (br s, 1H, NH), 8.18 (s, 1H, 6-H), 5.88(d, J = 4.0 Hz, 1H, 1’-H), 5.47 (dd, J=8.0 Hz and J = 8.0 Hz, 1H, 2’-H), 5.33~5.35 (m, 1H, 3’-H), 4.31~4.36 (m, 1H, 4’-H), 4.21~4.27 (m, 2H, 5’-H), 2.06, 2.07, 2.08(3s, 3H, 3H, 3H, OAc); UV (in CH
3CN): λmax=257.0nm, λmax=226.5nm。
(3) 2 ', 3 ', 5 '-O-triacetyl-5-(2-thienyl) uridine is synthetic
By 2 '; 3 '; 5 '-O-triacetyl-5-ioduria glycosides (0.60 g, 1.21 mmol), be dissolved in anhydrous one or four dioxane of 60 ml; argon shield; add tributyl tin alkyl thiophene (1.03 g, 2.76 mmol), bi triphenyl phosphorus palladium chloride (0.02 g; 0.029 mmol), reaction 3 hours (reaction of tlc tracking monitor) under 90 ℃ of conditions.After stopped reaction, cooling, diatomite filtration, except the yellow oil that desolventizing obtains, 0.51 g that weighs to obtain after the post separation, yield 92.73 %.m. p. 178-181℃。
1H NMR(400 MHz,DMSO-d
6)(ppm): 11.83(brs,1H,N-H),8.17(s,1H,6-H),7.46- 7.50(m ,2H,5
,,-H,3
,,-H),7.07(m,1H,4
,,-H), 5.94-5.95(d, 1H, J = 4.0 Hz, 1
,-H), 5.57-5.60(t, 1H, J = 12.0 Hz, 3’-H),5.34-5.39 (m, 1H, 2’-H),4.25-4.36 (m, 3H, 4’-H, 5’-H), 2.04-2.06(m,9H, CH
3); UV-Vis(in CH
3CN): λmax/nm:262.0, λmax/nm:304.0。
(4) 4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-thienyl) uridine is synthetic
By 2 '; 3 '; 5 '-O-triacetyl-5-(2-thienyl) uridine (0.40 g; 0.88 mmol); be dissolved in anhydrous one or four dioxane of 40 ml; add thiophosphoric anhydride (0.41 g, 1.83 mmol), reaction 4 hours (reaction of tlc tracking monitor) under 105 ℃ of conditions.After stopped reaction, cooling, filter, desolventize, column separating purification obtains yellow solid 0.23 g, yield 56.1%.m. p.171-173℃。
1H NMR (400 MHz, DMSO-d
6) (ppm):13.07(brs,1H,N-H),8.05(s,1H,6-H),7.57- 7.58(d,1H,J=4.0Hz,5
,,-H),7.29-7.30(d,1H,J=4Hz,3
,,-H),7.06-7.08(t,1H,J=4Hz,4
,,-H),5.93-5.94(d, 1H, J = 4.0 Hz, 1’-H), 5.60-5.63(t, 1H, J = 4.0 Hz，,8.0Hz,3’-H),5.35-5.41 (m, 1H, 2’-H),4.24-4.36 (m, 3H, 4’-H, 5’-H), 2.07(m,9 H, CH
3); UV-Vis (in CH
3CN): λmax/nm: 239, λmax/nm:285, λmax/nm:348。
(5) 4-sulphur-5-(2-thienyl) uridine is synthetic
By 4-sulphur-2 ', 3 ', 5 '-O-triacetyl-5-(2-thienyl) uridine (1.00 g; 2.14 mmol) be dissolved in 60 ml ammonia methyl alcohol saturated solutions; add 10ml ammoniacal liquor, 80ml methyl alcohol, stirring at room 5 hours (reaction of tlc tracking monitor).Column separating purification obtains yellow solid 0.33 g, yield 45.21 %.m. p.185-187℃。
1H NMR (400 MHz, DMSO-d
6) (ppm): 12.89(brs,1H, N-H), 8.51(s,1H, 6-H), 7.47-7.48(d,1H,J=4.0Hz,5
,,H),7.27-7.28(m,1H,3
,,-H),6.98-7.00(m,1H,4
,,-H),5.75 -5.76(d, 1H, J = 4.0 Hz, 1’-H), 5.50-5.51(d, 1H, J = 4.0 Hz, OH),5.30-5.32 (t, 1H, J=4Hz,OH),5.06-5.07 (d,1H,J=4.0Hz 5’-OH), 4.10-4.14(m,1 H,3
,-H) 4.00-4.04(m,1 H,2
,-H),3.89-3.90（m,1H,4
,-H）3.56-3.72(m,2H,5
,-H); UV-Vis (in CH
3CN): λmax/nm: 239, λmax/nm:287, λmax/nm:356。
Embodiment 3: a kind of 4-sulphur-5-(2-furyl)-2'-deoxyuridine and its intermediate and synthetic method comprise the steps:
(1) 3', the iodo-2'-deoxyuridine of 5'-O-dioxy ethanoyl-5-synthetic
In the three-necked flask of 100 mL, add the iodo-2'-deoxyuridine of 5-(1.0 g, 2.82 mmol), anhydrous pyridine (15 mL, 183 mmol), after fully dissolving, it adds the diacetyl oxide of purifying (3.0 mL, 32 mmol), reaction 16 h under condition of ice bath, except desolventizing, then add methylene chloride and each 10 mL of benzene under reduced pressure, again remove desolventizing under reduced pressure, add methylene chloride again (20 mL), remove desolventizing under reduced pressure.Thick product is dissolved in methylene dichloride (250 mL), then adds saturated NaHCO
3(80 mL), use dichloromethane extraction three times.Organic phase anhydrous Na SO
4drying, filter, and filtrate removed under reduced pressure to desolventizing.The ethanol that adds 1.5 mL 95%, then be placed in mixture cooling 24 h of refrigerator freezing layer, separates out white solid 3', the iodo-2'-deoxyuridine of 5'-O-dioxy ethanoyl-5-(1.13 g, 2.58 mmol), and yield is 91%, m. p. 156-157 ℃.
1H NMR (400 MHz, DMSO-d
6) δ: 11.78 (br s, 1H, NH), 8.05 (s, 1H, 6-H), 6.11 (t, J=4.0 Hz, 8.0 Hz, 1H, 1'-H), 5.17-5.19 (m, 1H, 3'-H), 4.26 (d, J=4.0 Hz, 2H, 5'-H), 4.20 (s, 1H, 4'-H), 2.28-2.33 (m, 2H, 2'-H), 2.06 (s, 3H, -OC=OCH
3), 2.11 (s, 3H, -OC=OCH
3); HRMS (ES-TOF): 460.9842 [M+Na
+], Calcd for C
13H
15N
2O
7NaI: 460.9822; IR (film)/cm
-1 1740.2, 1708.7(C=O), 1689.4 (amide C=O) , 1611.6(C=C)。
(2) 3', 5'-O-dioxy ethanoyl-5-(2-furyl)-2'-deoxyuridine synthetic
By 3'; iodo-2'-deoxyuridine (0.50 g of 5'-O-dioxy ethanoyl-5-; 1.14 mmol); be dissolved in anhydrous one or four dioxane of 30 ml, argon shield, add tributyl tin alkyl furans (1.22 g; 3.42 mmol); bi triphenyl phosphorus palladium chloride (0.016 g, 0.023 mmol), reaction 3 hours (reaction of tlc tracking monitor) under 90 ℃ of conditions.After stopped reaction, cooling, diatomite filtration, except the yellow oil that desolventizing obtains, white solid 0.33 g that weighs to obtain after the post separation, yield 75.84 %.m. p.133-135℃。
1H NMR(500 MHz,DMSO-d
6)(ppm):11.72(brs,1H,N-H),7.98(s,1H,6-H),7.66(m ,1H,5
,,-H),6.89-6.90(m,1H,3
,,-H),6.54-6.55（dd,1H,J=4.0Hz,4
,,-H）,6.22- 6.25(m,1H,1
,-H) 5.22- 5.24(d, 1H, J = 8.0 Hz,3
,-H),4.27-4.29 (m, 3H, 4’-H,5’-H),2.35-2.46(m,2H,2
,-H), 2.08-2.10(m,6 H, CH3); UV-Vis (in CH
3CN): λmax/nm:246.5, λmax/nm:313.5。
(3) 4-sulphur-3 ', 5 '-O-triacetyl-5-(2-furyl)-2'-deoxyuridine synthetic
By 3'; 5'-O-dioxy ethanoyl-5-(2-furyl)-2'-deoxyuridine (0.5876 g; 1.55 mmol); be dissolved in anhydrous one or four dioxane of 40 ml; add thiophosphoric anhydride (0.6985 g; 3,15 mmol), reaction 3 hours (reaction of tlc tracking monitor) under 105 ℃ of conditions.After stopped reaction, cooling, filter, desolventize, column separating purification obtains yellow solid 0.30g, yield 49.18%.m. p. 156-159℃。
1H NMR (400 MHz, DMSO-d
6) (ppm): 13.00(br s,1H, N-H), 8.08(s,1H, 6-H), 7.67（s,1H,5
,,-H）,7.37(s,1H, 3
,,-H),6.55(s,1H,4
,,H)6.14-6.17(t, 1H, J =8.0Hz, 4.0 Hz,1’-H),5.22(s,1H,3’-H),4.27-4.33 (m,3H, 4’-H, 5’-H),3.57-3.64 (m, 3H,2
,-H), 2.03-2.08(m,9 H, CH
3); UV-Vis (in CH
3CN): λmax/nm: 231.5, λmax/nm:286, λmax/nm:362.5。
(4) synthesizing of 4-sulphur-5-(2-furyl)-2'-deoxyuridine
By 4-sulphur-3 ', 5 '-O-triacetyl-5-(2-furyl)-2'-deoxyuridine (0.28 g, 0.71 mmol) is dissolved in 45 ml ammonia methyl alcohol saturated solutions, stirring at room 5 hours (reaction of tlc tracking monitor).Column separating purification obtains yellow solid 0.10g, yield 45.45 %.m. p.196-199℃。
1H NMR(400 MHz,DMSO-d
6)(ppm):12.83(brs,1H,N-H),8.43(s,1H,6-H),7.56（s,1H, 5
,,-H）,7.26(m,1H, 3
,,-H),6.46-6.47(m,1H,4
,,H)，,6.06 -6.10(t, 1H, J = 8.0 Hz, 1’-H), 4.21-4.22(d, 1H, J = 4.0 Hz, 3’-H), ,3.81 (s, 1H, 4’-H), 3.51-3.60(dd,2 H, J = 12.0 Hz 5’-H) 2.17-2.19(t,2 H, J = 4.0 Hz ,2’-H); UV-Vis (in CH
3CN): λmax/nm: 234.0, λmax/nm:286.0, λmax/nm:363.0。
Embodiment 4: a kind of 4-sulphur-5-(2-thienyl)-2'-deoxyuridine and its intermediate and synthetic method comprise the steps:
(1) 3', the iodo-2'-deoxyuridine of 5'-O-dioxy ethanoyl-5-synthetic
In the three-necked flask of 100 mL, add the iodo-2'-deoxyuridine of 5-(1.0 g, 2.82 mmol), anhydrous pyridine (15 mL, 183 mmol), after fully dissolving, it adds the diacetyl oxide of purifying (3.0 mL, 32 mmol), reaction 16 h under condition of ice bath, except desolventizing, then add methylene chloride and each 10 mL of benzene under reduced pressure, again remove desolventizing under reduced pressure, add methylene chloride again (20 mL), remove desolventizing under reduced pressure.Thick product is dissolved in methylene dichloride (250 mL), then adds saturated sodium bicarbonate (80 mL), uses dichloromethane extraction three times.The organic phase anhydrous sodium sulfate drying, filter, and filtrate removed under reduced pressure to desolventizing.The ethanol that adds 1.5 mL 95%, then be placed in mixture cooling 24 h of refrigerator freezing layer, separates out white solid 3', the iodo-2'-deoxyuridine of 5'-O-dioxy ethanoyl-5-(1.13 g, 2.58 mmol), and yield is 91%, m. p. 156-157 ℃.
1H NMR (400 MHz, DMSO-d
6) δ: 11.78 (br s, 1H, NH), 8.05 (s, 1H, 6-H), 6.11 (t, J=4.0 Hz, 8.0 Hz, 1H, 1'-H), 5.17-5.19 (m, 1H, 3'-H), 4.26 (d, J=4.0 Hz, 2H, 5'-H), 4.20 (s, 1H, 4'-H), 2.28-2.33 (m, 2H, 2'-H), 2.06 (s, 3H, -OC=OCH
3), 2.11 (s, 3H, -OC=OCH
3); HRMS (ES-TOF): 460.9842 [M+Na
+], Calcd for C
13H
15N
2O
7NaI: 460.9822; IR (film)/cm
-1 1740.2, 1708.7(C=O), 1689.4 (amide C=O) , 1611.6(C=C)。
(2) 3', 5'-O-dioxy ethanoyl-5-(2-thienyl)-2'-deoxyuridine synthetic
By 3'; iodo-2'-deoxyuridine (0.50 g of 5'-O-dioxy ethanoyl-5-; 1.14 mmol); be dissolved in anhydrous one or four dioxane of 40 ml, argon shield, add tributyl tin alkyl thiophene (1.28 g; 3.42 mmol); bi triphenyl phosphorus palladium chloride (0.02 g, 0.0284 mmol), reaction 3 hours (reaction of tlc tracking monitor) under 95 ℃ of conditions.After stopped reaction, cooling, diatomite filtration, except the yellow oil that desolventizing obtains, white solid 0.40 g that weighs to obtain after the post separation, yield 88.89 %.m. p.98-100℃。
1H NMR(400 MHz,DMSO-d
6)(ppm):11.78(brs,1H,N-H),8.03(s,1H, 6-H),7.47- 7.50(m,2H,5
,,-H，3
,,-H),7.07-7.09（t,1H,J=4.0Hz,4
,,-H）, 6.18-6.21(t,1H, J =8.0Hz,4.0Hz,1
,-H)5.21-5.22(d,1H,J=8.0Hz,3
,-H),4.30(m,2H,5
,-H)4.23(m,2H,4
，-H),2.58-2.65(m,1H,2
,-H),2.32-2.38(m,1H,2
,-H),2.01-2.07(m, 6H,CH3); UV-Vis(in CH
3CN)：λmax/nm:258, λmax/nm:315
(3) 4-sulphur-3 ', 5 '-O-triacetyl-5-(2-thienyl)-2'-deoxyuridine synthetic
By 3'; 5'-O-dioxy ethanoyl-5-(2-thienyl)-2'-deoxyuridine (0.45 g; 1.14 mmol); be dissolved in anhydrous one or four dioxane of 25 ml; add thiophosphoric anhydride (0.45 g; 2.03 mmol), reaction 3 hours (reaction of tlc tracking monitor) under 105 ℃ of conditions.After stopped reaction, cooling, filter, desolventize, column separating purification obtains yellow solid 0.27g, yield 57.45%.m. p.80-83℃。
1H NMR (400 MHz, DMSO-d
6) (ppm): 13.01(br s,1H, N-H), 7.90(s,1H, 6-H), 7.56-7.57(d,1H,J=4.0Hz,5
,,-H),7.28-7.29(m,1H,3
,,-H),7.05-7.07(m,1H,4
,,H)6.11-6.15(m,1H,1’-H),5.20-5.22(d,1H,J=8.0Hz,3’-H),4.27 (m,3H, 4’-H, 5’-H),2.62-2.67(m,1H,2
,-H),2.33-2.40(m,1H,2
,-H),2.07(m,3H,CH
3),1.91(m,3H,CH
3);UV-Vis (in CH
3CN): λmax/nm: 239.0, λmax/nm:286, λmax/nm:352.0。
(4) synthesizing of 4-sulphur-5-(2-thienyl)-2'-deoxyuridine
By 4-sulphur-3 ', 5 '-O-triacetyl-5-(2-thienyl)-2'-deoxyuridine (0.27 g, 0.66 mmol) is dissolved in 43 ml ammonia methyl alcohol saturated solutions, stirring at room 5 hours (reaction of tlc tracking monitor).Column separating purification obtains yellow solid 0.10g, yield 47.62 %.m. p.181-183℃。
1H NMR(400 MHz,DMSO-d
6)(ppm):12.91(brs,1H,N-H),8.44(s,1H,6-H), 7.50-
7.51(d,1H,J=4.0Hz,5
,,-H),7.31-7.32(d,1H,J=4.0Hz,3
,,-H),7.02-7.04(m,1H,4
,,-H),6.12-6.15(t,1H,J=8.0 Hz,4.0 Hz,1
，-H),5.28-5.29(d,1H,J=4.0Hz,5
,-OH),5.21-5.24(t,1H,J = 4.0 Hz,8.0Hz, 3’-OH),4.28- 4.30(m,1H,3
,-H),3.85-3.86(d,1H,J=4.0Hz,4’-H),3.58-3.69(m,2 H,5’-H)，2.23-2.32(m,2 H, 2’-H); UV-Vis (in CH
3CN): λmax/nm: 239.0,λmax/nm:287.0,λmax/nm:356.0。
Embodiment 5: test In Vitro Anti mouse melanoma B16-F10 cytoactive
1, to the restraining effect of mouse melanoma B16-F10
The B16-F10 cell of taking the logarithm vegetative period, regulating cell concn with the DMEM nutrient solution containing 10% foetal calf serum and antibiotic is 10 * 10
5/ ml, add the 96 flat Tissue Culture Plates in hole, and every hole 100ul(approximately 10
4individual cell), put into 37 ℃, spend the night in 5% CO2gas incubator.Next day, will add containing the nutrient solution of different pharmaceutical in 96 orifice plates, every hole 100ul, and every kind of drug regimen is established three parallel holes, and the final concentration of medicine is 200um/L, 400um/L, 600um/L, 800um/L, 1000um/L, and control group only adds nutrient solution.Put into 37 ℃, cultivate 48 hours in 5% CO2gas incubator.
[0055] 2, MTT experiment (tetrazolium bromide colorimetry)
After cultivation finishes, every hole adds 20ulMTT solution (5mg/ml) to continue to cultivate 3 hours, takes out 96 orifice plates, discards whole supernatant liquors in hole, and dips in gently the debris in dry 96 orifice plates with clean paper handkerchief.Every hole adds 100ulDMSO, dissolves the light absorption value while then by microplate reader, getting wavelength 570nm 30 minutes.Record experimental result, processing data.Result is as shown in Fig. 2, Fig. 3, Fig. 4, Fig. 5.
The LD of table four kind of material
50concentration
| Material | LD 50Concentration/um/L |
| 4S5ThioU | 296 |
| 4S5ThiodU | 415 |
| 4S5FurU | 380 |
| | 400 |
From Fig. 2, Fig. 3, Fig. 4, Fig. 5, can find out, four kinds of compounds have good restraining effect to mouse melanoma B16-F10 cell.Can be found out four kinds of materials restraining effect to mouse melanoma B16-F10 cell, 4-sulphur-5-(2-thienyl by form) restraining effect of uridine is best comparatively speaking.
Claims (5)
1. a sulfur-bearing uridine cancer therapy drug, be 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,-deoxyuridine medicine, is characterized in that, 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,the chemical general formula I of-deoxyuridine is:
Wherein: R
1represent H;
R
2represent H or OH.
2. a sulfur-bearing uridine cancer therapy drug intermediate, it is 5-(2-furyl or thienyl)-4-sulphur uridine or 5-(2-furyl or thienyl)-4-sulphur-2
,the intermediate of-deoxyuridine medicine, is characterized in that, the chemical general formula I of intermediate is:
Wherein:
R
1represent ethanoyl;
R
2represent OR
1perhaps H.
3. a synthetic method for preparing sulfur-bearing uridine cancer therapy drug, comprise the steps:
The first step, preparation 5-ioduria glycosides: under the condition of 110 ℃, uridine and iodine are in the salpeter solution of 3 mol/L, tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1), reaction product is colourless to lower floor's solution with petroleum ether extraction, and lower floor's solution left standstill recrystallization obtains 5-ioduria glycosides sterling;
Second step, acetylize: under the condition of 0 ℃, 5-iodo-2
,the protection reagent diacetyl oxide of-deoxyuridine or 5-ioduria glycosides and hydroxyl reacts in pyridine solvent, and ethyl acetate and sherwood oil recrystallization for product obtain the product of purifying;
The 3rd step, upper thiphene ring or furan nucleus: under the condition that argon shield is 90 ℃, by the second step products therefrom in the dioxane solvent with 2-(tributyl tin alkyl) furans or thiophene, bi triphenyl phosphorus palladium chloride react, tlc (TLC) monitoring reaction (sherwood oil that developping agent is volume ratio: ethyl acetate=1:1), the oily product obtained adds the normal hexane vibration, the solid methylene dichloride obtained: methyl alcohol=1:1 recrystallization obtains purified product;
The 4th step, sulphur replaces oxygen: the 3rd step products therefrom is reacted with thiophosphoric anhydride in the dioxane solvent, obtain the product that 4-position sulphur replaces uridine; Wherein, 1 ~ 1.5 times of equivalent that the consumption of thiophosphoric anhydride is the 3rd step products therefrom;
The 5th step, deacetylated: as ammonia to be filled in methanol solution to the saturated methanol solution for preparing ammonia, then the 4th step products therefrom to be added in the saturated methanol solution of ammonia and reacted, obtain 5-(2-furyl or thienyl)-4-sulphur uridine.
4. 5-(2-furyl or thienyl according to claim 3)-synthetic method of 4-sulphur uridine and analogue thereof, it is characterized in that in described the 3rd step, 2-(tributyl tin alkyl) consumption of furans or the thiophene 4-6 times of equivalent that be the second step product.
5. 5-(2-furyl or thienyl according to claim 4)-synthetic method of 4-sulphur uridine and analogue thereof, it is characterized in that, the method of described the 5th step purified product is, remove desolventizing under underpressure distillation, thick product is purified with silica gel column chromatography, eluent is followed successively by a, methylene dichloride b, methylene dichloride: methyl alcohol=200:1 c, methylene dichloride: methyl alcohol=50:1, then go down to desolventize in vacuum.
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| CN104706654A (en) * | 2015-02-16 | 2015-06-17 | 大连大学 | Application of near ultraviolet irradiation 4-sulf-5-thienyl uridine in resisting melanin tumor cells and colon cancer cells |
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| CN113387895A (en) * | 2021-07-20 | 2021-09-14 | 新乡学院 | Synthesis method of nitric acid catalyzed 5-iodopyrimidine derivative |
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| CN106699827A (en) * | 2016-12-21 | 2017-05-24 | 江南大学 | Extended type fluorescent nucleoside analog and preparing method thereof |
| CN110105416A (en) * | 2019-06-17 | 2019-08-09 | 大连大学 | A kind of 4-S-5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods |
| CN111875654A (en) * | 2020-07-27 | 2020-11-03 | 大连大学 | Method for purifying 4-thionucleoside compound |
| CN113387895A (en) * | 2021-07-20 | 2021-09-14 | 新乡学院 | Synthesis method of nitric acid catalyzed 5-iodopyrimidine derivative |
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