CN104558077B - Glucose derivatives of glaucocalyxin A as well as preparation method and application of glucose derivatives - Google Patents
Glucose derivatives of glaucocalyxin A as well as preparation method and application of glucose derivatives Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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Abstract
The invention relates to glucose derivatives of glaucocalyxin A. The glucose derivatives have a structure represented by a formula I or a formula II, wherein R1 represents hydrogen or methoxyl, R2 represents hydrogen or acetyl, and n represents 0 or 1. The invention further relates to a preparation method and application of the glucose derivatives. By virtue of a cytotoxic activity evaluation experiment, a result shows that the glucose derivatives of glaucocalyxin A have relatively strong inhibitory activity for human tumor cell proliferation, and the activity is superior to that of a parent compound, namely glaucocalyxin A. (The formula is shown in the description).
Description
Technical field
The present invention relates to field of medicine invention, and in particular to the glucose of glaucocalyxin (glaucocalyxin A, GLA)
Derivant and its preparation method and application.
Background technology
Glaucocalyxin (glaucocalyxin A, GLA), chemical name is：(5 β, 7 α, 9 β, 10 α) -7,14- dihydroxy shellfishes
Shell China fir -16- alkene -3,15- diketone；Also known as leukamenin F, molecular formula is C20H28O4, molecular weight：332.43, CAS registrations
Number：79498-31-0, density：1.22g/cm3, fusing point：513.4 DEG C, methanol, ethanol is soluble in, its structural formula is formula III institute
Show.
Glaucocalyxin is Labiatae Rabdosia plant Rabdosia japonica (Isodon japonica
Var.glaucocalyx main pharmacodynamics composition), and Yunlong et al. about 1981 (Yunlong perhaps, Sun Xichang, Dong Sun Han. Yunnan plant
Research .1981,3 (03):1-3) the isolated glaucocalyxin from Rabdosia japonica first, is that a class has Ent-kauran
The tetracyclic diterpene compound of alkanes skeleton, its Rabdosia japonica be dried leaf in content be up to 1.03%.
Inside and outside anti-tumor experiment shows, glaucocalyxin to various people's cancer cells strain such as CE-1, U87, A549, MCF-7,
Hela, K562, Hep G2, NCI-H460, KB, LEG-3, K562, HL-60 etc. are acted on significant Inhibit proliferaton, especially right
Non-hormone dependence prostate cancer (DU-145), rectal cancer (Lovo) cell are most sensitive, and antitumor spectra is wide；Lewis lungs can be suppressed
The growth of the solid tumors such as cancer, S180 solid types and HCA solid types, hence it is evident that increase lotus S180 ascitic types and lotus HCA ascitic types are little
The increase in life span of Mus, it is in dose-dependence that its antineoplastic is strong and weak.
[Li Wen Gao, Jian Zhang, Wen the Hua Yang, Bin Wang, Jian Wen such as Koryo text (sound)
Wang.Toxicology in Vitro 2011,25:51-63] Rabdosia japonica A prime is reported by mitochondrion-regulation way
Footpath is apoptosis-induced, suppresses people in loop propagation；Document report in 2014 [Xiao X, Cao W, Jiang X,
Zhang W,Zhang Y,Liu B,Cheng J,Huang H,Huo J,Zhang X.Acta Biochim Biophys
Sin.2014,45,946-952], glaucocalyxin is protein kinase AKT inhibitor, induces brain colloid by suppressing AKT phosphorylations
Blastoma U87MG apoptosis, and on normal neurogliocyte without impact, is a kind of very promising treatment leukemia, pernicious
The lead compound of glioma.
Glaucocalyxin has stronger antitumor action in vitro, but needs heavy dose of long-time produce drug effect in vivo
[Zhang Chong, Shang Jiaojun, Ma Suying, Bai Suping. medical Leader, 2013,32,1399-1402], bioavailability is relatively low.Therefore, need
Structural modification is carried out to the lead compound, expect to obtain the more preferable derivant of anti-tumor activity.
There are patent [CN101993359A, publication date 2011.03.30；CN101993370A, publication date 2011.03.30；
CN101993373A, publication date 2011.03.30；CN102584780A, publication date 2012.01.16] report its 7 and 14
The fatty acid of hydroxyl, aromatic esters, dibasic acid ester, polypeptide and acetals structural modification.
In medicine research and develop in, using sugared small toxicity, structure is novel and diversified, targeting is good the features such as to some have biology
The group or lead compound of activity carries out structural modification, it is desirable to improves curative effect of medication, reduce poison by mutual synergism
Side effect, raising affinity, increase bioavailability, with searching and developing new drug.
Study through for many years, inventor is found that a kind of glucosan derivative of new better glaucocalyxin.
The content of the invention
It is an object of the invention to provide a kind of derivant of the glaucocalyxin containing glucose group.
The invention provides a kind of glucosan derivative of glaucocalyxin, the analog derivative has shown in Formulas I or Formula II to be tied
Structure：
Wherein, R1For hydrogen or methoxyl group, R2It is independently each hydrogen or acetyl group, n is 0 or 1.
The glucosan derivative of the glaucocalyxin is Formulas I a-Ic or compound shown in Formula II a-IIc：
Present invention also offers the preparation method of said derivative, the method is comprised the following steps：
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose：
With glucose as raw material, by acetylation, bromo, azido reaction, full acetylated acetylbromoglycose and complete is obtained
Acetylation nitrine glucose intermediate product.Its chemical equation is as follows：
Step 2, the preparation containing terminal acetylene or the benzaldehyde derivative of carboxyl
With substituted hydroxy benzaldehyde as raw material, by there is nucleophilic substitution with 3- propargyl bromides, obtain containing terminal acetylene
Benzaldehyde derivative；By there is nucleophilic substitution with monoxone, carboxylic benzaldehyde derivative is obtained.
Its chemical equation is as follows：
Step 3, the preparation of substituted benzaldehyde acetyl glucosaminidase
Benzaldehyde derivative containing terminal acetylene prepared by the full acetylated nitrine glucose prepared with step 1 and step 2
For raw material, reacted by click, obtain the substituted benzaldehyde acetyl glucosaminidase containing triazole group.Its chemical equation is such as
Under：
Or, with step 1 prepare full acetylated acetylbromoglycose and step 2 prepare carboxylic benzaldehyde derivative or
Substituted hydroxy benzaldehyde is raw material, by nucleophilic substitution, obtains important intermediate product, substituted benzaldehyde acetyl glucosamine
Glycosides.Its chemical equation is as follows：
Step 4, the preparation of glaucocalyxin glucosan derivative
The important intermediate substituted benzaldehyde acetyl glucosaminidase prepared with step 3 and glaucocalyxin pass through as raw material
Condensation reaction, obtains glucosan derivative Ia Ic, the IIa IIc of target product glaucocalyxin.Its compound reaction equation is as follows：
Specifically, the method comprising the steps of：
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose：Glucose is massaged with sodium acetate
You are than being 1:1.0-1:2.0 mix, and are heated to reflux 2-3h in acetic anhydride, and reaction is cooled down after terminating, and adds frozen water to separate out white
Solid, filters, the distilled water wash measured with 5-6 times, is dried, obtains full acetylated glucose；The full acetylated glucose of gained is molten
In dichloromethane, Deca hydrogen bromide-acetic acid solution, room temperature reaction 20-30h, frozen water is added to terminate reaction, dichloromethane extraction afterwards
Take, organic layer uses distilled water, saturated sodium bicarbonate, brine It, dry, concentrating under reduced pressure to obtain full acetylated bromo successively
Glucose；The full acetylated acetylbromoglycose of gained is dissolved in organic solvent, adds Hydrazoic acid,sodium salt, 60-90 DEG C of reaction 5-12h, cooling
To room temperature, add frozen water to separate out solid, filter, be dried, obtain full acetylated nitrine glucose；
Step 2, the preparation containing terminal acetylene or the benzaldehyde derivative of carboxyl：Substituted hydroxy benzaldehyde is pressed with 3- propargyl bromides
Mol ratio is 1:1-1:2 in organic solvent stirring and dissolving, add 0.6-1 molar equivalents Anhydrous potassium carbonate, the iodine of catalytic amount
Change potassium, 40-60 DEG C of reaction 6-10 hour, reaction add the isopyknic distilled water of reactant liquor, ethyl acetate extraction, extraction after terminating
Liquid anhydrous magnesium sulfate is dried, and filters, and concentrating under reduced pressure, silica gel column chromatography separating purification, petroleum ether-ethyl acetate system eluting are obtained
To the benzaldehyde derivative containing terminal acetylene；Or
Substituted hydroxy benzaldehyde is placed in 5% sodium hydroxide solution, regulation pH value is 8-9, is added dropwise over 1.4-1.6 times and measures
Chloroacetic unsaturated carbonate potassium solution, adds the potassium iodide of catalytic amount, continues reaction after being heated to reflux being in crocus to solution
2-4 hours, stopped reaction, system are cooled to room temperature, and concentrated hydrochloric acid adjusts solution ph for 1-2, Precipitation, sucking filtration, and 5-6 times is measured
Distilled water wash repeatedly, gained solid alcohol-water recrystallization, after vacuum drying, obtains carboxylic benzaldehyde derivative；
Step 3, the preparation of substituted benzaldehyde acetyl glucosaminidase：The full acetylated nitrine glucose of gained and step in step 1
In rapid 2, benzaldehyde derivative of the gained containing terminal acetylene is with mol ratio as 1:1.0-1:1.5 are dissolved in organic solvent, under condition of ice bath
Copper sulfate, the L-AA sodium of catalytic amount is added, 0-5h under room temperature condition, is reacted, the steaming of 1.5-2 times of reactant liquor volume is added
Distilled water, ethyl acetate extraction, successively with distilled water, saturated common salt water washing, anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure, post
Chromatography purification, petroleum ether-ethyl acetate system eluting obtain the substituted benzaldehyde acetyl glucosaminidase containing triazole group；
Or
The carboxylic benzaldehyde derivative of gained or replacement in full acetylated acetylbromoglycose obtained by step 1 and step 2
Hydroxy benzaldehyde is with mol ratio 1:1.0-1:1.5 are dissolved in organic solvent, add the amount tetrabutyl phosphonium bromide of 1.0-1.5 times of material
It is 8-10,50-80 DEG C of reaction 2-10h that ammonium and unsaturated carbonate potassium solution or 5% sodium hydroxide solution adjust pH, is cooled to room temperature
Afterwards, dichloromethane extraction, successively with distilled water, saturated ammonium chloride, saturated common salt water washing, anhydrous magnesium sulfate is dried, concentration, post
Chromatography purification, petroleum ether-ethyl acetate system eluting, obtains substituted benzaldehyde acetyl glucosaminidase；
Step 4, the preparation of glaucocalyxin glucosan derivative：Gained benzaldehyde acetyl glucosaminidase and blue calyx in step 3
A prime is with mol ratio as 1:0.5‐1:1.5 are dissolved under organic solvent, acid condition and react 1 5h, add dichloromethane extraction, according to
Secondary saturated sodium bicarbonate, saturated aqueous common salt are washed, anhydrous MgSO4It is dried, filters, concentration, column chromatographic isolation and purification, stone
Oily ether/ethyl acetate system eluting, obtains end-product Ia Ic, IIa IIc.
In said method：
In the step 1：Described organic solvent be tetrahydrofuran, N, N dimethylformamides, dimethyl sulfoxide, acetonitrile,
1,4 dioxane, dichloromethane or chloroform etc..
In the step 2：Described organic solvent be tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or
1,4- dioxane.
In the step 3：Described organic solvent be tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile,
1,4- dioxane, n-butyl alcohol, n-butanol-water, dichloromethane, chloroform or acetonitrile.
In the step 4：Described organic solvent be tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile,
1,4- dioxane, dichloromethane, chloroform etc.；The acid condition includes various mineral acids, such as dry hydrogen chloride gas, phosphorus
Acid, sulphuric acid etc., organic acid, such as trifluoroacetic acid, aromatic acid, toluenesulfonic acid, sulfamic acid etc., non-proton Lweis are sour, such as tri-chlorination
Ferrum, ammonium ferric sulfate, aluminum sulfate, copper methanesulfonate etc.；Reaction temperature is 10-30 DEG C.
Present invention also offers the preparation of the glucosan derivative of glaucocalyxin, said preparation is by the derivant and pharmaceutically may be used
The carrier composition of acceptance.
It is the preparation, including but not limited to tablet, capsule, flexible glue agent, spray, gel, gel inhalant, oral
Agent, suspensoid, electuary, patch, ointment, pill, powder, injection, infusion solution, freeze dried injection, lipidosome injection, targeting
Administration injection agent, suppository, slow releasing preparation or controlled release preparation.
The pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, selected from filler, binding agent, collapses
One or more in solution agent, lubricant, suspending agent, wetting agent, solvent, surfactant or correctivess.
The filler is selected from starch, sucrose, Lactose, Mannitol, Sorbitol, xylitol, Microcrystalline Cellulose or glucose
Deng；
Described adhesive is selected from cellulose derivative, alginate, gelatin or polyvinylpyrrolidone etc.；
The disintegrating agent is selected from Microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low substituted hydroxy-propyl
Cellulose or Croscarmellose Sodium；
The lubricant is selected from stearic acid, Polyethylene Glycol, Calcium Carbonate, sodium bicarbonate, micropowder silica gel, Pulvis Talci or stearic acid
Magnesium；
The suspending agent is selected from micropowder silica gel, Cera Flava, cellulose, solid polyethylene glycol；
The wetting agent is selected from glycerol, tween 80, ethoxy aluminium Oleum Ricini or lecithin；
The solvent selected from ethanol, liquid polyethylene glycol, isopropanol, tween 80, glycerol, Propylene Glycol or vegetable oil, it is described
Vegetable oil is selected from soybean oil, Oleum Ricini, Oleum Arachidis hypogaeae semen, mixed oil etc.；
The surfactant is selected from dodecylbenzene sodium sulfonate, stearic acid, Pluronic F68, fat
Pyrusussuriensiss are smooth or Polysorbate (tween) etc. for fat acid；
The sweeting agent is selected from aspartame, Sucralose, essence, citric acid or saccharin sodium.
Present invention also offers application of the glucosan derivative of the glaucocalyxin in the medicine for preparing treatment tumor,
The tumor is preferably hepatocarcinoma, cervical cancer, leukemia, choriocarcinoma and pulmonary carcinoma.
Glaucocalyxin derivant provided by the present invention has advantages below：
1. inventor uses chemical reaction, by two hydroxyls of the 7 of glaucocalyxin and 14 and introducing glucosyl group
There is acetalation in the benzaldehyde of group, on the premise of glaucocalyxin pharmacophoric group α, β-unsaturation ring pentanone is retained, ingenious
Introduce the glucose glycosyl group with physiological function.
2., in the partial derivatives of glaucocalyxin, also introduce while glucose glycosyl is introduced and there is certain biology
The triazole group of activity, further increases the anti-tumor activity of derivant.
3., in glaucocalyxin derivatization process, by acetalation, two hydroxyls of 7 and 14 simultaneously participate in reaction,
Target product is clear and definite, without other isomer products, it is easy to purification.
4. compared with prior art, 7 α of glaucocalyxin, what 2 hydroxyls and various aldehyde (ketone) acetal (ketone) of 14 β-position were changed
Derivant (CN201210015481.4 (CN102584780A)：The derivant of the present invention is had with the derivant structure of this 2 patents
Similarity, is all 7 α of glaucocalyxin, the acetalation product of 2 hydroxyls of 14 β-position.But the present invention is different from part：
Compare with the glaucocalyxin derivant in the first two invention, it is ingenious on the phenyl ring of its fragrant acetalation derivant to introduce physiology work(
Energy group glucose glycosyl and bio-active group triazole group, anti-tumor activity are greatly improved.Disclosed two
Analog in invention, the IC of the tumor cell line to testing50Be worth for 14 μM-more than 100 μM, and present invention introduces glucose is sugared
Glaucocalyxin derivant after group, the IC of the tumor cell line to testing50Value is mostly 0.41 μM -50 μM, anti-tumor activity
Strengthen.
5. the glucosan derivative of glaucocalyxin according to the present invention, Jing cytotoxic activity evaluation experimentals, as a result find tool
There is stronger human tumor cells proliferation inhibition activity, it is thin especially for human leukemia cell, Choriocarcinoma cell line and cervical cancer
Born of the same parents, anti-tumor activity are better than parent compound glaucocalyxin.
Description of the drawings
Fig. 1 is the glaucocalyxin derivative I a's of 1,2,3- triazole glucoses1H-NMR；
Fig. 2 is the glaucocalyxin derivative I b's of 1,2,3- triazole glucoses1H-NMR；
Fig. 3 is the glaucocalyxin derivative I c's of 1,2,3- triazole glucoses1H-NMR；
Fig. 4 is the glaucocalyxin derivative I Ia of full acetylated glucose sugar ester1H-NMR；
Fig. 5 is the glaucocalyxin derivative I Ib of full acetylated Fructus Vitis viniferae glycosyloxy glycosides1H-NMR；
Fig. 6 is the glaucocalyxin derivative I Ic of full acetylated Fructus Vitis viniferae glycosyloxy glycosides1H-NMR。
Specific embodiment
Following examples are used for illustrating the present invention, but are not limited to the scope of the present invention.
Preparation process described in following examples, all chemical reagent for being adopted are as pure in being analysis without especially mark.
Embodiment 1：The preparation of glaucocalyxin glucosan derivative Ia, Ib, Ic containing triazole group
Reaction equation is as follows：
1.1：The preparation of full acetylated glucose
Weigh anhydrous sodium acetate 8.287g to be placed in crucible, adjusting temperature makes which lose whole moisture, turns after cooling immediately
Enter in mortar, add dry glucose (10.636g, 590mmol), after mix homogeneously, be transferred to 250mL round-bottomed flasks
In, acetic anhydride 150mL is added, temperature is adjusted to 100 DEG C, reacts 2-3h.Room temperature is cooled to, reactant liquor is poured in frozen water, is had
White solid is separated out, and after sucking filtration, full acetylated glucose is obtained with 5 times of amount distilled water washs, white is obtained solid after being dried
Body 17.707g, yield 77%.
1.2：The preparation of full acetylated acetylbromoglycose
Take in 1.1 gained compounds (4.985g, 12.7mmol) addition 100mL round-bottomed flasks, add 20mL dichloromethanes
Alkane, after all dissolving, is added dropwise over the hydrogen bromide-acetic acid solution 35mL of brand-new with constant pressure funnel, 28h is stirred at room temperature.
After reaction terminates, reactant liquor is proceeded in separatory funnel, appropriate frozen water is added immediately, 30mL dichloromethane is added, successively
With frozen water, saturated sodium carbonate solution, saturated common salt water washing three times, the anhydrous MgSO of organic layer4It is dried, filters, concentration obtains light
Yellow, viscous liquid, Glass rod stirring 10min, can obtain Off-white solid 4.875g, yield 92.8%.
1.3：The preparation of full acetylated nitrine glucose
1.2 gained compounds (4.418g, 10.8mmol) are taken, in adding the round-bottomed flask of 100mL, dimethyl sulfoxide is used
(DMSO), after 45mL dissolvings, NaN is added in two batches3(1.893g, 29.1mmol), temperature are adjusted to 60 DEG C, react 12h.Treat system
After being cooled to room temperature, reactant liquor is poured in frozen water, there are a large amount of white solids to separate out immediately, sucking filtration obtains white solid after being dried
3.225g, yield 80.2%.
1HNMR(400MHz,CDCl3)δH5.20-5.25 (t, J=12Hz, 1H, H-3), 5.09-5.14 (t, J=12Hz,
1H, H-4), 4.94-4.99 (t, J=12Hz, 1H, H-2), 4.64-4.67 (d, J=12Hz, 1H, H-1), 4.26-4.30 (dd,
J=12Hz, 4Hz, 1H, H-6), 4.19-4.16 (dd, J=12Hz, 2.4Hz, 1H, H-6), 3.78-3.82 (ddd, J=10Hz,
4.4Hz,2Hz,1H,H-5),2.11(s,3H,-COCH3),2.08(s,3H,-COCH3),2.04(s,3H,-COCH3),2.02
(s,3H,-COCH3).
1.4：Preparation containing terminal acetylene or the benzaldehyde derivative of carboxyl
1.4.1：The preparation of 4- propargyloxy benzaldehydes
Disubstituted-4-hydroxy benzaldehyde (3.155g, 25.8mmol) and 3- propargyl bromides (3.074g, 25.8mmol), add 100mL
Round-bottomed flask in, add the DMF (DMF) of 50mL, stir to sample and all dissolve, add anhydrous carbon
Sour potassium 2.632g, potassium iodide 134mg, 40 DEG C of reaction 8h, TLC detection raw material points disappear, after system is cooled to room temperature, will reaction
Liquid is transferred in separatory funnel, adds 50mL distilled water, is extracted with ethyl acetate 50mL × 3, saturated common salt water washing, anhydrous sulfur
Sour magnesium is dried overnight, and filters, concentration.Crude product Jing silica gel column chromatography purification, petrol ether/ethyl acetate (5/1) carry out eluting, obtain
White powder 3.985g, yield:96%.1HNMR(400MHz,CDCl3)δH9.91 (s, 1H, CHO), 7.85-7.88 (dt, J=
12Hz,2.4Hz,2H,CHAr), 7.08-7.11 (dt, J=8Hz, 2.8Hz, 2H, CHAr),4.78(s,1H,CH2,4.79(s,1H,
CH2), 2.58-2.57 (t, J=2.4Hz, 1H, CH).
1.4.2：The preparation of 3- methoxyl group -4- propynyloxy benzaldehydes
With Vanillin and 3- propargyl bromides as raw material, the same 1.4.1 of preparation method prepares 3- first
Epoxide -4- propynyloxy benzaldehydes, white solid, yield 94%.1HNMR(400MHz,CDCl3)δH 10.49(s,1H,CHO),
7.85-7.88(m,1H,CHAr),7.11-7.55(m,2H,CHAr),4.84(s,1H,CH2),4.79(s,1H,CH2),2.58,
2.57 (t, J=2.4Hz, 1H, CH).
1.4.3：The preparation of 2- propargyloxy benzaldehydes
With Benzaldehyde,2-hydroxy and 3- propargyl bromides as raw material, the same 1.4.1 of preparation method prepares 2- propargyloxy benzene
Formaldehyde, white solid, yield 92%.1HNMR(400MHz,CDCl3)δH10.49 (s, 1H, CHO), 7.85-7.87 (dd, J=
8Hz,4Hz,1H,CHAr),7.55-7.59(m,1H,CHAr), 7.05-7.13 (d, J=12Hz, 1H, CHAr),7.05-7.09(d,
J=4Hz, 1H, CHAr)4.84(s,1H,CH2),4.83(s,1H,CH2), 2.58-2.59 (t, J=2.4Hz, 1H, CH).
1.5：The preparation of the substituted benzaldehyde acetyl glucosaminidase containing triazole group
1.5.1：The preparation of the substituted benzaldehyde acetyl glucosaminidase 7 containing triazole group
Take full acetyl nitrine glucose (2.305g, 6.2mmol) and 4- propynyloxies benzaldehyde obtained by 1.4.1 obtained by 1.3
(0.985g, 6.2mmol) adds the DMF of 20mL in the round-bottomed flask that 50mL is dried, and stirs after solid is all dissolved, ice
10min is reacted under the conditions of bath, is added catalyst (anhydrous cupric sulfate, L-AA sodium, BPDS) reaction 0.5h, is withdrawn frozen water
Bath, continues to react 5h under room temperature condition.Reaction adds ethyl acetate 50mL after terminating, successively distilled water 50mL × 3, saturated common salt
Water washing, anhydrous MgSO4 are dried, and filter, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 1:1 eluting, obtains white
Color crystalline powder 2.837g, yield 86%.
1HNMR(400MHz,CDCl3)δH 9.90(s,1H,CHO),7.89(s,1H,CH(heterocycle)),7.84-7.87
(dt, J=12Hz, 2.4Hz, 2H, CHAr), 7.09-7.12 (dt, J=8Hz, 2.8Hz, 2H, CHAr),5.89-5.90(m,1H,
CH),5.42-5.43(m,2H,CH2),5.30(s,2H,CH2),3.99-5.26(m,4H,H1-4),2.08(s,3H,-COCH3),
2.07(s,3H,CH3),2.02(s,3H,CH3),1.83(s,3H,CH3).
1.5.2：The preparation of the substituted benzaldehyde acetyl glucosaminidase 8 containing triazole group
Take full acetyl nitrine glucose (2.305g, 6.2mmol) and 3- methoxyl groups -4- propynyloxies obtained by 1.4.2 obtained by 1.3
Benzaldehyde (1.178g, 6.2mmol), with 1.4.1 operating process, obtains white crystalline powder 2.861g, yield 82%.
1HNMR(400MHz,CDCl3)δH 9.86(s,1H,CHO),7.91(s,1H,CH(heterocycle)),7.43-7.45
(dt, J=12Hz, 2.4Hz, 2H, CHAr), 7.16-7.18 (dt, J=8Hz, 2.8Hz, 2H, CHAr),5.87-5.90(m,1H,
CH),5.41-5.43(m,2H,CH2),3.94-5.38(m,4H,H1-4),2.08(s,3H,-COCH3),2.07(s,3H,-
COCH3),2.03(s,3H,-COCH3),1.84(s,3H,-COCH3).
1.5.3：The preparation of the substituted benzaldehyde acetyl glucosaminidase 9 containing triazole group
Take full acetyl nitrine glucose (2.305g, 6.2mmol) and 2- propynyloxies benzaldehyde obtained by 1.4.3 obtained by 1.3
(0.985g, 6.2mmol), with 1.4.1 operating process, obtains white crystalline powder 2.869g, yield 87%.
1HNMR(400MHz,CDCl3)δH 10.48(s,1H,CHO),7.94(s,1H,CH(heterocycle)),7.84-7.86
(dd, J=7.6Hz, 2Hz, 1H, CHAr),7.55-7.59(m,1H,CHAr), 7.13-7.15 (d, J=8Hz, 1H, CHAr),
7.06-7.10 (t, J=8Hz, 1H, CHAr),5.90-5.92(m,1H,CH),5.44-5.46(m,2H,CH2),5.35(s,2H,
CH2), 5.24-5.28 (m, 1H, CH), 4.30-4.35 (dd, J=16Hz, 8Hz, 1H, CH), 4.15-4.18 (dd, J=12Hz,
2Hz, 1H, CH), 4.03-4.05, (ddd, J=12Hz, 4.8Hz, 2Hz, 1H, CH), 2.09 (s, 3H ,-COCH3),2.07(s,
3H,-COCH3),2.03(s,3H,-COCH3),1.84(s,3H,-COCH3).
1.6：The preparation of full acetylated glucosan derivative Ia, Ib, Ic of glaucocalyxin
1.6.1：The preparation of the full acetylated glucosan derivative Ia of glaucocalyxin
Take compound obtained by 1.5.1 (1.750g, 3.28mmol) and Rabdosia japonica A prime (1.112g, 3.28mmol) in
In the round-bottomed flask that 50mL is dried, the dichloromethane that Deca 10mL is dried is stirred at room temperature to sample and dissolves.Add the dense sulfur of 2 drops
Acid, reacts 2h, adds dichloromethane 50mL afterwards, and saturated sodium bicarbonate 50ml × 3, saturated common salt water washing, anhydrous successively
MgSO4It is dried, filters, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 2:1 eluting, obtains white solid
1.206g, end-product Ia, yield 43%.
1HNMR(400MHz,CDCl3)δH 7.84(s,1H,CH(heterocycle)),7.32-7.28(m,2H,CHAr),6.93-
6.91(m,2H,CHAr), 6.20 (s, 1H, CH), 5.88 (d, J=8Hz, 1H, CH), 5.83 (s, 1H, CH), 5.47-5.39 (m,
3H,CH),5.24(m,1H,CH),5.18(s,2H,CH2), 4.42 (dd, J=12Hz, 4Hz, 1H, CH), 4.30 (dd, J=
12Hz, 4Hz, 1H, CH), 4.01 (ddd, J=12Hz, 4.8Hz, 2Hz, 1H, CH), 3.20 (s, 1H, CH), 2.59-1.13 (m,
37H,CH,CH2,CH3).
1.6.2：The preparation of the full acetylated glucosan derivative Ib of glaucocalyxin
Compound obtained by 1.5.2 and glaucocalyxin is taken, with the preparation method of 1.6.1, glaucocalyxin derivative I b had both been obtained, and had been produced
Rate 47%.1HNMR(400MHz,CDCl3)δH7.84(s,1H,CH(heterocycle)),6.95-6.89(m,3H,CHAr),6.20(s,
1H, CH), 5.85 (d, J=16Hz, 1H, CH), 5.82 (s, 1H, CH), 5.46-5.38 (m, 3H, CH), 5.25 (s, 2H, CH2),
5.22 (m, 1H, CH), 4.43 (dd, J=16Hz, 8Hz, 1H, CH), 4.28 (dd, J=12Hz, 4Hz, 1H, CH), 3.99 (m,
1H,CH),3.86(s,3H,CH3),3.21(s,1H,CH),2.61-1.13(m,37H,CH,CH2,CH3).
1.6.3：The preparation of the full acetylated glucosan derivative Ic of glaucocalyxin
Compound obtained by 1.5.3 and glaucocalyxin is taken, with the preparation method of 1.6.1, glaucocalyxin derivative I c had both been obtained, and had been produced
Rate 40%.
1HNMR(400MHz,CDCl3)δH 7.80(s,1H,CH(heterocycle)),7.45-6.95(m,4H,CHAr),6.30
(s,1H,CH),6.20(s,1H,CH),5.87(m,1H,CH),5.45-5.38(m,1.5H,CH),5.26-5.20(m,1.5H,
), CH 4.79 (s, 1H, CH), 4.41 (dd, J=12Hz, 4Hz, 1H, CH), 4.30 (dd, J=12Hz, 4Hz, 1H, CH), 4.15-
4.09 (m, 2H, CH), 4.02-3.98 (ddd, J=10Hz, 5.2Hz, 2.4Hz, 1H, CH), 3.21 (s, 1H, CH), 2.62-
1.11(m,23H,CH,CH2,CH3).
Embodiment 2：The preparation of the glaucocalyxin derivative I Ia of glucose sugar ester
Reaction equation is as follows：
2.1：The preparation of 2- (4- formoxyl -2- Difluoro-phenoxies)-acetic acid
Take monoxone (4.822g, 51.3mmol) and add appropriate unsaturated carbonate potassium solution, it is 9 to adjust solution ph, makes sample
Product all dissolve, and are transferred to standby in constant pressure funnel.Take Vanillin (5.198g, 34.2mmol)
In the flask of 250mL bottoms, add appropriate 5% sodium hydroxide solution to adjust pH value and be about 9, stirring makes sample all dissolve, and adjusts
Constant pressure funnel, makes to be fully transferred in round-bottomed flask in sample 30min, adds potassium iodide 321mg, 110 DEG C of backflow 5h,
Be cooled to room temperature, it is 1 that concentrated hydrochloric acid adjusts solution ph, and Precipitation, sucking filtration, distilled water are repeatedly washed, gained solid with ethanol-
Water recrystallization (1:1), it is vacuum dried, obtains white solid 3.817g, yield 62%.
2.2：The preparation of benzaldehyde glucose ester glycosides 10
Take the dichloromethane for adding 15mL in the round-bottomed flask that 2.1 gained compounds (1.002g, 4.77mmol) add 50mL
Alkane, after sample is all dissolved, adds 5% sodium hydroxide solution to adjust pH value and is about 9, add tetrabutyl ammonium bromide (TBAB)
(1.536g, 4.77mmol), after reaction 15min, add in embodiment 1 full acetylated acetylbromoglycose obtained by 1.2 (1.956g,
4.77mmol), 60 DEG C of reaction 6h, after being cooled to room temperature, reactant liquor proceeds to separatory funnel, adds dichloromethane 50mL, uses successively
Distilled water 50ml × 3, saturated ammonium chloride 50mL × 3, saturated aqueous common salt are washed, anhydrous MgSO4It is dried, filters, reduces pressure dense
Contracting, column chromatographic isolation and purification, petrol ether/ethyl acetate 3:1 carries out eluting, obtains white solid 1.437g, yield 59%.
2.3：The preparation of the full acetylated glucosan derivative IIa of glaucocalyxin
2.2 gained compounds and glaucocalyxin is taken, with the preparation method of 1.6.1 in embodiment 1, the indigo plant of glucose sugar ester is obtained
Calyx A prime derivative I Ia, white solid, yield 63%.
1HNMR (400MHz, CDCl3) δ H 6.98-6.76 (m, 3H, CHAr), 6.18 (d, J=12Hz, 4Hz, 1H, CH2),
6.35(s,1H,CH),5.82(s,1H,CH),5.38(m,1H,CH),5.20(m,1H,CH),5.13(m,2H,CH2),4.73-
4.69 (m, 2H, CH), 4.43 (dd, J=12Hz, 5Hz, 1H, CH2), 4.29 (dd, J=12.8Hz, 4.8Hz, 1H, CH), 3.85
(s,3H,CH3),3,20(s,1H,CH),2.57-1.13(m,23H,CH,CH2,CH3).
Embodiment 3：The preparation of glaucocalyxin the derivative I Ib and IIc of Fructus Vitis viniferae glycosyloxy glycosides
Reaction equation is as follows：
3.1：The preparation of the full acetylated Fructus Vitis viniferae glycosyloxy glycosides that benzaldehyde replaces
3.1.1：Full acetylated acetylbromoglycose (2.498g, 6.09mmol) obtained by 1.2 in Example 1 and 3- methoxies
Base -4- hydroxy benzaldehydes (0.926g, 6.09mmol) in the round-bottomed flask of 100mL adds 25mL dichloromethane, makes sample complete
After portion's dissolving, TBAB (1.961g, 6.09mmol) and unsaturated carbonate potassium solution 20mL, 60 DEG C of reaction 5h are added, room is cooled to
Wen Hou, reactant liquor are proceeded in separatory funnel, add dichloromethane 50mL, successively with distilled water 50mL × 3, saturated ammonium chloride 50mL
× 3, saturated common salt water washing, anhydrous MgSO4It is dried, filters, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate
3:1 carries out eluting, obtains white powdery solids 1.758g, yield 63.9%.
3.1.2：Full acetylated acetylbromoglycose (2.498g, 6.09mmol) obtained by 1.2 in Example 1 and 2- hydroxy benzeness
Formaldehyde (0.742g, 6.09mmol), with the preparation method of 3.1.1, had both obtained product 1.597g, yield 58%.
3.2：The preparation of glaucocalyxin derivative I Ib, IIc of Fructus Vitis viniferae glycosyloxy glycosides
3.2.1：Take compound obtained by 3.1.1 and glaucocalyxin, with the preparation method of 1.6.1 in embodiment 1, both blue calyx
A prime derivative I Ib.Yield：63.9%.
1HNMR(400MHz,CDCl3)δH 7.84(s,1H,CH),6.95-6.89(m,3H,CHAr),6.20(s,1H,
), CH 5.85 (d, J=16Hz, 1H, CH), 5.82 (s, 1H, CH), 5.46-5.38 (m, 3H, CH), 5.25 (s, 2H, CH2),
5.22 (m, 1H, CH), 4.43 (dd, J=16Hz, 8Hz, 1H, CH), 4.28 (dd, J=12Hz, 4Hz, 1H, CH), 3.99 (m,
1H,CH),3.86(s,3H,CH3),3.21(s,1H,CH),2.61-1.13(m,37H,CH,CH2,CH3).
3.2.2：Take compound obtained by 3.1.2 and glaucocalyxin, with the preparation method of 1.6.1 in embodiment 1, both blue calyx
A prime derivative I Ic.Yield：52%.
1HNMR(400MHz,CDCl3)δH 7.48(s,1H,CH),7.27-6.80(m,4H,CHAr),6.18(s,1H,
CH), 5.25 (s, 2H, CH2), 4.81 (d, J=16Hz, 1H, CH), 4.44 (s, 1H, CH), 4.31 (dd, J=16Hz, 8Hz,
1H, CH), 4.28 (dd, J=12Hz, 4Hz, 1H, CH), 4.10 (s, 2H, CH2), 3.88 (m, 1H, CH), 3.19 (s, 1H, CH),
2.61-1.13(m,37H,CH,CH2,CH3).
Embodiment 4：The test of pesticide effectiveness of glaucocalyxin glucosan derivative
For human hepatoma HepG2 cell, human large cell lung cancer NCI-H460 cell, human choriocarcinoma's JEG-3 cells, people's urgency
Property (early children) granulocyte leukemia HL-60 cells, human chronic myelogenous leukemia's K562 cells, the life of human cervical carcinoma Hela cell
The pharmacodynamic experiment of long inhibitory action.
1. medicine and reagent：Given the test agent, DMEM, 1640 culture medium, 10% inactivation calf serum (FBS), PBS dissolvings
Liquid, dimethyl sulfoxide (DMSO), three liquid (10%SDS+5% isopropanol+12mM HCl), tetrazolium bromide (MTT), amycin (sun
Property comparison medicine).
2. instrument：Superclean bench, CO2Incubator, Multi-functional inverted microscope, centrifuge, automatic microplate reader, the training of 96 holes
Foster plate.
3. cell strain：Human liver cancer Hep G2 tumor cells, human large cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-
Acute (early children) the granulocyte leukemia HL-60 cells of 3 cells, people, human chronic myelogenous leukemia's K562 cells, human cervical carcinoma
Hela cells.
4. sample preparation：Take the glucosan derivative of the 1.6 obtained glaucocalyxin containing triazole group of above-described embodiment
Ia, Ib, Ic, the glaucocalyxin derivative I Ia of glucose sugar ester obtained in embodiment 2.3, embodiment 3.2 are obtained Fructus Vitis viniferae glycosyloxy glycosides
Glaucocalyxin derivative I Ib, IIc and glaucocalyxin, be dissolved in DMSO, ultrasonic dissolution, concentration is 100mM, gained medicine
Preserve under the conditions of -20 DEG C of solution.
5. experimental technique
The medicine MTT experiment of 5.1 attached cells, which further includes：
The attached cell includes human liver cancer Hep G2 tumor cells, human large cell lung cancer NCI-H460 cell, human chorionic
Film cancer JEG-3 cell, human cervical carcinoma Hela cell.
Step 1.1：Exponential phase cell is collected, is suspended with complete DMEM culture medium, and concentration of cell suspension is adjusted for 3
× 104/mL, is inoculated with 96 porocyte culture plates, 100mL/ holes.37 DEG C are put, 5%CO2 incubators culture 24 hours, supernatant discarded,
Fresh complete DMEM culture medium, 90mL/ holes is added, and adds variable concentrations drug solution to be measured, 10mL/ holes, each concentration to set 3
Individual multiple holes；Blank well adds DMEM culture medium 10mL/ hole；This bottom outlet adds not celliferous culture medium 100mL/ hole.
Step 1.2：37 DEG C are put, 5%CO2 is incubated 48 hours.
Step 1.3：100uL MTT solution (0.5mg/mL, incomplete DMEM culture medium are prepared) is added per hole, continues to put training
Foster case is incubated 4 hours.
Step 1.4：Terminate culture after 4 hours, supernatant discarded adds 150mL dimethyl sulfoxide, puts low speed on shaking table per hole
Vibration 5min, makes crystal fully dissolve.
Step 1.5：The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument 570nm.
The medicine MTT experiment of 5.2 suspension cells, which further includes：
The suspension cell includes acute (early children) the granulocyte leukemia HL-60 cells of people, human chronic myelogenous leukemia
K562 cells.
Step 2.1：Exponential phase cell is collected, is suspended with complete RPMI1640 culture medium, cell counting, and adjust thin
Born of the same parents' concentration is 3 × 105/mL, is inoculated with 96 porocyte culture plates, 90mL/ holes.Add variable concentrations drug solution to be measured, 10mL/
Hole, each concentration set 3 multiple holes；Blank well adds 1640 culture medium 10mL/ holes；This bottom outlet adds not celliferous culture medium
100mL/ holes.
Step 2.2：37 DEG C are put, 5%CO2 is incubated 48 hours.
Step 2.3：10mL MTT solution (5mg/1mL, 1640 culture medium are prepared) is added per hole, continues to put incubator incubation
4 hours.
Step 2.4：Three liquid (10%SDS+5% isopropanol+12mM HCl) are added, 10mL/ holes, 37 DEG C of incubations 12 are little
When.
Step 2.5：Each hole OD values, Detection wavelength 570nm are detected in microplate reader.
6. experimental result：The glucosan derivative of glaucocalyxin is to human hepatoma HepG2 cell, human large cell lung cancer NCI-
Acute (early children) the granulocyte leukemia HL-60 cells of H460 cells, human choriocarcinoma's JEG-3 cells, people, people's chronic granulocyte are white
Disorders of blood K562 cells, human cervical carcinoma Hela cell's growth inhibition effect are as shown in the table：
Table 1：Glucosan derivative Ia-Ic, IIa-IIc of glaucocalyxin is to cancer cell strain Proliferation Ability result
7. test result indicate that：Glucosan derivative Ia, Ib, Ic, IIa, IIb, IIc of glaucocalyxin, to human liver cancer
Acute (early children) the white blood of granulocyte of HepG2 cells, human large cell lung cancer NCI-H460 cell, human choriocarcinoma's JEG-3 cells, people
The cancer cell strains such as sick HL-60 cells, human chronic myelogenous leukemia's K562 cells, human cervical carcinoma Hela cell show stronger
Cell inhibitory effect activity.
8. conclusion：The glucosan derivative Ia of glaucocalyxin, Ib, Ic, II a, II b, II c have prepare cancer therapy drug should
With prospect, and which is applied to cancer patient.Which is in treatment hepatocarcinoma, pulmonary carcinoma, cervical cancer, choriocarcinoma, the white blood of acute myelogenous
There is specially good effect in terms of disease and chronic myelocytic leukemia, especially glaucocalyxin is substantially better than in terms of leukemia.
The above is that the specific embodiment of the present invention is enumerated, reagent, equipment for wherein not detailed statement, operation
Method etc., it should be understood that take this area existing common and conventional reagent, equipment, operational approach etc. to be practiced.
Although above having used general explanation, specific embodiment and test, the present invention having been made to retouch in detail
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (11)
1. a kind of glucosan derivative of glaucocalyxin, the analog derivative have structure shown in Formulas I or Formula II：
Wherein, R1For hydrogen or methoxyl group, R2It is independently each hydrogen or acetyl group, n is 0 or 1.
2. derivant according to claim 1, it is characterised in that the derivant is Formulas I a-Ic：
3. derivant according to claim 1, it is characterised in that the derivant is compound shown in Formula II a-IIc：
4. a kind of method for preparing the derivant described in any one of claim 1-3, it is characterised in that the method includes following step
Suddenly：
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose：With glucose as raw material, by second
Acylation, bromo, azido reaction obtain full acetylated acetylbromoglycose and full acetylated nitrine glucose；
Step 2, the preparation containing terminal acetylene or the benzaldehyde derivative of carboxyl：With substituted hydroxy benzaldehyde as raw material, by with
There is nucleophilic substitution in 3- propargyl bromides, obtain the benzaldehyde derivative containing terminal acetylene, or nucleophilic displacement of fluorine occurs with monoxone
Reaction, obtains carboxylic benzaldehyde derivative；
Step 3, the preparation of substituted benzaldehyde acetyl glucosaminidase：The full acetylated nitrine glucose prepared with step 1 and step 2
The benzaldehyde derivative containing terminal acetylene for preparing is raw material, is reacted by click, obtains the substituted benzoyl containing triazole group
Aldehyde acetyl glucosaminidase；
Or, the carboxylic benzaldehyde derivative or replacement of the full acetylated acetylbromoglycose prepared with step 1 and step 2 preparation
Hydroxy benzaldehyde is raw material, by nucleophilic substitution, obtains important intermediate product, substituted benzaldehyde acetyl glucosaminidase；
Step 4, the preparation of glaucocalyxin glucosan derivative：The substituted benzaldehyde acetyl glucosaminidase prepared with step 3 and indigo plant
Calyx A prime is raw material, by condensation reaction, obtains glucosan derivative Ia-Ic, IIa-IIc of target product glaucocalyxin.
5. method according to claim 4, it is characterised in that the method is comprised the following steps：
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose：Glucose is with sodium acetate in molar ratio
For 1:1.0-1:2.0 mix, and are heated to reflux 2-3h in acetic anhydride, and reaction is cooled down after terminating, and adds frozen water to separate out white solid,
Filter, the distilled water wash measured with 5-6 times, be dried, obtain full acetylated glucose；The full acetylated glucose of gained is dissolved in dichloro
Methane, Deca hydrogen bromide-acetic acid solution, room temperature reaction 20-30h add frozen water to terminate reaction afterwards, and dichloromethane extraction has
Machine layer uses distilled water, saturated sodium bicarbonate, brine It, dry, concentrating under reduced pressure to obtain full acetylated bromo Fructus Vitis viniferae successively
Sugar；The full acetylated acetylbromoglycose of gained is dissolved in organic solvent, adds Hydrazoic acid,sodium salt, 60-90 DEG C of reaction 5-12h to be cooled to room
Temperature, adds frozen water to separate out solid, filters, be dried, obtain full acetylated nitrine glucose；
Step 2, the preparation containing terminal acetylene or the benzaldehyde derivative of carboxyl：Substituted hydroxy benzaldehyde and 3- propargyl bromides by mole
Than for 1:1-1:2 in organic solvent stirring and dissolving, add 0.6-1 molar equivalents Anhydrous potassium carbonate, the potassium iodide of catalytic amount,
40-60 DEG C of reaction 6-10 hour, reaction add the isopyknic distilled water of reactant liquor after terminating, ethyl acetate extraction, extract without
Water magnesium sulfate is dried, and filters, and concentrating under reduced pressure, silica gel column chromatography separating purification, petroleum ether-ethyl acetate system eluting are contained
The benzaldehyde derivative of terminal acetylene；
Substituted hydroxy benzaldehyde is placed in 5% sodium hydroxide solution, and regulation pH value is 8-9, is added dropwise over the 1.4-1.6 times of chloroethene measured
The unsaturated carbonate potassium solution of acid, adds the potassium iodide of catalytic amount, continues reaction 2-4 little after being heated to reflux being in crocus to solution
When, stopped reaction, system are cooled to room temperature, and concentrated hydrochloric acid adjusts solution ph for 1-2, Precipitation, sucking filtration, the 5-6 times of steaming measured
Distilled water washing is multiple, and gained solid alcohol-water recrystallization, after vacuum drying, obtains carboxylic benzaldehyde derivative；
Step 3, the preparation of substituted benzaldehyde acetyl glucosaminidase：In step 1 in the full acetylated nitrine glucose of gained and step 2
Benzaldehyde derivative of the gained containing terminal acetylene is with mol ratio as 1:1.0-1:1.5 are dissolved in organic solvent, add under condition of ice bath
The copper sulfate of catalytic amount, L-AA sodium, react 0-5h under room temperature condition, add the distilled water of 1.5-2 times of reactant liquor volume,
Ethyl acetate is extracted, and successively with distilled water, saturated common salt water washing, anhydrous magnesium sulfate is dried, and filters, concentrating under reduced pressure, column chromatography
Isolate and purify, petroleum ether-ethyl acetate system eluting obtains the substituted benzaldehyde acetyl glucosaminidase containing triazole group；
Or, carboxylic benzaldehyde derivative obtained by full acetylated acetylbromoglycose obtained by step 1 and step 2 or replacement hydroxyl
Benzaldehyde is with mol ratio 1:1.0-1:1.5 are dissolved in organic solvent, add the amount tetrabutyl ammonium bromide of 1.0-1.5 times of material
It is 8-10,50-80 DEG C of reaction 2-10h that pH is adjusted with unsaturated carbonate potassium solution or 5% sodium hydroxide solution, after being cooled to room temperature,
Dichloromethane is extracted, and successively with distilled water, saturated ammonium chloride, saturated common salt water washing, anhydrous magnesium sulfate is dried, concentration, post layer
Analysis is isolated and purified, petroleum ether-ethyl acetate system eluting, obtains substituted benzaldehyde acetyl glucosaminidase；
Step 4, the preparation of glaucocalyxin glucosan derivative：Gained substituted benzaldehyde acetyl glucosaminidase and blue calyx in step 3
A prime is with mol ratio as 1:0.5‐1:1.5 are dissolved under organic solvent, acid condition and react 1 5h, add dichloromethane extraction, according to
Secondary saturated sodium bicarbonate, saturated aqueous common salt are washed, anhydrous MgSO4It is dried, filters, concentration, column chromatographic isolation and purification, stone
Oily ether/ethyl acetate system eluting, obtains end-product Ia Ic, IIa IIc.
6. method according to claim 5, it is characterised in that in the step 1：Described organic solvent is tetrahydrochysene furan
Mutter, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 1,4- dioxane, dichloromethane or chloroform；
In the step 2：Described organic solvent is tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile or 1,4-
Dioxane.
7. method according to claim 5, it is characterised in that in the step 3, described organic solvent are tetrahydrochysene furan
Mutter, N,N-dimethylformamide, dimethyl sulfoxide, 1,4- dioxane, n-butyl alcohol, n-butanol-water, dichloromethane, chloroform or second
Nitrile.
8. method according to claim 5, it is characterised in that in the step 4, the acid condition are mineral acid, have
Machine acid or aprotic acid.
9. the preparation of the derivant described in any one of 1-3 containing claim, it is characterised in that the preparation is by the derivant and medicine
Acceptable carrier composition on.
10. the preparation described in the derivant or claim 9 described in any one of claim 1-3 is preparing the medicine for the treatment of tumor
In application.
11. applications according to claim 10, it is characterised in that the tumor is hepatocarcinoma, cervical cancer, leukemia, fine hair
Film cancer and pulmonary carcinoma.
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