CN101215303B - Xylosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic - Google Patents

Xylosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic Download PDF

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CN101215303B
CN101215303B CN2008100017098A CN200810001709A CN101215303B CN 101215303 B CN101215303 B CN 101215303B CN 2008100017098 A CN2008100017098 A CN 2008100017098A CN 200810001709 A CN200810001709 A CN 200810001709A CN 101215303 B CN101215303 B CN 101215303B
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xylosyl
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ethanoyl
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CN101215303A (en
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张书圣
詹天荣
杨波
程坤
夏有凤
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Qingdao University of Science and Technology
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Abstract

The invention discloses a group xylose thiourea heterocyclic compound and a preparation process and heterocyclic compound. The heterocyclic compound is showed by following general formula, and B in the general formula is defined in instruction book. The invention introduces a process with six steps which comprises using xylose, bromine water, lead sulfocyanide, heterocyclic base, ethyl chloroacetate and hydrazine hydrate as raw material, using glacial acetic acid, trifluoroacetic acid, xylol, toluene, ethylbenzene, N, N- dimethyl formamide, dimethyl sulfoxide, dioxane, pyridine, methyl alcohol, ethyl alcohol, isopropyl alcohol, absolute methanol and absolute ethyl alcohol as solution, using sodium hydride, anhydrous potassium carbonate and sodium methoxide as basic catalyst, synthesizing xylose thiourea heterocyclic compound. The compound of the invention plays habitation role with different degrees for human lung cancer cell lines and human liver cancer cell lines.

Description

Xylosyl thiourea heterocyclic compound and compound method thereof and in the application of anti-tumor aspect
Technical field:
The present invention relates to one group of xylosyl thiourea heterocyclic compound; The invention still further relates to the compound method of said all compounds and in the application of anti-tumor aspect.
Background technology:
Saccharide compound is familiar with by people as the storage carrier of energy in vivo already; Deep development along with molecular biology and cytobiology; Other biological function of sugar is also disclosed by people gradually; As playing an important role in its many in vivo recognition process of informational molecule, like [Cleophax, J. such as bacterium and virus infection organism, signal conduction; Olesker.A.; Rolland, A.; Gero, S.D.Tetrahedron 1977,33, and 1303.], the research of carbohydrate has become hot fields [(a) Spedaliere, a C.J.; Ginter, J.M.; Johnston, M.V.; Mueller, E.G.Am.Chem.Soc.2004,126,12758. (b) Chayajarus, K.; Chambers, D.J.; Chughtai, M.J.; Fairbanks, A.J.Org.Lett.2004,3797. (c) Xu, R.; Hanson.S.R.; Zhang, Z.W.; Yang, Y.Y.; Schultz, P.G.; Wong, C.H.J.Am.Chem.Soc.2004,126,15654. (d) Casas-Solvas, J.M.; Vargas-Berenguel, A.; Capit á n-Vallvey, L.F.; Santoyo-Gonzfilez, F.Org.Lett.2004,6 (21), 3687.], saccharide compound is almost being participated in all bioprocesss in the life entity, is a kind of important biological material.The verivate that experiment showed, sugar also has many biological activitys, has anti-tumor activity [(a) Sun Lvjun, Qi Yuxin, Li Aixia, Zhang Huakun, Zhang Jianguo like 5 FU 5 fluorouracil glucose nitrogen glycosides; China's pharmaceutical chemistry magazine, 1999,9,245. (b) Sun Lvjun, Wang Yigui, Chen Zaicheng, Xue Peng; Hu Weifeng, Xu Beili, Zhao Yueran, Wang Meiling, SCI, 1994; 15,1168.], 1,7-diaryl-3, the glucose oxygen glycosides of 5-heptanediol has activity [Akihito, the Y. of cell killing toxin; Yoshihiro, M.; Hiroshi, S.; Yutaka, S.J.Nat.Prod.2002,65,283.], phenyl methyl ketone class glucoside has Burdock activity [Araceli, S.; Maria, C.R.; Rosa Manri á, G.; Salvador, M.; Jos ó-Luis, R.J.Nat.Prod.2001,64,1360.], the flavonoid glucoside has anti-oxidant activity [Hou, L.F.; Zhou, B.; Yang, L.; Liu, Z.L.Org.Bioorg.Chem.2004,2,1419.], ganoderan, lentinan are used for the cancer-resisting activity, Bay g 5421 (Acarbose) treatment diabetic activity etc. [Service, R.F.Science 2001,291, and 2340.].
Thiourea derivative receives people's attention [Schroeder, D.C.Chem Rev, 1995,181.] with its wide biological activity.But the synthetic and property research of glycosyl thiourea derivative rarely has report [Goodman, I.A dv CarbohydrChem, 1958; 13:233.], and as the saccharide compound of biological intravital adaptive molecule, can the signaling molecule sugared ginseng and nearly all bioprocess [Ajit Varki.Glycobiology in the life entity; 1993,3 (2), 97.]; And nitrogen glycosides compound itself also shows numerous important physical active [Garg, H.G; Jeanloz, R.W.A dv CarbohydrChem Biochem, 1985,43,135.], in addition, the pulsating introducing of glycosyl can improve the water-soluble of amido thiourea significantly.Therefore, synthesize at same intramolecularly and not only contained glycosyl but also contained compound significant work of ten minutes beyond doubt of amido thiocarbamide.At present, the research in this field has obtained carrying out, like [Yu Jianxin, Liu Fangming such as Yu Jianxins; Li Yanping, Cheng Liang, model is admired; Liu Yuting. applied chemistry, 1996,16 (4); 41.] having synthesized 1-aroyl-4-(1 '-N-β-D-pyranose form xylosyl) thiosemicarbazide compound, general formula is 1, primary structure is the glycosyl thiosemicarbazide in this compounds; Another one molecule segment is an aryl, and Given this outstanding biological activity that compound had of class formation and good physicochemical property (good water solubility) are synthesized the very big concern that new glycosyl thiosemicarbazide verivate has attracted vast chemistry and medical science men.Up to now, aryl is mainly the verivate of benzene in this compounds, comprises benzo class heterocyclic base, and the work of carrying out is not a lot, and aryl by natural base and verivate thereof the compound that forms of establishment do not appear in the newspapers.
Figure S2008100017098D00021
Be research glycosyl thiosemicarbazide heterogeneous ring compound, compound method and anti-tumor activity thereof; The present invention has synthesized xylosyl thiosemicarbazide VITAMIN B4, xylosyl thiosemicarbazide benzoglyoxaline, xylosyl thiosemicarbazide methoxybenzoyl phenalgin and imidazoles; And carry out the research of anti-tumor activity, obtain novel glycosyl thiosemicarbazide heterocyclic antineoplastic compound in the hope of screening.
Xylosyl thiosemicarbazide VITAMIN B4 provided by the present invention, xylosyl thiosemicarbazide benzoglyoxaline, xylosyl thiosemicarbazide methoxybenzoyl phenalgin and imidazoles are so far and do not see the new compound that relevant report is arranged.
Summary of the invention:
Deficiency and this area research and demands of applications to prior art the purpose of this invention is to provide one group of xylosyl thiourea compound; The present invention simultaneously also provides the compound method of said all compounds and in the application of anti-tumor aspect.
The present invention is to be the skeleton of target compound with the xylosyl thiocarbamide; With reference to 1-aroyl-4-(1 '-N-β-D-pyranose form xylosyl) thiosemicarbazide compound structure characteristics; Aroyl is wherein replaced with the fragrant acyl group of hetero-aromatic ring; Through polystep reaction, one type of novel xylosyl thiosemicarbazide VITAMIN B4, xylosyl thiosemicarbazide benzoglyoxaline, xylosyl thiosemicarbazide methoxybenzoyl phenalgin and imidazoles have been synthesized in design, and have studied their anti-tumor activity.
One group of glycosyl thiourea heterogeneous ring compound provided by the invention, its structure is suc as formula shown in (I):
Figure S2008100017098D00031
Wherein:
B is one of VITAMIN B4, guanine, purinethol, xanthoglobulin, cytosine(Cyt), uracil, thymus pyrimidine, triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned heterocyclic base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C1-C5 alkyl, C2-C5 thiazolinyl or C2-C5 alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C1-C5 alkoxyl group, C2-C5 alkenyloxy or C2-C5 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C1-C5 alkylthio, C2-C5 alkenyl thio or C2-C5 sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C1-C5 ester group.
The present invention is the wood sugar with full acid esterification, bromine water, and plumbous rhodanate, heterocyclic base, ethyl chloroacetate, Hydrazine Hydrate 80 are raw material, synthetic through six steps, synthetic route is following:
Figure S2008100017098D00032
Reaction?conditions：i)P，Br 2；ii)Pb(SCN) 2，(CH 3) 2C 6H 4；iii)NaH，ClCH 2COOC 2H 5；
iv)H 2NNH 2·H 2O，MeOH/EtOH；v)Ar，DMF；vi)MeONa/MeOH，pH＝8.0.
Wherein, identical in B and the claim 1.
The first step: 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose synthetic
Add red phosphorus and acid solvent in the there-necked flask, add bromine water with tap funnel, mixed reaction solution stirred 0.2～10 hour under 10～80 ℃ of conditions, filtered and discarded red phosphorus.Add full acetylated wood sugar, react under the same temperature, the wood sugar full acetylated up to the thin-layer chromatography detecting reactant all disappears.Acid solvent is removed in decompression, and residue is with saturated sodium carbonate and chloroform extraction, and organic extract liquid is with saturated common salt water washing 2～5 times, and anhydrous sodium sulfate drying reduces pressure and removes organic solvent and get white solid 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose.
This step is applicable to all above-mentioned 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose synthetic.
Second step: 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3 with tap funnel after the reflux; The xylene solution of 4-three-O-ethanoyl-alpha-D-xylose, reaction solution back flow reaction 0.5～72 hour is filtered and is discarded remaining plumbous rhodanate; Removal of solvent under reduced pressure, residue get white crystalline solid 2 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; 3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates.
This step is applicable to that all are above-mentioned 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates synthetic.
The 3rd step: hetero-aromatic ring guanidine-acetic acid ethyl ester synthetic
Hetero-aromatic ring base and anhydrous alkaline inert solvent add in the there-necked flask, add basic catalyst, stirring at room 2 hours after the ice-water bath cooling in batches; Ethyl chloroacetate dropwised with tap funnel in 0.5～6 hour; Reacting liquid temperature is controlled at and reacted under 0～50 ℃ 0.5～72 hour again, and vacuum distilling removes and desolvates, and residue is poured in the water and stirred; Leach the solid of separating out, get light yellow crystal hetero-aromatic ring guanidine-acetic acid ethyl ester with the alcoholic solvent recrystallization again.
This step is applicable to the synthetic of all above-mentioned hetero-aromatic ring guanidine-acetic acid ethyl esters.
The 4th step: hetero-aromatic ring base acethydrazide synthetic
Hetero-aromatic ring guanidine-acetic acid ethyl ester is dissolved in the alcoholic solvent, and reacting by heating liquid dissolves up to solid fully, adds Hydrazine Hydrate 80, and temperature is controlled at 10～90 ℃ of following stirring reactions, and solid continued stirring reaction 0.5～72 hour appears in reaction solution.Reaction solution carries out suction filtration, and to neutral, vacuum-drying gets white solid hetero-aromatic ring base acethydrazide to the gained solid with the absolute alcohol solvent wash.
This step is applicable to the synthetic of all above-mentioned hetero-aromatic ring base acethydrazides.
The 5th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl)-thiosemicarbazide synthetic
Hetero-aromatic ring base acethydrazide and anhydrous alkaline inert solvent add there-necked flask, stir this suspension-s and are heated to 140 ℃, continue reaction up to becoming homogeneous reaction liquid; Reaction solution slowly is cooled to 0～70 ℃; Be dissolved in 2,3 in the anhydrous alkaline inert solvent, 4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates forms solution; With tap funnel it is added reaction flask, temperature is controlled at 0～70 ℃ and reacted 0.5～72 hour down.Solvent removed in vacuo; Pale brown look residue is used silica gel mixed sample after with the absolute alcohol dissolution with solvents, and column chromatography behind the grind into fine powder after the solvent evaporation is collected component; Remove desolvate faint yellow solid powder 1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl) thiosemicarbazide.
This step be applicable to all above-mentioned 1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl) thiosemicarbazide synthetic.
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-xylosyl) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-xylosyl) thiosemicarbazide is dissolved in the absolute alcohol solvent, adjusts PH between 7.5～10.5 with the basic catalyst that is dissolved in the alcoholic solvent, and temperature is controlled at 0～70 ℃ and reacted 0.5～18 hour down; Up to thin-layer chromatography detecting reactant 1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl) the thiosemicarbazide completely dissolve.Reaction solution is handled with Zeo-karb has to the neutrality floss to occur, suction filtration, the vacuum-drying of gained solid, white solid powder 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-xylosyl) thiosemicarbazide.
This step is applicable to the synthetic of all above-mentioned 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-xylosyl) thiosemicarbazide.
Wherein the acid solvent in the first step reaction is that volume percent is 5%～95% the acetate or the aqueous solution of trifluoroacetic acid; Benzene series solvent in the reaction of second step is YLENE, toluene or ethylbenzene; Alkaline inert solvent in the three-step reaction is N, dinethylformamide, DMSO 99.8MIN., dioxane, pyridine; Basic catalyst is sodium hydride, Anhydrous potassium carbonate, sodium methylate; Alcoholic solvent is methyl alcohol, ethanol, Virahol, anhydrous methanol, absolute ethyl alcohol; Alcoholic solvent in the four-step reaction is with the 3rd step; Alkaline inert solvent in the reaction of the 5th step, alcoholic solvent are with the 4th step; Alcoholic solvent in the six-step process, alkaline inert solvent, basic catalyst are with the 3rd step.In the base in the above-mentioned reaction all hetero-aromatic ring base B be one of VITAMIN B4, guanine, purinethol, xanthoglobulin, cytosine(Cyt), uracil, thymus pyrimidine, triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned heterocyclic base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C1-C5 alkyl, C2-C5 thiazolinyl or C2-C5 alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C1-C5 alkoxyl group, C2-C5 alkenyloxy or C2-C5 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C1-C5 alkylthio, C2-C5 alkenyl thio or C2-C5 sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C1-C5 ester group.
In the preparation method of above-mentioned xylosyl thiourea heterocyclic compound, it is 5%～95% acetic acid aqueous solution that the acid solvent in the first step reaction is preferably volume percent; Benzene series solvent in the reaction of second step is preferably YLENE; Alkaline inert solvent in the three-step reaction is preferably N, dinethylformamide; Basic catalyst is preferably sodium hydride; Alcoholic solvent is preferably methyl alcohol; Alcoholic solvent in the four-step reaction is preferably methyl alcohol; Alkaline inert solvent in the reaction of the 5th step is preferably N, dinethylformamide; Alcoholic solvent is preferably methyl alcohol; Alcoholic solvent in the six-step process is preferably methyl alcohol; The alkalescence inert solvent is preferably N, dinethylformamide; Basic catalyst is preferably sodium methylate.In the base in the above-mentioned reaction all hetero-aromatic ring base B be preferably one of VITAMIN B4, guanine, purinethol, xanthoglobulin, cytosine(Cyt), uracil, thymus pyrimidine, triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned heterocyclic base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C1-C5 alkyl, C2-C5 thiazolinyl or C2-C5 alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C1-C5 alkoxyl group, C2-C5 alkenyloxy or C2-C5 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C1-C5 alkylthio, C2-C5 alkenyl thio or C2-C5 sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C1-C5 ester group.
The present invention also provides the application of said xylosyl thiourea heterocyclic compound in the preparation antitumor drug.
Above-described a kind of medicine with antitumor action, wherein base B is one of VITAMIN B4, guanine, purinethol, xanthoglobulin, cytosine(Cyt), uracil, thymus pyrimidine, triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles in the compound general formula.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned heterocyclic base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C1-C5 alkyl, C2-C5 thiazolinyl or C2-C5 alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C1-C5 alkoxyl group, C2-C5 alkenyloxy or C2-C5 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C1-C5 alkylthio, C2-C5 alkenyl thio or C2-C5 sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C1-C5 ester group.
In the content of the present invention, can be a kind of pharmaceutical composition, its characteristics are to comprise formula (I) compound of significant quantity, and its purposes is as treatment and prevents various optimum or malignant tumours.Wherein said tumour comprises lung cancer, liver cancer, prostatitis cancer, white blood disease, skin carcinoma, cancer of the stomach, mammary cancer, ovarian cancer, cervical cancer, lymphatic cancer, large bowel cancer, nasopharyngeal carcinoma, oral cancer, wherein is meant lung cancer and liver cancer especially.
Said pharmaceutical composition contains formula at least (I) compound of active constituents of medicine itself or the mixture of itself and one or more pharmaceutically useful lazy element vehicle or carrier.
Below with xylosyl thiourea heterocyclic compound according to the invention antitumor, especially the experiment of Human Lung Cancer cell (PG) and human liver cancer cell aspects such as (BEL-7402) is further set forth its application.
Adopt mtt assay, measure The compounds of this invention in external restraining effect to Human Lung Cancer cell strain (PG) and human liver cancer cell strain (BEL-7402).In the anti-tumor activity research, Human Lung Cancer cell strain (PG) and human liver cancer cell strain (BEL-7402) are target cell, and cell culture medium is 1640 substratum that contain 10%BCS, the logarithmic phase cell with trysinization after, the adjusting cell density is 3～5 * 10 3Individual/hole, be seeded in 96 well culture plates, every hole 100 μ l, putting into temperature is 37 ℃, CO 2Content is to cultivate 24 hours in 0.5% the incubator.The sample of the different concns for preparing is added 50 μ l/ holes in 96 well culture plates, (put into temperature is 37 ℃ to the positive control drug zidovudine of different weaker concns, CO for Zidovudine, AZT) the positive contrast of soup 2Content is to continue in 0.5% the incubator to cultivate 48 hours.Take out 96 well culture plates, every hole adds the MTT of the 5mg/mL of 20 μ l, continues to cultivate 4 hours.Take out culture plate, pour out substratum, every hole adds 150 μ lDMSO, and 37 ℃ vibrated 6 minutes, and the 490nm place measures the OD value in each hole.Calculate inhibiting rate: (OD Negative control-OD Sample)/OD Negative control* 100%.
Compound of the present invention and pharmaceutical composition can be used for preparing the medicine of tumour.
The various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional working method preparation of pharmaceutical field, are made into required formulation then.
Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-95%.
According to aforementioned said synthetic route and method, can stablize, repeatable the The compounds of this invention for preparing; Adopt the inventive method to prepare compound according to the invention, with low cost, easy and simple to handle; Repeatedly the extracorporeal antivirus effect activity test proves, The compounds of this invention is antiviral good with anti-tumor activity test result circulation ratio.
The antitumor activity in vitro result of The compounds of this invention shows: all test compounds all have restraining effect to Human Lung Cancer cell strain (PG) and human liver cancer cell (BEL-7402).
Embodiment:
Following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.The structure warp of all compounds 1H-NMR, 13C-NMR confirms.
Embodiment 1: (compound number is a) synthetic to 1-adeninyl-ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide
(1) the 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose synthetic
(4.5g, 3.63mmol) with the 60mL Glacial acetic acid min. 99.5, (12mL, 234.10mmol), the reaction mixed reaction solution stirs half a hour at ambient temperature, filters and discards red phosphorus to add bromine water with tap funnel while stirring in the 250mL there-necked flask, to add red phosphorus.(36g 100mmol), reacts under the same temperature, and the D-wood sugar full acetylated up to the thin-layer chromatography detecting reactant all disappears to add full acetylated D-wood sugar.Glacial acetic acid min. 99.5 is removed in decompression, and residue is with saturated sodium carbonate and chloroform extraction three times, and organic extract liquid is with saturated common salt water washing three times, and anhydrous sodium sulfate drying reduces pressure and removes organic solvent and get white solid 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose.
(2) 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates synthetic
(9.69g 30mmol) adds in the 250mL there-necked flask, after the reflux with 50mL anhydrous dimethyl benzene plumbous rhodanate; Add 1-bromo-2,3,4 with tap funnel; 6-four-O-ethanoyl-alpha-D-xylose (7.3g, 10mL anhydrous dimethyl benzole soln 20mmol), reaction solution back flow reaction 3.5～8.5 hours; Filtration discards remaining plumbous rhodanate, removal of solvent under reduced pressure, and residue is with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; Get white crystalline solid 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates.
(3) adeninyl ETHYLE ACETATE is synthetic
VITAMIN B4 (5.0g, 37mmol) adding fills the anhydrous N of 100mL, in the 250mL there-necked flask of dinethylformamide, stirs; Add sodium hydride NaH (6.1g, 0.15mol, 60% oily dispersion liquid) after the ice-water bath cooling in batches; Reaction solution stirring at room 2 hours, (150mL 140mmol) dropwised with tap funnel in 2 hours ethyl chloroacetate; Reacted under the room temperature condition 2 hours, vacuum distilling removes and desolvates again, and residue is poured in the 250mL water and stirred; Leach the solid of separating out, get light yellow crystal adeninyl ETHYLE ACETATE 5.56g with recrystallizing methanol again, productive rate is 70%.
(4) the adeninyl acethydrazide is synthetic
(5.0g 23mmol) is dissolved in the 100mL there-necked flask that fills 30mL methyl alcohol adeninyl ETHYLE ACETATE, and reacting by heating liquid dissolves up to solid fully; Add 80% Hydrazine Hydrate 80 (2.8mL; 48mmol), stirring reaction under the room temperature solid continued stirring reaction 8 hours occur at reaction solution.Reaction solution carries out suction filtration, and to neutral, vacuum-drying gets white solid adeninyl acethydrazide 3.60g, productive rate 81% to the gained solid with absolute ethanol washing.
(5) 1-adeninyl-ethanoyl-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl)-thiosemicarbazide synthetic
(248mg 1.2mmol) joins in the 100mL there-necked flask that fills 15mL the adeninyl acethydrazide, and the suspension-s of formation is heated to 140 ℃, and stirring reaction is up to becoming homogeneous phase, and reaction solution slowly is cooled to 70 ℃.2,3, and 4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates (343mg, 1mmol) being dissolved in 5mL does not have anhydrous water N, in the dinethylformamide, it is added reaction flask with tap funnel in batches, and reaction solution is cooled to stirring at room reaction 8 hours.Solvent removed in vacuo, pale brown look residue is used silica gel mixed sample, column chromatography behind the grind into fine powder after the solvent evaporation with anhydrous methanol dissolving back; Collect component; Remove desolvate faint yellow solid powder 1-adeninyl-ethanoyl-4-(1 '-N-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-xylosyl)-and thiosemicarbazide 404mg, productive rate 77%.Mp:183-184 ℃. 1H NMR (500MHz, DMSO-d 6): δ 9.83 (1H, s, NH), 8.53 (1H, s, NH), 7.95 (1H, s, NH), and 8.14 (1H, s, adenine ring-H), 8.04 (1H, s, adenine ring-H), 3.50-5.75 (7H, m, gly-H), 7.26 (2H, s, NH 2), 4.24 (2H s, COCH 2), 1.86-2.00 (9H, m, CH 3CO); Ultimate analysis C 19H 24N 8O 8S theoretical value: C, 43.51; H, 4.61; N, 21.36. observed value: C, 43.57; H, 4.65; N, 31.44.ESI-MS: (MH +) 525.5.
(6) 1-adeninyl-ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide (a) is synthetic
1-adeninyl-ethanoyl-4-(1 '-N-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-xylosyl)-(566mg 1mmol) is dissolved in the 15mL anhydrous methanol thiosemicarbazide, and using the methanol solution adjustment PH of sodium methylate is about 8; Stir under the room temperature up to thin-layer chromatography detecting reactant 1-adeninyl-ethanoyl-4-(1 '-N-2 '; 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glycosyl)-the thiosemicarbazide completely dissolve.Reaction solution is handled to neutrality with Zeo-karb has floss to separate out, suction filtration, the vacuum-drying of gained solid, white solid powder 1-adeninyl-ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide 347mg, productive rate 87%. 1H NMR (500MHz, DMSO-d 6): δ 10.41 (1H, bs, NH), 9.75 (1H, bs, NH), 8.27 (1H, bs, NH), 7.71 (s, 2H, NH 2), 8.13 (1H, s, adenine ring-H), 7.97 (1H, s, adenine ring-H), 3.07-5.23 (9H, m, gly-H, wereoverlapped with H of H-O), 3.60 (2H, m, COCH 2); Ultimate analysis C 13H 18N 8O 5S theoretical value: C, 39.19; H, 4.55; N, 12.80. observed value: C, 39.26; H, 4.51; N, 12.87.ESI-MS: (MH +) 399.4.
Embodiment 2: 1-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide (compound number is b) synthetic
(1) the 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose synthetic
Adopt the method and the condition of (1) among the embodiment 1 synthetic.
(2) 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates synthetic
Adopt the method and the condition of (2) among the embodiment 1 synthetic.
(3) benzimidazolyl-ETHYLE ACETATE is synthetic
Adopt the method and the condition of (3) among the embodiment 1 synthetic, only change VITAMIN B4 into benzoglyoxaline.
(4) the benzimidazolyl-acethydrazide is synthetic
Adopt the method and the condition of (4) among the embodiment 1 synthetic, only change adeninyl ETHYLE ACETATE into benzimidazolyl-ETHYLE ACETATE.
(5) 1-benzimidazolyl--ethanoyl-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl)-thiosemicarbazide synthetic
Adopt the method and the condition of (5) among the embodiment 1 synthetic, only change reactant into the benzimidazolyl-acethydrazide, get faint yellow solid 447mg, productive rate 88%. 1H NMR (500MHz, DMSO-d 6): δ 10.21 (1H, bs, NH), 9.83 (1H, bs, NH), 8.72 (1H, bs, NH), 7.15～8.16 (5H, m, benzimidazole ring-H), 3.98～5.87 (8H, m, gly-H and COCH 2), 1.83～2.15 (9H, 3s, CH 3CO); Ultimate analysis C 21H 25N 5O 8S theoretical value: C, 49.70; H, 4.97; N, 13.80. observed value: C, 49.62; H, 5.03; N, 13.71.ESI-MS: (MH +) 508.5.
(6) 1-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide (b) is synthetic
Adopt the method for (6) among the embodiment 2 synthetic with condition, only with reactant change into 1-benzimidazolyl--ethanoyl-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-xylosyl)-thiosemicarbazide, must white solid powder 332mg, productive rate 87%. 1H NMR (500MHz, DMSO-d 6): δ 10.33 (1H, bs, NH), 9.45 (1H, bs, NH), 8.47 (1H, bs, NH), 7.18～8.39 (5H, m, benzimidazole ring-H), 3.12～5.28 (11H, m, gly-H and COCH 2, were overlapped with H of H-O); Ultimate analysis C 15H 19N 5O 5S theoretical value: C, 47.24; H, 5.02; N, 18.36. observed value: C, 47.31; H, 4.97; N, 18.31.ESI-MS: (MH +) 382.4.
Can synthesize with above-mentioned same similarly method and to obtain 1-[2-(4-methoxyl group)]-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-xylosyl)-thiosemicarbazide (compound number is c) etc.
Embodiment 3: to the inhibition determination of activity of Human Lung Cancer cell strain (PG)
Adopting mtt assay, be target cell with Human Lung Cancer cell strain (PG), and cell culture medium is 1640 substratum that contain 10%BCS, the logarithmic phase cell with trysinization after, the adjusting cell density is 3～5 * 10 3Individual/hole, be seeded in 96 well culture plates, every hole 100 μ l, putting into temperature is 37 ℃, CO 2Content is to cultivate 24 hours in 0.5% the incubator.The sample of the different concns for preparing is added 50 μ l/ holes in 96 well culture plates, (put into temperature is 37 ℃ to the positive control drug medicine zidovudine of different weaker concns, CO for Zidovudine, AZT) the positive contrast of soup 2Content is to continue in 0.5% the incubator to cultivate 48 hours.Take out 96 well culture plates, every hole adds the MTT of the 5mg/mL of 20 μ l, continues to cultivate 4 hours.Take out culture plate, pour out substratum, every hole adds 150 μ l DMSO, and 37 ℃ vibrated 6 minutes, and the 490nm place measures the OD value in each hole.Calculate inhibiting rate: (OD Negative control-OD Sample)/OD Negative control* 100%, and adopt Reed & Muench method to calculate medicine medium effective concentration (EC in cell cultures 50)
Embodiment 4: to the inhibition determination of activity of human liver cancer cell strain (BEL-7402)
It is active to the inhibition of human liver cancer cell strain (BEL-7402) to measure said compound with embodiment 3 similar approach.
Said each compound suppresses Human Lung Cancer cell (PG) and human transitional cell bladder carcinoma cell line (T 24) activity data it is as shown in the table:
Table 1: the xylosyl thiourea heterocyclic compound suppresses the activity data of lung carcinoma cell (PG) and liver cancer cell (BEL-7402)
Compound EC 50(μM) a
PG b BEL-7402 c
a b c Zidovudine ＞200 ＞200 73.7 0.58 ＞100 ＞200 36.7 4.62
aEffective concentration 50.
bHuman pneumonocyte.
cThe H human hepatocytes
The result shows: all test compounds of the present invention all have restraining effect in various degree to Human Lung Cancer cell (PG) and human liver cancer cell (BEL-7402); Wherein have only compound c good inhibitory effect, EC to be arranged to Human Lung Cancer cell (PG) with to human liver cancer cell (BEL-7402) 50Be respectively 73.7 μ M and 36.7 μ M, and a and b have more weak inhibition activity, EC 50All greater than 100 μ M.

Claims (4)

1. one group of xylosyl thiourea heterocyclic compound, its structure is as shown in the formula shown in (I):
Figure FSB00000503130000011
Wherein:
B is one of adeninyl, guanyl-, purinethol base, xanthoglobulin base, benzimidazolyl-, benzopyrazoles base, and B can be by one or more C 1-C 5Alkyl replaces.
2. the preparation method of the said xylosyl thiourea heterocyclic compound of claim 1 is characterized in that said target compound is synthetic through six steps:
The first step: 1-bromo-2,3,4-three-O-ethanoyl-alpha-D-xylose synthetic
Add red phosphorus and acid solvent in the there-necked flask, add bromine water with tap funnel, mixed reaction solution stirred 0.2～10 hour under 10～80 ℃ of conditions; Filtration discards red phosphorus, adds full acetylated wood sugar, reacts under the same temperature; The wood sugar full acetylated up to the thin-layer chromatography detecting reactant all disappears, and acid solvent is removed in decompression, and residue is with saturated sodium carbonate and chloroform extraction; Organic extract liquid is with saturated common salt water washing 2～5 times, anhydrous sodium sulfate drying, and decompression is removed organic solvent and is got white solid 1-bromo-2; 3,4-three-O-ethanoyl-alpha-D-xylose;
Second step: 2,3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3 with tap funnel after the reflux; The xylene solution of 4-three-O-ethanoyl-alpha-D-xylose, reaction solution back flow reaction 0.5～72 hour is filtered and is discarded remaining plumbous rhodanate; Removal of solvent under reduced pressure, residue get white crystalline solid 2 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; 3,4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates;
The 3rd step: hetero-aromatic ring guanidine-acetic acid ethyl ester synthetic
Hetero-aromatic ring base and anhydrous alkaline inert solvent add in the there-necked flask, add basic catalyst, stirring at room 2 hours after the ice-water bath cooling in batches; Ethyl chloroacetate dropwised with tap funnel in 0.5～6 hour; Reacting liquid temperature is controlled at and reacted under 0～50 ℃ 0.5～72 hour again, and vacuum distilling removes and desolvates, and residue is poured in the water and stirred; Leach the solid of separating out, get light yellow crystal hetero-aromatic ring guanidine-acetic acid ethyl ester with the alcoholic solvent recrystallization again;
The 4th step: hetero-aromatic ring base acethydrazide synthetic
Hetero-aromatic ring guanidine-acetic acid ethyl ester is dissolved in the alcoholic solvent; Reacting by heating liquid dissolves up to solid fully, adds Hydrazine Hydrate 80, and temperature is controlled at 10～90 ℃ of following stirring reactions; Solid continued stirring reaction 0.5～72 hour appears in reaction solution; Reaction solution carries out suction filtration, and to neutral, vacuum-drying gets white solid hetero-aromatic ring base acethydrazide to the gained solid with the absolute alcohol solvent wash;
The 5th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 '-three-O-ethanoyl-β-D-xylosyl)-thiosemicarbazide synthetic
Hetero-aromatic ring base acethydrazide and anhydrous alkaline inert solvent add there-necked flask, stir this suspension-s and are heated to 140 ℃, continue reaction up to becoming homogeneous reaction liquid; Reaction solution slowly is cooled to 0～70 ℃, is dissolved in 2,3 in the anhydrous alkaline inert solvent; 4-three-O-ethanoyl-alpha-D-xylose base lsothiocyanates forms solution, with tap funnel it is added reaction flask, and temperature is controlled at 0～70 ℃ and reacted 0.5～72 hour down; Solvent removed in vacuo, pale brown look residue are used silica gel mixed sample, column chromatography behind the grind into fine powder after the solvent evaporation after with the absolute alcohol dissolution with solvents; Collect component; Remove desolvate faint yellow solid powder 1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 '-three-O-ethanoyl-β-D-xylosyl) thiosemicarbazide;
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-xylosyl) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 4 '-three-O-ethanoyl-β-D-xylosyl) thiosemicarbazide is dissolved in the absolute alcohol solvent; With being dissolved in basic catalyst adjustment pH in the alcoholic solvent between 7.5～10.5, temperature is controlled at 0～70 ℃ of reaction 0.5～18 hour down, up to thin-layer chromatography detecting reactant 1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 '; 4 '-three-O-ethanoyl-β-D-xylosyl) thiosemicarbazide completely dissolve, reaction solution are handled to neutrality with Zeo-karb has floss suction filtration to occur; The vacuum-drying of gained solid, white solid powder 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-xylosyl) thiosemicarbazide.
3. the preparation method of the said xylosyl thiourea heterocyclic compound of claim 2 is characterized in that, the acid solvent in the first step reaction is that volume percent is 5%～95% acetic acid aqueous solution; Benzene series solvent in the reaction of second step is a YLENE; Alkaline inert solvent in the three-step reaction is N, dinethylformamide; Basic catalyst is a sodium hydride; Alcoholic solvent is a methyl alcohol; Alcoholic solvent in the four-step reaction is a methyl alcohol; Alkaline inert solvent in the reaction of the 5th step is N, dinethylformamide; Alcoholic solvent is a methyl alcohol; Alcoholic solvent in the six-step process is a methyl alcohol; Basic catalyst is a sodium methylate.
4. the thiourea heterocyclic compound of xylosyl described in the claim 1 application that is used to prepare antitumor drug.
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于建新等.1-芳酰基-4-( 1′-N-β-D-吡喃型糖基) 氨基硫脲类化合物的合成.《应用化学》.1999,第16卷(第4期),41-46. *

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