CN101215305A - Glucosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic - Google Patents
Glucosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic Download PDFInfo
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- CN101215305A CN101215305A CNA2008100017115A CN200810001711A CN101215305A CN 101215305 A CN101215305 A CN 101215305A CN A2008100017115 A CNA2008100017115 A CN A2008100017115A CN 200810001711 A CN200810001711 A CN 200810001711A CN 101215305 A CN101215305 A CN 101215305A
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- 238000010189 synthetic method Methods 0.000 title description 5
- 230000000118 anti-neoplastic effect Effects 0.000 title description 2
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- 238000000034 method Methods 0.000 claims abstract description 16
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a group glucose 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 glucose, 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 glucose 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
Technical field:
The present invention relates to one group of glucosyl group thiourea heterocyclic compound; The invention still further relates to the synthetic method of said all compounds and in the application of anti-tumor aspect.
Background technology:
Saccharide compound is familiar with by people already as the storage carrier of energy in vivo, 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, as bacterium and virus infection organism, [Cleophax such as signal conduction, J.Olesker.A.Rolland, A.Gero, S.D.Tetrahedron 1977,33,1303.], the research of carbohydrate has become hot fields [(a) Spedaliere, 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 participating in all bioprocesss in the life entity, is a kind of important biological material.The derivative that experiment showed, sugar also has many biological activitys, has anti-tumor activity [(a) Sun Lvjun as 5 FU 5 fluorouracil glucose nitrogen glycosides; Qi Yuxin, Li Aixia, Zhang Huakun; Zhang Jianguo, Chinese 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, Y.Yoshihiro, the M.Hiroshi of cell killing toxin; S.Yutaka, S.J.Nat.Prod.2002,65; 283.], phenyl methyl ketone class glucoside has anti-inflammation 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 is used for the cancer-resisting activity, and Bay g 5421 (Acarbose) treatment diabetic activity etc. [Service, R.F.Science 2001; 291,2340.].
Thiourea derivative is subjected to 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 activity [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 very significant work beyond doubt of amido thiocarbamide.At present; the research in this field has obtained carrying out; as [Yu Jianxins such as Yu Jianxins; Liu Fangming; Li Yanping; Cheng Liang, model is admired, Liu Yuting. applied chemistry; 1996; 16 (4), 41.] 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 derivative has attracted vast chemistry and medical science men.Up to now, aryl is mainly the derivative of benzene in this compounds, comprises benzo class heterocyclic base, and the work of carrying out is not a lot, sets up the compound that forms and does not appear in the newspapers and aryl is natural base and derivative thereof.
Be research glycosyl thiosemicarbazide heterogeneous ring compound, synthetic method and anti-tumor activity thereof, the present invention has synthesized glucosyl group thiosemicarbazide VITAMIN B4, glucosyl group thiosemicarbazide benzoglyoxaline, glucosyl group 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.
Glucosyl group thiosemicarbazide VITAMIN B4 provided by the present invention, glucosyl group thiosemicarbazide benzoglyoxaline, glucosyl group thiosemicarbazide methoxybenzoyl phenalgin and imidazoles are so far and do not see the new compound that relevant report is arranged.
Summary of the invention:
At the deficiencies in the prior art and this area research and demands of applications, the purpose of this invention is to provide one group of glucosyl group thiourea compound; The present invention simultaneously also provides the synthetic method of described all compounds and in the application of anti-tumor aspect.
The present invention is to be the skeleton of target compound with the glucosyl group 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; novel glucosyl group thiosemicarbazide VITAMIN B4, glucosyl group thiosemicarbazide benzoglyoxaline, glucosyl group thiosemicarbazide methoxybenzoyl phenalgin and the imidazoles of a class synthesized in design, and 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):
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 glucose with full acid esterification, bromine water, and plumbous rhodanate, heterocyclic base, ethyl chloroacetate, hydrazine hydrate are raw material, synthetic through six steps, synthetic route is as follows:
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-2,3,4,6-four-O-ethanoyl-alpha-D-glucose synthetic
Add red phosphorus and acid solvent in the there-necked flask, add bromine water with dropping funnel, mixed reaction solution stirred 0.2～10 hour under 10～80 ℃ of conditions, filtered and discarded red phosphorus.Add full acetylated glucose, react under the same temperature, the glucose full acetylated up to the thin-layer chromatography detecting reactant all disappears.Acid solvent is removed in decompression, residue saturated sodium carbonate and chloroform extraction, organic extract liquid saturated common salt water washing 2～5 times; anhydrous sodium sulfate drying, decompression is removed organic solvent and is got white solid 1-bromo-2,3; 4,6-four-O-ethanoyl-alpha-D-glucose.
This step is applicable to all above-mentioned 1-bromo-2,3,4,6-four-O-ethanoyl-alpha-D-glucose synthetic.
Second step: 2,3,4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3 with dropping funnel after the reflux; 4; the xylene solution of 6-four-O-ethanoyl-alpha-D-glucose, reaction solution back flow reaction 0.5～72 hour is filtered and is discarded remaining plumbous rhodanate; removal of solvent under reduced pressure; residue gets white crystalline solid 2,3 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; 4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates.
This step is applicable to that all are above-mentioned 2,3,4,6-four-O-ethanoyl-alpha-D-glucose 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 after the ice-water bath cooling in batches, stirring at room 2 hours, ethyl chloroacetate dropwised with dropping 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 fully up to solid, adds hydrazine hydrate, and temperature is controlled at 10～90 ℃ of following stirring reactions, and reaction solution occurs continuing stirring reaction 0.5～72 hour behind the solid.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-glucosyl group)-thiosemicarbazide synthetic
Hetero-aromatic ring base acethydrazide and anhydrous alkaline inert solvent add there-necked flask; stir this suspension and be 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; 6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates forms solution, with dropping 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 is used silica gel mixed sample after using the absolute alcohol dissolution with solvents; column chromatography behind the grind into fine powder after the solvent evaporation; collect 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-glucosyl group) 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-glucosyl group) thiosemicarbazide synthetic.
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-glucosyl group) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 '; 4 '; 6 '-four-O-ethanoyl-β-D-glucosyl group) 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-glucosyl group) 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-glucosyl group) thiosemicarbazide.
This step is applicable to the synthetic of all above-mentioned 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-glucosyl group) 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 dimethylbenzene, toluene or ethylbenzene; Alkaline inert solvent in the three-step reaction is N, dinethylformamide, dimethyl sulfoxide (DMSO), dioxane, pyridine; Basic catalyst is sodium hydride, Anhydrous potassium carbonate, sodium methylate; Alcoholic solvent is methyl alcohol, ethanol, Virahol, anhydrous methanol, dehydrated 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 glucosyl group 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 dimethylbenzene; 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 described glucosyl group 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, leukemia, skin carcinoma, cancer of the stomach, mammary cancer, ovarian cancer, cervical cancer, lymphatic cancer, large bowel cancer, nasopharyngeal carcinoma, oral carcinoma, wherein is meant lung cancer and liver cancer especially.
Described 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 inert element vehicle or carrier.
Below with glucosyl group thiourea heterocyclic compound of the present invention antitumor, especially its application is further set forth in the experiment of Human Lung Cancer cell (PG) and human liver cancer cell aspects such as (BEL-7402).
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 optical density 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 production 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 of the present invention, with low cost, easy and simple to handle; Repeatedly the extracorporeal antivirus effect activity test proves, The compounds of this invention is antiviral and anti-tumor activity test result circulation ratio is good.
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 determines.
Embodiment 1: (compound number is a) synthetic to 1-adeninyl-ethanoyl-4-(1 '-N-β-D-glucosyl group)-thiosemicarbazide
(1) the 1-bromo-2,3,4,6-four-O-ethanoyl-alpha-D-glucose synthetic
(4.5g, 3.63mmol) with the 60mL Glacial acetic acid, (12mL, 234.10mmol), the reaction mixed reaction solution stirs half an hour at ambient temperature, filters and discards red phosphorus to add bromine water with dropping funnel while stirring to add red phosphorus in the 250mL there-necked flask.(39g 100mmol), reacts under the same temperature, and the D-glucose full acetylated up to the thin-layer chromatography detecting reactant all disappears to add full acetylated D-glucose.Glacial acetic acid is removed in decompression, residue usefulness saturated sodium carbonate and chloroform extraction three times, organic extract liquid saturated common salt water washing three times; anhydrous sodium sulfate drying, decompression is removed organic solvent and is got white solid 1-bromo-2,3; 4,6-four-O-ethanoyl-alpha-D-glucose.
(2) 2,3,4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates synthetic
Plumbous rhodanate (9.69g; 30mmol) add in the 250mL there-necked flask with 50mL anhydrous dimethyl benzene; after the reflux; add 1-bromo-2 with dropping funnel; 3; 4,6-four-O-ethanoyl-alpha-D-glucose (7.9g, 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, the residue toluene and the sherwood oil mixed solvent recrystallization of equal proportion; get white crystalline solid 2; 3,4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates.
(3) the adeninyl ethyl acetate is synthetic
VITAMIN B4 (5.0g, 37mmol) adding fills the anhydrous N of 100mL, in the 250mL there-necked flask of dinethylformamide, stir, add sodium hydride NaH (6.1g after the ice-water bath cooling in batches, 0.15mol, 60% oily dispersion liquid), reaction solution stirring at room 2 hours, ethyl chloroacetate (150mL, 140mmol) dropwised with dropping funnel in 2 hours, reacted under the room temperature condition 2 hours again, vacuum distilling removes and desolvates, residue is poured in the 250mL water and is stirred, leach the solid of separating out, get light yellow crystal adeninyl ethyl 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 the adeninyl ethyl acetate, and reacting by heating liquid dissolves fully up to solid, add 80% hydrazine hydrate (2.8mL, 48mmol), stirring reaction under the room temperature continued stirring reaction 8 hours after solid appears in 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-glucosyl group)-thiosemicarbazide synthetic
(248mg 1.2mmol) joins in the 100mL there-necked flask that fills 15mL the adeninyl acethydrazide, and the suspension of formation is heated to 140 ℃, and stirring reaction is up to becoming homogeneous phase, and reaction solution slowly is cooled to 70 ℃.2,3,4, and 6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates (373mg, 1mmol) being dissolved in 5mL does not have anhydrous water N, in the dinethylformamide, it is added reaction flask with dropping funnel in batches, and reaction solution is cooled to stirring at room reaction 8 hours.Solvent removed in vacuo; pale brown look residue dissolves the back silica gel mixed sample with anhydrous methanol; column chromatography behind the grind into fine powder after the solvent evaporation; collect component; remove desolvate faint yellow solid powder 1-adeninyl-ethanoyl-4-(1 '-N-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-glucosyl group)-and thiosemicarbazide 495mg, productive rate 83%.Mp:171-173 ℃ of .IR (KBr, v
Max): 3340 (NH), 1643,1574 (C=O), 1369 (Me), 1232 (gly-H), 1041 (C=S) cm
-1 1H NMR (500MHz, DMSO-d
6): δ 9.81 (1H, s, NH), 8.90 (1H, s, NH), 8.68 (1H, s, NH), 8.25 (1H, s, adenine ring-H), 8.07 (1H, s, adeninering-H), 7.27 (2H s, NH
2), 3.97-5.91 (7H, m, gly-H, CH
2), 4.29 (2H s, COCH
2), 1.75-2.03 (12H, m, CH
3CO); Ultimate analysis C
22H
28N
8O
10S theoretical value: C, 44.29; H, 4.73; N, 18.78. observed value: C, 44.24; H, 4.66; N, 18.54.ESI-MS:(MH
+) 597.6.
(6) 1-adeninyl-ethanoyl-4-(1 '-N-β-D-glucosyl group)-thiosemicarbazide (a) is synthetic
1-adeninyl-ethanoyl-4-(1 '-N-2 '; 3 '; 4 '; 6 '-four-O-ethanoyl-β-D-glucosyl group)-(596mg 1mmol) is dissolved in the 15mL anhydrous methanol thiosemicarbazide, and adjusting PH with the methanol solution 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-glucosyl group)-thiosemicarbazide 390mg, productive rate 91%.
1H NMR (500MHz, DMSO-d
6): δ 9.71 (1H, bs, NH), 8.35 (1H, bs, NH), 8.10 (1H, bs, NH), 8.15 (1H, s, adeninering-H), 8.09 (1H, s, adenine ring-H), 7.28 (2H, s, NH
2), 5.31-4.95 (11H, m, gly-H, were overlapped with H of H-O), 3.13-3.69 (2H, m, COCH
2); Ultimate analysis C
14H
20N
8O
6S theoretical value: C, 39.25; H, 4.71; N, 26.15. observed value: C, 39.02; H, 4.69; N, 25.99.ESI-MS:(MH
+) 429.4.
Embodiment 2: 1-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-glucosyl group)-thiosemicarbazide (compound number is b) synthetic
(1) the 1-bromo-2,3,4,6-four-O-ethanoyl-alpha-D-glucose synthetic
Adopt the method and the condition of (1) among the embodiment 1 synthetic.
(2) 2,3,4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates synthetic
Adopt the method and the condition of (2) among the embodiment 1 synthetic.
(3) the benzimidazolyl-ethyl 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 the adeninyl ethyl acetate into the benzimidazolyl-ethyl acetate.
(5) 1-benzimidazolyl--ethanoyl-4-(1 '-N-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucosyl group)-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 527mg, productive rate 91%.
1H NMR (500MHz, DMSO-d
6): δ 10.22 (1H, bs, NH), 9.85 (1H, bs, NH), 8.54 (1H, bs, NH), 7.20～8.15 (5H, m, benzimidazole ring-H), 3.94～5.32 (9H, m, gly-H and COCH
2), 1.80～2.09 (12H, 3s, CH
3CO); Ultimate analysis C
24H
29N
5O
10S theoretical value: C, 49.74; H, 5.04; N, 12.08. observed value: C, 49.67; H, 5.06; N, 12.14.ESI-MS:(MH
+) 580.6.
(6) 1-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-glucosyl group)-thiosemicarbazide (b) is synthetic
Adopt the method and the condition of (6) among the embodiment 2 synthetic, only reactant is changed into 1-benzimidazolyl--ethanoyl-4-(1 '-N-2 ', 3 '; 4 '; 6 '-four-O-ethanoyl-β-D-glucosyl group)-and thiosemicarbazide, get white solid powder 370mg, productive rate 90%.
1H NMR (500MHz, DMSO-d
6): δ 10.41 (1H, bs, NH), 9.90 (1H, bs, NH), 8.58 (1H, bs, NH), 7.28～8.48 (5H, m, benzimidazole ring-H), 3.30～5.78 (13H, m, gly-H and COCH
2, were overlapped with H of H-O); Ultimate analysis C
16H
21N
5O
6S theoretical value: C, 46.71; H, 5.14; N, 17.02. observed value: C, 46.75; H, 5.11; N, 17.09.ESI-MS:(MH
+) 412.4.
Can synthesize with above-mentioned same similarly method and to obtain 1-[2-(4-methoxyl group)]-benzimidazolyl--ethanoyl-4-(1 '-N-β-D-glucosyl group)-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 optical density value in each hole.Calculate inhibiting rate: (OD
Negative control-OD
Sample)/OD
Negative control* 100%, and adopt Reed ﹠amp; The Muench method calculates medicine medium effective concentration (EC50) in cell cultures
Embodiment 4: to the inhibition determination of activity of human liver cancer cell strain (BEL-7402)
Measure the inhibition activity of described compound with embodiment 3 similar approach to human liver cancer cell strain (BEL-7402).
Described 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 glucosyl group 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 | ＞100 ＞100 82.4 0.58 | 86.2 ＞200 76.4 4.62 |
aEffective concentration 50.
bHuman pneumonocyte.
cThe H human hepatocytes
The result shows: all test compounds of the present invention all have in various degree restraining effect to Human Lung Cancer cell (PG) and human liver cancer cell (BEL-7402), and wherein compound c has good inhibitory effect, EC to Human Lung Cancer cell (PG)
50Be 82.4 μ M, a and b have more weak inhibition activity, EC
50All greater than 100 μ M; And compound a and c have good inhibitory effect to human liver cancer cell (BEL-7402), EC
50Be respectively 86.2 μ M and 76.4 μ M, b has more weak inhibition activity, EC
50Greater than 100 μ M.
Claims (5)
1. one group of glucosyl group thiourea heterocyclic compound, its structure is as shown in the formula shown in (I):
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.
2. the preparation method of the described glucosyl group thiourea heterocyclic compound of claim 1 is characterized in that described target compound is synthetic through six steps:
The first step: 1-bromo-2,3,4,6-four-O-ethanoyl-alpha-D-glucose synthetic
Add red phosphorus and acid solvent in the there-necked flask, add bromine water with dropping funnel, mixed reaction solution stirred 0.2～10 hour under 10～80 ℃ of conditions, filtered and discarded red phosphorus.Add full acetylated glucose, react under the same temperature, the glucose full acetylated up to the thin-layer chromatography detecting reactant all disappears.Acid solvent is removed in decompression, residue saturated sodium carbonate and chloroform extraction, organic extract liquid saturated common salt water washing 2～5 times; anhydrous sodium sulfate drying, decompression is removed organic solvent and is got white solid 1-bromo-2,3; 4,6-four-O-ethanoyl-alpha-D-glucose.
Second step: 2,3,4,6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3 with dropping funnel after the reflux; 4; the xylene solution of 6-four-O-ethanoyl-alpha-D-glucose, reaction solution back flow reaction 0.5～72 hour is filtered and is discarded remaining plumbous rhodanate; removal of solvent under reduced pressure; residue gets white crystalline solid 2,3 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; 4,6-four-O-ethanoyl-alpha-D-glucose 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 after the ice-water bath cooling in batches, stirring at room 2 hours, ethyl chloroacetate dropwised with dropping 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, and reacting by heating liquid dissolves fully up to solid, adds hydrazine hydrate, and temperature is controlled at 10～90 ℃ of following stirring reactions, and reaction solution occurs continuing stirring reaction 0.5～72 hour behind the solid.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 ', 6 '-four-O-ethanoyl-β-D-glucosyl group)-thiosemicarbazide synthetic
Hetero-aromatic ring base acethydrazide and anhydrous alkaline inert solvent add there-necked flask; stir this suspension and be 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; 6-four-O-ethanoyl-alpha-D-glucose base lsothiocyanates forms solution, with dropping 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 is used silica gel mixed sample after using the absolute alcohol dissolution with solvents; column chromatography behind the grind into fine powder after the solvent evaporation; collect 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-glucosyl group) thiosemicarbazide.
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-β-D-glucosyl group) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 '; 4 '; 6 '-four-O-ethanoyl-β-D-glucosyl group) 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-glucosyl group) 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-glucosyl group) thiosemicarbazide.
3. the preparation method of the described glucosyl group 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% the acetate or the aqueous solution of trifluoroacetic acid; Benzene series solvent in the reaction of second step is dimethylbenzene, toluene or ethylbenzene; Alkaline inert solvent in the three-step reaction is N, dinethylformamide, dimethyl sulfoxide (DMSO), dioxane, pyridine; Basic catalyst is sodium hydride, Anhydrous potassium carbonate, sodium methylate; Alcoholic solvent is methyl alcohol, ethanol, Virahol, anhydrous methanol, dehydrated 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.
4. the preparation method of the described glucosyl group thiourea heterocyclic compound of claim 3 is characterized in that, 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 dimethylbenzene; 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.
5. any described glucosyl group thiourea heterocyclic compound is used as anti-tumor drug in the claim 1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101519417B (en) * | 2009-04-20 | 2012-06-27 | 中国科学技术大学 | Preparation method and application of effective ingredients of rose fragrance emitting agent for cigarettes |
| CN104151371A (en) * | 2014-07-31 | 2014-11-19 | 淮海工学院 | N-acetylglucosamine-N'-acylamino thiourea as well as synthesis method and application thereof |
| CN105017349A (en) * | 2014-04-18 | 2015-11-04 | 杭州师范大学 | Glycosyl indole derivative and preparation and applications thereof |
| CN113461752A (en) * | 2020-03-30 | 2021-10-01 | 博美利克斯技术公司 | Novel benzimidazole derivative, method for preparing same, and anticancer agent use thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101519417B (en) * | 2009-04-20 | 2012-06-27 | 中国科学技术大学 | Preparation method and application of effective ingredients of rose fragrance emitting agent for cigarettes |
| CN105017349A (en) * | 2014-04-18 | 2015-11-04 | 杭州师范大学 | Glycosyl indole derivative and preparation and applications thereof |
| CN105017349B (en) * | 2014-04-18 | 2018-04-20 | 杭州师范大学 | A kind of glycosyl indole derivatives and its preparation and application |
| CN104151371A (en) * | 2014-07-31 | 2014-11-19 | 淮海工学院 | N-acetylglucosamine-N'-acylamino thiourea as well as synthesis method and application thereof |
| CN113461752A (en) * | 2020-03-30 | 2021-10-01 | 博美利克斯技术公司 | Novel benzimidazole derivative, method for preparing same, and anticancer agent use thereof |
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