CN101215304B - Lactosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic - Google Patents
Lactosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic Download PDFInfo
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- CN101215304B CN101215304B CN2008100017100A CN200810001710A CN101215304B CN 101215304 B CN101215304 B CN 101215304B CN 2008100017100 A CN2008100017100 A CN 2008100017100A CN 200810001710 A CN200810001710 A CN 200810001710A CN 101215304 B CN101215304 B CN 101215304B
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- lactose
- base
- solvent
- hetero
- aromatic ring
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a group lactose 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 lactose, 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 lactose 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 lactose base 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 [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 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, Qi Yuxin, Li Aixia as 5 FU 5 fluorouracil glucose nitrogen glycosides, 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, the Y. of cell killing toxin; Yoshihiro, M.; Hiroshi, 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 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 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 lactose base thiosemicarbazide VITAMIN B4, lactose base thiosemicarbazide benzoglyoxaline, lactose base 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.
Lactose base thiosemicarbazide VITAMIN B4 provided by the present invention, lactose base thiosemicarbazide benzoglyoxaline, lactose base 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 lactose base 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 lactose base 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 lactose base thiosemicarbazide VITAMIN B4, lactose base thiosemicarbazide benzoglyoxaline, lactose base 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 lactose with full acid esterification, bromine water, and plumbous rhodanate, heterocyclic base, ethyl chloroacetate, hydrazine hydrate are raw material, and be synthetic through six steps:
The first step: 1-bromo-2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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 lactose, react under the same temperature, the lactose 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-2,3,6,2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose.
This step is applicable to all above-mentioned 1-bromo-2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose synthetic.
Second step: 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3,6 with dropping funnel after the reflux; 2 ', 3 ', 4 '; the xylene solution of 6 '-seven-O-ethanoyl-lactose, 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 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion; 3,6,2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose base lsothiocyanates.
This step is applicable to that all are above-mentioned 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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 ', 6 ', 2 ", 3 " and, 4 ", 6 "-seven-O-ethanoyl-lactose base)-thiosemicarbazide synthetic
Hetero-aromatic ring base acethydrazide and anhydrous alkaline inert solvent add there-necked flask, stir this suspension and are heated to 140 ℃, continue reaction up to becoming homogeneous reaction liquid; reaction solution slowly is cooled to 0～70 ℃; be dissolved in 2,3,6 in the anhydrous alkaline inert solvent; 2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose base lsothiocyanates forms solution; with dropping 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 using the absolute alcohol dissolution with solvents; 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 '; 6 ', 2 ", 3 "; 4 ", 6 "-seven-O-ethanoyl-lactose base) thiosemicarbazide.
This step be applicable to all above-mentioned 1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 6 ', 2 ", 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base) thiosemicarbazide synthetic.
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-lactose base) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 ', 3 ', 6 '; 2 ", 3 ", 4 "; 6 "-seven-O-ethanoyl-lactose base) 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 ', 6 '; 2 "; 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base) 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-lactose base) thiosemicarbazide.
This step is applicable to the synthetic of all above-mentioned 1-hetero-aromatic ring acyl group-4-(1 '-N-lactose base) thiosemicarbazide.
The synthetic route of above-mentioned lactose base thiourea heterocyclic compound following (wherein, identical in B and the claim 1):
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 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 lactose base 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 lactose base 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 lactose base 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-lactose base)-thiosemicarbazide
(1) the 1-bromo-2,3,6, and 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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.(67.9g 100mmol), reacts under the same temperature, and the lactose full acetylated up to the thin-layer chromatography detecting reactant all disappears to add full acetylated lactose.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-2,3,6,2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose.
(2) 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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-2,3,6 with dropping funnel; 2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose (14g; 20mL anhydrous dimethyl benzole soln 20mmol); reaction solution back flow reaction 3.5～8.5 hours is filtered and is discarded 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 2,3,6; 2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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 ', 6 ', 2 ", 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base)-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 ℃.2,3,6,2 '; 3 ', 4 ', and 6 '-seven-O-ethanoyl-lactose base lsothiocyanates (678mg, 1mmol) being dissolved in 5mL does not have anhydrous water N; in the dinethylformamide, it is added reaction flask with dropping funnel, reaction solution is cooled to stirring at room reaction 8 hours in batches.Solvent removed in vacuo; pale brown look residue is used silica gel mixed sample with anhydrous methanol dissolving back, and column chromatography behind the grind into fine powder after the solvent evaporation is collected component; remove desolvate faint yellow solid powder 1-adeninyl-ethanoyl-4-(1 '-N-2 '; 3 ', 6 ', 2 "; 3 "; 4 ", 6 "-seven-O-ethanoyl-lactose base)-thiosemicarbazide 717mg, productive rate 81%.Mp：165-167℃。
1H?NMR(500MHz，DMSO-d
6)：δ10.31(1H，s，N
H)，9.99(1H，s，N
H)，8.68(1H，s，N
H)，8.16(1H?s，adenine?ring-
H)，8.13(1H，s，adenine?ring-
H)，3.98-5.95(10H，m，gly-
H，C
H)，7.27(2H，s，NH
2)，4.25(6H，m，C
H 2)，1.84-2.50(21H，m，C
H 3CO)；Anal.Calcd?for?C
34H
44N
8O
18S：C，46.15；H，5.01；N，12.66.Found：C，46.12；H，5.07；N，12.74.ESI-MS：(MH
+)885.8.
(6) 1-adeninyl-ethanoyl-4-(1 '-N-lactose base)-thiosemicarbazide (a) is synthetic
1-adeninyl-ethanoyl-4-(1 '-N-2 ', 3 ', 6 '; 2 ", 3 ", 4 "; 6 "-seven-O-ethanoyl-lactose base)-(886mg 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 ', 6 '; 2 "; 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base)-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-lactose base)-thiosemicarbazide 496mg, productive rate 84%.
1H NMR (500MHz, DMSO-d
6): δ 9.88,9.72,8.16 (3H, bs, N
H), 8.08 (s, 2H), 8.15 (1H s), 7.99 (1H s) (adenine ring-
H), 3.13-5.36 (21H, m, gly-
H, were overlapped with H of
H-O, C
H 2); Ultimate analysis C
20H
30N
8O
11S theoretical value: C, 40.68; H, 5.12; N, 18.97. observed value: C, 44.73; H, 5.08; N, 19.04.ESI-MS:(MH
+) 591.6.
Embodiment 2: 1-benzimidazolyl--ethanoyl-4-(1 '-N-lactose base)-thiosemicarbazide (compound number is b) synthetic
(1) the 1-bromo-2,3,6, and 2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose synthetic
Adopt the method and the condition of (1) among the embodiment 1 synthetic.
(2) 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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 ', 6 ', 2 ", 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base)-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 773mg, productive rate 89%.
1H NMR (500MHz, DMSO-d
6): δ 10.08 (1H, bs, NH), 9.77 (1H, bs, NH), 8.54 (1H, bs, NH), 7.12～8.24 (5H, m, benzimidazole ring-H), 3.86～5.92 (16H, m, gly-H and COCH
2), 1.75～2.22 (21H, 5s, CH
3CO); Ultimate analysis C
36H
45N
5O
18S theoretical value: C, 49.82; H, 5.23; N, 8.07. observed value: C, 49.89; H, 5.19; N, 8.12.ESI-MS:(MH
+) 868.8.
(6) 1-benzimidazolyl--ethanoyl-4-(1 '-N-lactose base)-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 ', 6 '; 2 ", 3 ", 4 "; 6 "-seven-O-ethanoyl-lactose base)-and thiosemicarbazide, get white solid powder 382mg, productive rate 95%.
1H NMR (500MHz, DMSO-d
6): δ 10.45 (1H, bs, NH), 9.63 (1H, bs, NH), 8.47 (1H, bs, NH), 7.09～8.38 (5H, m, benzimidazole ring-H), 3.08～5.85 (23H, m, gly-H and COCH
2, were overlapped with H of H-O); Ultimate analysis C
22H
31N
5O
11S theoretical value: C, 46.07; H, 5.45; N, 12.21. observed value: C, 46.01; H, 5.48; N, 12.17.ESI-MS:(MH
+) 574.6.
Can synthesize with above-mentioned same similarly method and to obtain 1-[2-(4-methoxyl group)]-benzimidazolyl--ethanoyl-4-(1 '-N-lactose base)-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 (EC in cell cultures
50)
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: lactose base 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 | 56.3 94.1 22.1 0.58 | 30.7 ＞100 19.6 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 stronger restraining effect, EC to Human Lung Cancer cell (PG)
50Value has reached 22.1 μ M, and a and b then have medium inhibition activity, EC
50Value is respectively 56.3 μ M and 94.1 μ M; Compound c has stronger restraining effect, EC to human liver cancer cell (BEL-7402)
50Reached 19.6 μ M, compound a also has strong active, EC
50Value is 30.7 μ M, and the EC of compound b
50Then greater than 100 μ M.
Claims (4)
1. one group of lactose base thiourea heterocyclic compound, its structure is as shown in the formula shown in (I):
Wherein:
B is one of adeninyl, guanyl-, purinethol base, xanthoglobulin base, benzimidazolyl-, benzotriazole base, benzopyrazoles base, and B can be by one or more C
1-C
5Alkyl replaces.
2. the preparation method of the described lactose base of claim 1 thiourea heterocyclic compound is characterized in that described target compound is synthetic through six steps:
The first step: 1-bromo-2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl lactose 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, filtration discards red phosphorus, adds full acetylated lactose, reacts under the same temperature, the lactose 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-2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl lactose;
Second step: 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose base lsothiocyanates synthetic
Plumbous rhodanate, dry-out benzene series solvent add in the there-necked flask, add 1-bromo-2,3,6 with dropping funnel after the reflux, 2 ', 3 ', 4 ', the xylene solution of 6 '-seven-O-ethanoyl lactose, 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 with the toluene and the sherwood oil mixed solvent recrystallization of equal proportion, 3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose 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, vacuum distilling removes and desolvates, residue is poured in the water and is 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, described hetero-aromatic ring base is a VITAMIN B4, guanine, purinethol, xanthoglobulin, benzoglyoxaline, benzotriazole, one of benzopyrazoles, this hetero-aromatic ring base can be by one or more C
1-C
5Alkyl replaces;
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 fully up to solid, add hydrazine hydrate, temperature is controlled at 10～90 ℃ of following stirring reactions, 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 ', 6 ', 2 ", 3 " and, 4 ", 6 "-seven-O-ethanoyl-lactose base)-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 ℃, be dissolved in 2 in the anhydrous alkaline inert solvent, 3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-lactose base lsothiocyanates forms solution, with dropping 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, column chromatography behind the grind into fine powder after the solvent evaporation after using 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 ', 6 '; 2 "; 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base) thiosemicarbazide;
The 6th step: 1-hetero-aromatic ring acyl group-4-(1 '-N-lactose base) thiosemicarbazide synthetic
1-hetero-aromatic ring acyl group-4-(1 '-N-2 '; 3 '; 6 '; 2 "; 3 "; 4 ", 6 "-seven-O-ethanoyl-lactose base) 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; 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 ', 6 '; 2 "; 3 ", 4 ", 6 "-seven-O-ethanoyl-lactose base) the thiosemicarbazide completely dissolve; reaction solution is handled to neutrality with Zeo-karb has floss to occur; suction filtration, the vacuum-drying of gained solid, white solid powder 1-hetero-aromatic ring acyl group-4-(1 '-N-lactose base) thiosemicarbazide.
3. the preparation method of the described lactose base of claim 2 thiourea heterocyclic compound 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 dimethylbenzene; 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 base of lactose described in the claim 1 thiourea heterocyclic compound application that is used to prepare antitumor drug.
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Non-Patent Citations (4)
| Title |
|---|
| Juan Manuel Benito, et al.Synthesis and anomeric stability of (1-6)-thiourea-linked pseudooligosaccharides.《Carbohydrate Research》.1999,第320卷37-48. * |
| 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. * |
| 李会香.糖苷类化合物的合成及其立体结构研究.《中国优秀博硕士学位论文全文数据库（硕士） 工程科技Ⅰ辑》.2006,(第11期),第24-25页. * |
| 李纪志.功能糖苷类化合物的合成及其立体结构研究.《中国优秀博硕士学位论文全文数据库(硕士) 工程科技Ⅰ辑》.2005,(第06期),第22-24页. * |
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Application publication date: 20080709 Assignee: QINGDAO JIAHUA ENVIRONMENT ENGINEERING CO., LTD. Assignor: Qingdao University of Science & Technology Contract record no.: 2012370000203 Denomination of invention: Galactosyl thiourea heterocyclic compounds, synthetic method thereof and antineoplastic applications Granted publication date: 20101222 License type: Exclusive License Record date: 20120822 |
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