CN104558077A - 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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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- 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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- C07H19/056—Triazole or tetrazole radicals
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- C07H1/00—Processes for the preparation of sugar derivatives
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- 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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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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, be specifically related to glucose-derivative of glaucocalyxin A (glaucocalyxin A, GLA) and its preparation method and application.
Background technology
Glaucocalyxin A (glaucocalyxin A, GLA), chemical name is: (5 β, 7 α, 9 β, 10 α)-7,14-dihydroxyl kaur-16-ene-3,15-diketone; Have another name called leukamenin F, molecular formula is C20H28O4, molecular weight: 332.43, CAS registration number: 79498-31-0, density: 1.22g/cm
3, fusing point: 513.4 DEG C, is soluble in methyl alcohol, ethanol, and its structural formula is for shown in formula III.
Glaucocalyxin A is the main pharmacodynamics composition of Labiatae Rabdosia plant rabdosia japonica (Isodon japonica var.glaucocalyx), about 1981, the people such as Yunlong (is permitted Yunlong, Sun Xichang, Dong Sun Han. Yunnan plant research .1981,3 (03): 1-3) from rabdosia japonica, separation obtains glaucocalyxin A first, the tetracyclic diterpene compound that a class has ent-Kauranoids skeleton, its in the dry leaf of rabdosia japonica content up to 1.03%.
Inside and outside anti-tumor experiment shows, glaucocalyxin A has significant Inhibit proliferaton effect to the strain of various human cancer cell such as CE-1, U87, A549, MCF-7, Hela, K562, Hep G2, NCI-H460, KB, LEG-3, K562, HL-60 etc., the most responsive to non-hormone dependence prostate cancer (DU-145), the rectum cancer (Lovo) cell especially, antitumor spectra is wide; Can suppress the growth of the solid tumors such as Lewis lung cancer, S180 solid-type and HCA solid-type, obviously increase the increase in life span of lotus S180 ascitic type and lotus HCA ascitic type mouse, its antineoplastic power is dose-dependence.
[the Li Wen Gao such as Koryo literary composition (sound), Jian Zhang, Wen Hua Yang, Bin Wang, Jian Wen Wang.Toxicology in Vitro 2011,25:51-63] to report rabdosia japonica A prime apoptosis-induced by plastosome-adjustment approach, suppresses people in loop propagation; Bibliographical information [Xiao X, Cao W, Jiang X in 2014, ZhangW, Zhang Y, Liu B, Cheng J, Huang H, Huo J, Zhang X.Acta Biochim Biophys Sin.2014,45,946-952], glaucocalyxin A is protein kinase AKT inhibitor, by suppressing AKT phosphorylation induction Gliblastoma U87MG apoptosis, and on normal neurogliocyte without impact, be the lead compound of a kind of very promising treatment leukemia, glioblastoma.
Glaucocalyxin A is external has stronger antitumor action, but need in body heavy dose of could produce for a long time drug effect [Zhang Chong, Shang Jiaojun, Ma Suying, Bai Suping. medical Leader, 2013,32,1399-1402], bioavailability is lower.Therefore, need to carry out structural modification to this lead compound, expect to obtain the better derivative 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 the lipid acid of its 7 and 14 hydroxyls, aromatic esters, diester, polypeptide class and acetals structural modification.
In medicine in research and development, the features such as sugared toxicity is little, novel structure is various, targeting is good are utilized to have bioactive group to some or lead compound carries out structural modification, wish to improve curative effect of medication by mutual synergy, reduce toxic side effect, improve affinity, increase bioavailability, to find and developing new drug.
Through studying for many years, contriver has found the glucose-derivative of the glaucocalyxin A that a kind of new effect is better.
Summary of the invention
The object of this invention is to provide a kind of derivative of the glaucocalyxin A containing glucose group.
The invention provides a kind of glucose-derivative of glaucocalyxin A, this analog derivative has structure shown in formula I or formula II:
Wherein, R
1for hydrogen or methoxyl group, R
2be independently hydrogen or ethanoyl separately, n is 0 or 1.
The glucose-derivative of described glaucocalyxin A is compound shown in formula Ia-Ic or formula IIa-IIc:
Present invention also offers the preparation method of said derivative, the method comprises the following steps:
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose:
Take glucose as raw material, by acetylize, bromo, azido reaction, obtain full acetylated acetylbromoglycose and full acetylated nitrine glucose intermediate product.Its chemical equation is as follows:
Step 2, containing the preparation of the benzaldehyde derivative of terminal acetylene or carboxyl
With substituted hydroxy phenyl aldehyde for raw material, by with 3-propargyl bromide generation nucleophilic substitution reaction, obtain the benzaldehyde derivative containing terminal acetylene; By with Mono Chloro Acetic Acid generation nucleophilic substitution reaction, obtain carboxylic benzaldehyde derivative.
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, is reacted by click, obtains the substituted benzaldehyde acetyl glucosaminidase containing triazole group.Its chemical equation is as follows:
Or carboxylic benzaldehyde derivative prepared by the full acetylated acetylbromoglycose prepared with step 1 and step 2 or substituted hydroxy phenyl aldehyde, for raw material, by nucleophilic substitution reaction, obtain important intermediate product, substituted benzaldehyde acetyl glucosaminidase.Its chemical equation is as follows:
Step 4, the preparation of glaucocalyxin A glucose-derivative
With step 3 prepare important intermediate substituted benzaldehyde acetyl glucosaminidase and glaucocalyxin A for raw material, by condensation reaction, obtain target product glaucocalyxin A glucose-derivative Ia ?Ic, IIa ?IIc.Its compound reaction formula is as follows:
Concrete, said method comprising the steps of:
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose: glucose and sodium acetate are in molar ratio for 1:1.0-1:2.0 mixes, reflux 2-3h in diacetyl oxide, reaction terminates rear cooling, add frozen water and separate out white solid, filter, with the distilled water wash of 5-6 times amount, drying, obtains full acetylated glucose; The full acetylated glucose of gained is dissolved in methylene dichloride, drip hydrogen bromide-acetic acid solution, room temperature reaction 20-30h, add frozen water afterwards and terminate reaction, dichloromethane extraction, organic layer uses distilled water, saturated sodium bicarbonate, brine It successively, and dry, concentrating under reduced pressure, obtains full acetylated acetylbromoglycose; The full acetylated acetylbromoglycose of gained is dissolved in organic solvent, adds sodiumazide, and 60-90 DEG C of reaction 5-12h, is cooled to room temperature, adds frozen water and separates out solid, filter, dry, obtains full acetylated nitrine glucose;
Step 2, preparation containing the benzaldehyde derivative of terminal acetylene or carboxyl: substituted hydroxy phenyl aldehyde and 3-propargyl bromide are 1:1-1:2 stirring and dissolving in organic solvent in molar ratio, add the Anhydrous potassium carbonate of 0.6-1 molar equivalent, the potassiumiodide of catalytic amount, 40-60 DEG C of reaction 6-10 hour, the isopyknic distilled water of reaction solution is added after reaction terminates, extraction into ethyl acetate, extraction liquid anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating purification, petroleum ether-ethyl acetate system wash-out, obtains the benzaldehyde derivative containing terminal acetylene; Or
Substituted hydroxy phenyl aldehyde is placed in 5% sodium hydroxide solution, and adjust ph is 8-9, dropwise adds the chloroacetic unsaturated carbonate potassium solution of 1.4-1.6 times amount, add the potassiumiodide of catalytic amount again, reflux to solution is continue reaction 2-4 hour after safran, stopped reaction, system is cooled to room temperature, concentrated hydrochloric acid regulator solution pH value is 1-2, Precipitation, suction filtration, the distilled water wash of 5-6 times amount repeatedly, 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, gained is that 1:1.0-1:1.5 is dissolved in organic solvent with mol ratio containing the benzaldehyde derivative of terminal acetylene, the copper sulfate of catalytic amount is added under condition of ice bath, L-AA sodium, 0-5h is reacted under room temperature condition, add the distilled water of 1.5-2 times of reaction solution volume, extraction into ethyl acetate, use distilled water successively, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petroleum ether-ethyl acetate system wash-out, must containing the substituted benzaldehyde acetyl glucosaminidase of triazole group, or
In step 1, in the full acetylated acetylbromoglycose of gained and step 2, the carboxylic benzaldehyde derivative of gained or substituted hydroxy phenyl aldehyde are dissolved in organic solvent with mol ratio 1:1.0-1:1.5, adding 1.0-1.5 times of amount of substance Tetrabutyl amonium bromide and unsaturated carbonate potassium solution or 5% sodium hydroxide solution again regulates pH to be 8-10, 50-80 DEG C of reaction 2-10h, after being cooled to room temperature, dichloromethane extraction, use distilled water successively, saturated ammonium chloride, saturated common salt water washing, anhydrous magnesium sulfate drying, concentrated, column chromatographic isolation and purification, petroleum ether-ethyl acetate system wash-out, obtain substituted benzaldehyde acetyl glucosaminidase,
Step 4, the preparation of glaucocalyxin A glucose-derivative: in step 3 gained phenyl aldehyde acetyl glucosaminidase and glaucocalyxin A with mol ratio be 1:0.5 ?1:1.5 be dissolved in organic solvent, react under acidic conditions 1 ?5h, add dichloromethane extraction, wash with saturated sodium bicarbonate, saturated aqueous common salt successively, anhydrous MgSO
4drying, filters, concentrated, column chromatographic isolation and purification, petrol ether/ethyl acetate system wash-out, obtain end product Ia ?Ic, IIa ?IIc.
In aforesaid method:
In described step 1: described organic solvent be tetrahydrofuran (THF), N, N ?dimethyl formamide, methyl-sulphoxide, acetonitrile, 1,4 ?dioxane, methylene dichloride or chloroform etc.
In described step 2: described organic solvent is tetrahydrofuran (THF), DMF, methyl-sulphoxide, acetonitrile or Isosorbide-5-Nitrae-dioxane.
In described step 3: described organic solvent is tetrahydrofuran (THF), DMF, methyl-sulphoxide, acetonitrile, Isosorbide-5-Nitrae-dioxane, propyl carbinol, n-butanol-water, methylene dichloride, chloroform or acetonitrile.
In described step 4: described organic solvent is tetrahydrofuran (THF), DMF, methyl-sulphoxide, acetonitrile, Isosorbide-5-Nitrae-dioxane, methylene dichloride, chloroform etc.; Described acidic conditions comprises various mineral acid, as dry hydrogen chloride gas, phosphoric acid, sulfuric acid etc., organic acid, as trifluoroacetic acid, aromatic acid, toluenesulphonic acids, thionamic acid etc., non-proton Lweis acid, as iron trichloride, ferric ammonium sulfate, Tai-Ace S 150, copper methanesulfonate etc.; Temperature of reaction is 10-30 DEG C.
Present invention also offers the preparation of the glucose-derivative of glaucocalyxin A, said preparation is made up of this derivative and pharmaceutically acceptable carrier.
Described preparation, includes but not limited to tablet, capsule, flexible glue agent, sprays, gelifying agent, gel inhalation, oral preparation, suspensoid, electuary, patch, ointment, pill, powder, injection, infusion solution, freeze dried injection, lipidosome injection, target administration injection, suppository, sustained release preparation or controlled release preparation.
Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, is selected from one or more in weighting agent, tackiness agent, disintegrating agent, lubricant, suspending agent, wetting agent, solvent, tensio-active agent or correctives.
Described weighting agent is selected from starch, sucrose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose or glucose etc.;
Described tackiness agent is selected from derivatived cellulose, alginate, gelatin or polyvinylpyrrolidone etc.;
Described disintegrating agent is selected from Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or croscarmellose sodium;
Described lubricant is selected from stearic acid, polyoxyethylene glycol, calcium carbonate, sodium bicarbonate, micropowder silica gel, talcum powder or Magnesium Stearate;
Described suspending agent is selected from micropowder silica gel, beeswax, Mierocrystalline cellulose, solid polyethylene glycol;
Described wetting agent is selected from glycerine, tween-80, ethoxy aluminium Viscotrol C or Yelkin TTS;
Described solvent selected from ethanol, liquid polyethylene glycol, Virahol, tween-80, glycerine, propylene glycol or vegetables oil, described vegetables oil is selected from soybean oil, Viscotrol C, peanut oil, mediation wet goods;
Described tensio-active agent is selected from smooth or polysorbate (tween) of Sodium dodecylbenzene sulfonate, stearic acid, Pluronic F68, lipid acid sorb etc.;
Described sweeting agent is selected from aspartame, Sucralose, essence, citric acid or soluble saccharin.
Present invention also offers the application of glucose-derivative in the medicine of preparation treatment tumour of described glaucocalyxin A, described tumour is preferably liver cancer, cervical cancer, leukemia, choriocarcinoma and lung cancer.
Glaucocalyxin A derivative provided by the present invention has the following advantages:
1. contriver uses chemical reaction, by two hydroxyls and the phenyl aldehyde generation acetalation introducing glucose group of 7 of glaucocalyxin A and 14, at reservation glaucocalyxin A pharmacophoric group α, under the prerequisite of β-unsaturated cyclopentanone, ingenious introducing has the glucose glycosyl group of physiological function.
2., in the partial derivatives of glaucocalyxin A, also introduce while introducing glucose glycosyl and there is certain bioactive triazole group, further increase the anti-tumor activity of derivative.
3., in glaucocalyxin A derivatization process, by acetalation, two hydroxyls of 7 and 14 participate in reaction simultaneously, and target product is clear and definite, without other isomer products, is easy to purifying.
4. compared with prior art, 7 α of glaucocalyxin A, derivative (the CN201210015481.4 (CN102584780A): the derivant structure of derivative of the present invention and these 2 patents has similarity that 2 hydroxyls of 14 β-position and various aldehyde (ketone) acetal (ketone) are changed, it is all the acetalation product of 7 α of glaucocalyxin A, 2 hydroxyls of 14 β-position.But the present invention and its difference: the glaucocalyxin A derivative in inventing with the first two compares, ingeniously on the phenyl ring of its fragrant acetalation derivative introduce physiological function group glucose glycosyl and bio-active group triazole group, anti-tumor activity greatly improves.Analogue in disclosed two inventions, to the IC of the tumor cell line of experiment
50value is 14 μMs-be greater than 100 μMs, and the present invention introduces the glaucocalyxin A derivative after glucose glycosyl group, to the IC of the tumor cell line of experiment
50value is mostly 0.41 μM-50 μMs, and anti-tumor activity strengthens.
5. the glucose-derivative of the glaucocalyxin A that the present invention relates to, through cytotoxic activity evaluation experimental, found that there is stronger human tumor cells proliferation inhibition activity, especially for human leukemia cell, Choriocarcinoma cell line and cervical cancer cell, anti-tumor activity is better than parent compound glaucocalyxin A.
Accompanying drawing explanation
Fig. 1 is the glaucocalyxin A derivative I a's of 1,2,3-triazole glucose
1h-NMR;
Fig. 2 is the glaucocalyxin A derivative I b's of 1,2,3-triazole glucose
1h-NMR;
Fig. 3 is the glaucocalyxin A derivative I c's of 1,2,3-triazole glucose
1h-NMR;
Fig. 4 is the glaucocalyxin A derivative I Ia's of full acetylated glucose sugar ester
1h-NMR;
Fig. 5 is the glaucocalyxin A derivative I Ib's of full acetylated grape glycosyloxy glycosides
1h-NMR;
Fig. 6 is the glaucocalyxin A derivative I Ic's of full acetylated grape glycosyloxy glycosides
1h-NMR.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Preparation process described in following examples, all chemical reagent adopted are as being analytical pure without special mark.
Embodiment 1: containing the preparation of glaucocalyxin A glucose-derivative Ia, Ib, Ic of triazole group
Reaction formula is as follows:
1.1: the preparation of full acetylated glucose
Take anhydrous sodium acetate 8.287g and be placed in crucible, temperature is regulated to make it lose whole moisture, proceed to immediately in mortar after cooling, add dry glucose (10.636g, 590mmol), be transferred to after mixing in 250mL round-bottomed flask, then added diacetyl oxide 150mL, temperature is adjusted to 100 DEG C, reaction 2-3h.Be cooled to room temperature, poured into by reaction solution in frozen water, adularescent solid is separated out, and after suction filtration, can obtain full acetylated glucose, obtain white solid 17.707g after drying, productive rate 77% with 5 times amount distilled water washs.
1.2: the preparation of full acetylated acetylbromoglycose
Get 1.1 gained compounds (4.985g, 12.7mmol) to add in 100mL round-bottomed flask, then add 20mL methylene dichloride, after all dissolving, dropwise add the hydrogen bromide of brand-new-acetic acid solution 35mL, stirring at room temperature 28h with constant pressure funnel.After reaction terminates, reaction solution is proceeded in separating funnel, add appropriate frozen water immediately, then add 30mL methylene dichloride, use frozen water, saturated sodium carbonate solution, saturated common salt water washing three times successively, organic over anhydrous MgSO
4drying, filters, concentrated, obtains faint yellow viscous liquid, and glass stick stirs 10min, can obtain Off-white solid 4.875g, productive rate 92.8%.
1.3: the preparation of full acetylated nitrine glucose
Get 1.2 gained compounds (4.418g, 10.8mmol), add in the round-bottomed flask of 100mL, after dissolving with methyl-sulphoxide (DMSO) 45mL, add NaN in two batches
3(1.893g, 29.1mmol), temperature is adjusted to 60 DEG C, reaction 12h.Be cooled to after room temperature until system, reaction solution poured in frozen water, have a large amount of white solid to separate out immediately, suction filtration, obtain white solid 3.225g after drying, productive rate 80.2%.
1HNMR(400MHz,CDCl
3)δ
H5.20-5.25(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,-COCH
3),2.08(s,3H,-COCH
3),2.04(s,3H,-COCH
3),2.02(s,3H,-COCH
3).
1.4: containing the preparation of the benzaldehyde derivative of terminal acetylene or carboxyl
1.4.1:4-the preparation of propargyloxy phenyl aldehyde
Disubstituted-4-hydroxy phenyl aldehyde (3.155g, 25.8mmol) with 3-propargyl bromide (3.074g, 25.8mmol), add in the round-bottomed flask of 100mL, add the N of 50mL, dinethylformamide (DMF), be stirred to sample all to dissolve, add Anhydrous potassium carbonate 2.632g again, potassiumiodide 134mg, 40 DEG C of reaction 8h, TLC detects raw material point and disappears, be cooled to after room temperature until system, reaction solution is transferred in separating funnel, add 50mL distilled water, extract with ethyl acetate 50mL × 3, saturated common salt water washing, anhydrous magnesium sulfate drying spends the night, filter, concentrated.Thick product is through purification by silica gel column chromatography, and petrol ether/ethyl acetate (5/1) carries out wash-out, obtains white powder 3.985g, productive rate: 96%.
1HNMR(400MHz,CDCl
3)δ
H9.91(s,1H,CHO),7.85-7.88(dt,J＝12Hz,2.4Hz,2H,CH
Ar),7.08-7.11(dt,J＝8Hz,2.8Hz,2H,CH
Ar),4.78(s,1H,CH
2,4.79(s,1H,CH
2),2.58-2.57(t,J＝2.4Hz,1H,CH).
1.4.2:3-the preparation of methoxyl group-4-propynyloxy benzaldehyde
With Vanillin and 3-propargyl bromide for raw material, the same 1.4.1 of preparation method, prepares 3-methoxyl group-4-propynyloxy benzaldehyde, white solid, productive rate 94%.
1HNMR(400MHz,CDCl
3)δ
H10.49(s,1H,CHO),7.85-7.88(m,1H,CH
Ar),7.11-7.55(m,2H,CH
Ar),4.84(s,1H,CH
2),4.79(s,1H,CH
2),2.58,2.57(t,J＝2.4Hz,1H,CH).
1.4.3:2-the preparation of propargyloxy phenyl aldehyde
With Benzaldehyde,2-hydroxy and 3-propargyl bromide for raw material, the same 1.4.1 of preparation method, prepares 2-propargyloxy phenyl aldehyde, white solid, productive rate 92%.
1HNMR(400MHz,CDCl
3)δ
H10.49(s,1H,CHO),7.85-7.87(dd,J＝8Hz,4Hz,1H,CH
Ar),7.55-7.59(m,1H,CH
Ar),7.05-7.13(d,J＝12Hz,1H,CH
Ar),7.05-7.09(d,J＝4Hz,1H,CH
Ar)4.84(s,1H,CH
2),4.83(s,1H,CH
2),2.58-2.59(t,J＝2.4Hz,1H,CH).
1.5: containing the preparation of the substituted benzaldehyde acetyl glucosaminidase of triazole group
1.5.1: containing the preparation of the substituted benzaldehyde acetyl glucosaminidase 7 of triazole group
Get 1.3 gained full acetyl nitrine glucose (2.305g, 6.2mmol) with 1.4.1 gained 4-propynyloxy benzaldehyde (0.985g, 6.2mmol) in the round-bottomed flask of 50mL drying, add the DMF of 20mL, after stirring makes solid all dissolve, under condition of ice bath, react 10min, then add catalyzer (anhydrous cupric sulfate, L-AA sodium, BPDS) and react 0.5h, withdraw ice-water bath, under continuing room temperature condition, react 5h.Add ethyl acetate 50mL, distilled water 50mL × 3, saturated common salt water washing successively after reaction terminates, anhydrous MgSO4 is dry, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 1:1 wash-out, obtains white crystalline powder 2.837g, productive rate 86%.
1HNMR(400MHz,CDCl
3)δ
H9.90(s,1H,CHO),7.89(s,1H,CH
(heterocycle)),7.84-7.87(dt,J＝12Hz,2.4Hz,2H,CH
Ar),7.09-7.12(dt,J＝8Hz,2.8Hz,2H,CH
Ar),5.89-5.90(m,1H,CH),5.42-5.43(m,2H,CH
2),5.30(s,2H,CH
2),3.99-5.26(m,4H,H1-4),2.08(s,3H,-COCH
3),2.07(s,3H,CH
3),2.02(s,3H,CH
3),1.83(s,3H,CH
3).
1.5.2: containing the preparation of the substituted benzaldehyde acetyl glucosaminidase 8 of triazole group
Get 1.3 gained full acetyl nitrine glucose (2.305g, 6.2mmol) with 1.4.2 gained 3-methoxyl group-4-propynyloxy benzaldehyde (1.178g, 6.2mmol), with 1.4.1 operating process, obtain white crystalline powder 2.861g, productive rate 82%.
1HNMR(400MHz,CDCl
3)δ
H9.86(s,1H,CHO),7.91(s,1H,CH
(heterocycle)),7.43-7.45(dt,J＝12Hz,2.4Hz,2H,CH
Ar),7.16-7.18(dt,J＝8Hz,2.8Hz,2H,CH
Ar),5.87-5.90(m,1H,CH),5.41-5.43(m,2H,CH
2),3.94-5.38(m,4H,H1-4),2.08(s,3H,-COCH
3),2.07(s,3H,-COCH
3),2.03(s,3H,-COCH
3),1.84(s,3H,-COCH
3).
1.5.3: containing the preparation of the substituted benzaldehyde acetyl glucosaminidase 9 of triazole group
Get 1.3 gained full acetyl nitrine glucose (2.305g, 6.2mmol) and 1.4.3 gained 2-propynyloxy benzaldehyde (0.985g, 6.2mmol), with 1.4.1 operating process, obtain white crystalline powder 2.869g, productive rate 87%.
1HNMR(400MHz,CDCl
3)δ
H10.48(s,1H,CHO),7.94(s,1H,CH
(heterocycle)),7.84-7.86(dd,J＝7.6Hz,2Hz,1H,CH
Ar),7.55-7.59(m,1H,CH
Ar),7.13-7.15(d,J＝8Hz,1H,CH
Ar),7.06-7.10(t,J＝8Hz,1H,CH
Ar),5.90-5.92(m,1H,CH),5.44-5.46(m,2H,CH
2),5.35(s,2H,CH
2),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,-COCH
3),2.07(s,3H,-COCH
3),2.03(s,3H,-COCH
3),1.84(s,3H,-COCH
3).
1.6: the preparation of full acetylated glucose-derivative Ia, Ib, Ic of glaucocalyxin A
1.6.1: the preparation of the full acetylated glucose-derivative Ia of glaucocalyxin A
Get 1.5.1 gained compound (1.750g, 3.28mmol) and rabdosia japonica A prime (1.112g, 3.28mmol) in the round-bottomed flask of 50mL drying, drip the methylene dichloride of 10mL drying, stirring at room temperature is to sample dissolution.Add 2 vitriol oils again, reaction 2h, adds methylene dichloride 50mL, successively saturated sodium bicarbonate 50ml × 3, saturated common salt water washing, anhydrous MgSO afterwards
4drying, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 2:1 wash-out, obtains white solid 1.206g, end product Ia, productive rate 43%.
1HNMR(400MHz,CDCl
3)δ
H7.84(s,1H,CH
(heterocycle)),7.32-7.28(m,2H,CH
Ar),6.93-6.91(m,2H,CH
Ar),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,CH
2),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,CH
2,CH
3).
1.6.2: the preparation of the full acetylated glucose-derivative Ib of glaucocalyxin A
Get 1.5.2 gained compound and glaucocalyxin A, with the preparation method of 1.6.1, both obtain glaucocalyxin A derivative I b, productive rate 47%.
1hNMR (400MHz, CDCl
3) δ
h7.84 (s, 1H, CH
(heterocycle)), 6.95-6.89 (m, 3H, CH
ar), 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, CH
2), 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, CH
3), 3.21 (s, 1H, CH), 2.61-1.13 (m, 37H, CH, CH
2, CH
3).
1.6.3: the preparation of the full acetylated glucose-derivative Ic of glaucocalyxin A
Get 1.5.3 gained compound and glaucocalyxin A, with the preparation method of 1.6.1, both obtain glaucocalyxin A derivative I c, productive rate 40%.
1HNMR(400MHz,CDCl
3)δ
H7.80(s,1H,CH
(heterocycle)),7.45-6.95(m,4H,CH
Ar),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,CH
2,CH
3).
Embodiment 2: the preparation of the glaucocalyxin A derivative I Ia of glucose sugar ester
Reaction formula is as follows:
The preparation of 2.1:2-(4-formyl radical-2-Difluoro-phenoxy)-acetic acid
Get Mono Chloro Acetic Acid (4.822g, 51.3mmol) and add appropriate unsaturated carbonate potassium solution, regulator solution pH value is 9, and sample is all dissolved, and is transferred in constant pressure funnel for subsequent use.Get Vanillin (5.198g, 34.2mmol) in flask at the bottom of 250mL, add appropriate 5% sodium hydroxide solution adjust ph and be about 9, stirring makes sample all dissolve, regulate constant pressure funnel, make all to be transferred in round-bottomed flask in sample 30min, then add potassiumiodide 321mg, 110 DEG C of backflow 5h, be cooled to room temperature, concentrated hydrochloric acid regulator solution pH value is 1, Precipitation, suction filtration, distilled water repeatedly washs, gained solid with alcohol-water recrystallization (1:1), vacuum-drying, obtain white solid 3.817g, productive rate 62%.
2.2: the preparation of phenyl aldehyde glucose ester glycosides 10
Get 2.1 gained compound (1.002g, 4.77mmol) add in the round-bottomed flask of 50mL, add the methylene dichloride of 15mL, after sample is all dissolved, add 5% sodium hydroxide solution adjust ph and be about 9, add Tetrabutyl amonium bromide (TBAB) (1.536g, 4.77mmol), after reaction 15min, add the full acetylated acetylbromoglycose (1.956g of 1.2 gained in embodiment 1, 4.77mmol), 60 DEG C of reaction 6h, after being cooled to room temperature, reaction solution proceeds to separating funnel, add methylene dichloride 50mL, use distilled water 50ml × 3 successively, saturated ammonium chloride 50mL × 3, saturated aqueous common salt washs, anhydrous MgSO
4drying, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 3:1 carries out wash-out, obtains white solid 1.437g, productive rate 59%.
2.3: the preparation of the full acetylated glucose-derivative IIa of glaucocalyxin A
Get 2.2 gained compound and glaucocalyxin As, with the preparation method of 1.6.1 in embodiment 1, obtain the glaucocalyxin A derivative I Ia of glucose sugar ester, white solid, productive rate 63%.
1HNMR(400MHz,CDCl3)δH 6.98-6.76(m,3H,CHAr),6.18(d,J＝12Hz,4Hz,1H,CH
2),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 A derivative I Ib and IIc of grape glycosyloxy glycosides
Reaction formula is as follows:
3.1: the preparation of the full acetylated grape glycosyloxy glycosides that phenyl aldehyde replaces
3.1.1: the full acetylated acetylbromoglycose (2.498g of 1.2 gained in Example 1, 6.09mmol) with Vanillin (0.926g, 6.09mmol) in the round-bottomed flask of 100mL, add 25mL methylene dichloride, after sample is all dissolved, add TBAB (1.961g again, 6.09mmol) with unsaturated carbonate potassium solution 20mL, 60 DEG C of reaction 5h, after being cooled to room temperature, reaction solution proceeds in separating funnel, add methylene dichloride 50mL, use distilled water 50mL × 3 successively, saturated ammonium chloride 50mL × 3, saturated common salt water washing, anhydrous MgSO
4drying, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petrol ether/ethyl acetate 3:1 carries out wash-out, obtains white powdery solids 1.758g, productive rate 63.9%.
3.1.2: the full acetylated acetylbromoglycose (2.498g, 6.09mmol) of 1.2 gained and Benzaldehyde,2-hydroxy (0.742g, 6.09mmol) in Example 1, with the preparation method of 3.1.1, both obtained product 1.597g, productive rate 58%.
3.2: the preparation of glaucocalyxin A derivative I Ib, IIc of grape glycosyloxy glycosides
3.2.1: get 3.1.1 gained compound and glaucocalyxin A, with the preparation method of 1.6.1 in embodiment 1, both glaucocalyxin A derivative I Ib was obtained.Productive rate: 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: get 3.1.2 gained compound and glaucocalyxin A, with the preparation method of 1.6.1 in embodiment 1, both glaucocalyxin A derivative I Ic was obtained.Productive rate: 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 A glucose-derivative
For the pharmacodynamic experiment of the growth-inhibiting effect of human hepatoma HepG2 cell, National People's Congress cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-3 cell, people acute (early children) granulocyte leukemia HL-60 cell, human chronic myelogenous leukemia K562 cell, human cervical carcinoma Hela cell.
1. medicine and reagent: given the test agent, DMEM, 1640 substratum, 10% deactivation calf serum (FBS), PBS lysate, dimethyl sulfoxide (DMSO) (DMSO), three liquid (10%SDS+5% Virahol+12mM HCl), tetrazolium bromide (MTT), Zorubicin (positive control drug).
2. instrument: Bechtop, CO
2incubator, Multi-functional inverted microscope, whizzer, automatic microplate reader, 96 well culture plates.
3. cell strain: people liver cancer Hep G2 tumour cell, National People's Congress cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-3 cell, people acute (early children) granulocyte leukemia HL-60 cell, human chronic myelogenous leukemia K562 cell, human cervical carcinoma Hela cell.
4. sample preparation: glucose-derivative Ia, Ib, Ic of getting the obtained glaucocalyxin A containing triazole group of above-described embodiment 1.6, the glaucocalyxin A derivative I Ia of the glucose sugar ester that embodiment 2.3 is obtained, embodiment 3.2 obtains glaucocalyxin A derivative I Ib, IIc and the glaucocalyxin A of grape glycosyloxy glycosides, be dissolved in DMSO, ultrasonic dissolution, concentration is 100mM, preserves under gained drug solution-20 DEG C of conditions.
5. experimental technique
The medicine MTT experiment of 5.1 attached cells, it comprises further:
Described attached cell comprises people liver cancer Hep G2 tumour cell, National People's Congress cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-3 cell, human cervical carcinoma Hela cell.
Step 1.1: collect logarithmic phase cell, suspends with complete DMEM substratum, and to adjust concentration of cell suspension be 3 × 104/mL, inoculates 96 porocyte culture plates, 100mL/ hole.Put 37 DEG C, 5%CO2 incubator cultivates 24 hours, supernatant discarded, adds fresh complete DMEM substratum, 90mL/ hole, and adds different concns drug solution to be measured, 10mL/ hole, and each concentration establishes 3 multiple holes; Blank well adds DMEM substratum 10mL/ hole; This bottom outlet adds not celliferous substratum 100mL/ hole.
Step 1.2: put 37 DEG C, 5%CO2 hatches 48 hours.
Step 1.3: every hole adds 100uL MTT solution (0.5mg/mL, incomplete DMEM substratum preparation), continues to put incubator and hatches 4 hours.
Stop after step 1.4:4 hour cultivating, supernatant discarded, every hole adds 150mL dimethyl sulfoxide (DMSO), puts low-speed oscillation 5min on shaking table, crystallisate is fully dissolved.
Step 1.5: the light absorption value measuring each hole at enzyme-linked immunosorbent assay instrument 570nm place.
The medicine MTT experiment of 5.2 suspension cells, it comprises further:
Described suspension cell comprises people acute (early children) granulocyte leukemia HL-60 cell, human chronic myelogenous leukemia K562 cell.
Step 2.1: collect logarithmic phase cell, suspends with complete RPMI1640 substratum, cell counting, and to adjust cell concn be 3 × 105/mL, inoculates 96 porocyte culture plates, 90mL/ hole.Add different concns drug solution to be measured, 10mL/ hole, each concentration establishes 3 multiple holes; Blank well adds 1640 substratum 10mL/ holes; This bottom outlet adds not celliferous substratum 100mL/ hole.
Step 2.2: put 37 DEG C, 5%CO2 hatches 48 hours.
Step 2.3: every hole adds 10mL MTT solution (5mg/1mL, 1640 substratum preparations), continues to put incubator and hatches 4 hours.
Step 2.4: add three liquid (10%SDS+5% Virahol+12mM HCl), 10mL/ hole, hatches 12 hours for 37 DEG C.
Step 2.5: detect each hole OD value in microplate reader, determined wavelength 570nm.
6. experimental result: the glucose-derivative of glaucocalyxin A is as shown in the table to human hepatoma HepG2 cell, National People's Congress cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-3 cell, people acute (early children) granulocyte leukemia HL-60 cell, human chronic myelogenous leukemia K562 cell, the effect of human cervical carcinoma Hela cell's growth-inhibiting:
Table 1: glucose-derivative Ia-Ic, IIa-IIc of glaucocalyxin A are to cancer cell strain Proliferation Ability result
7. experimental result shows: glucose-derivative Ia, Ib, Ic, IIa, IIb, IIc of glaucocalyxin A, and the cell inhibitory effect stronger to the cancer cell strain display such as human hepatoma HepG2 cell, National People's Congress cell lung cancer NCI-H460 cell, human choriocarcinoma JEG-3 cell, people acute (early children) granulocyte leukemia HL-60 cell, human chronic myelogenous leukemia K562 cell, human cervical carcinoma Hela cell is active.
8. conclusion: glucose-derivative Ia, the Ib of glaucocalyxin A, Ic, II a, II b, II c have the application prospect preparing cancer therapy drug, and it is applied to cancer patients.It has special efficacy in Hepatoma therapy, lung cancer, cervical cancer, choriocarcinoma, acute myeloblastic leukemia and chronic myelocytic leukemia, and especially leukemia aspect is obviously better than glaucocalyxin A.
Foregoing is exemplifying of specific embodiments of the invention, for the reagent, equipment, working method etc. of wherein not detailed statement, should be understood to take this area existing common and conventional reagent, equipment, working method etc. to be implemented.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. a glucose-derivative for glaucocalyxin A, this analog derivative has structure shown in formula I or formula II:
Wherein, R
1for hydrogen or methoxyl group, R
2be independently hydrogen or ethanoyl separately, n is 0 or 1.
2. derivative according to claim 1, is characterized in that, described derivative is formula Ia-Ic:
3. derivative according to claim 1, is characterized in that, described derivative is compound shown in formula IIa-IIc:
4. prepare a method for the derivative described in any one of claim 1-3, it is characterized in that, the method comprises the following steps:
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose: take glucose as raw material, obtains full acetylated acetylbromoglycose and full acetylated nitrine glucose by acetylize, bromo, azido reaction;
Step 2, preparation containing the benzaldehyde derivative of terminal acetylene or carboxyl: with substituted hydroxy phenyl aldehyde for raw material, by with 3-propargyl bromide generation nucleophilic substitution reaction, obtain the benzaldehyde derivative containing terminal acetylene, or with Mono Chloro Acetic Acid generation nucleophilic substitution reaction, obtain carboxylic benzaldehyde derivative;
Step 3, the preparation of substituted benzaldehyde acetyl glucosaminidase: the benzaldehyde derivative containing terminal acetylene prepared by the full acetylated nitrine glucose prepared with step 1 and step 2 is for raw material, reacted by click, obtain the substituted benzaldehyde acetyl glucosaminidase containing triazole group;
Or carboxylic benzaldehyde derivative prepared by the full acetylated acetylbromoglycose prepared with step 1 and step 2 or substituted hydroxy phenyl aldehyde, for raw material, by nucleophilic substitution reaction, obtain important intermediate product, substituted benzaldehyde acetyl glucosaminidase;
Step 4, the preparation of glaucocalyxin A glucose-derivative: the important intermediate substituted benzaldehyde acetyl glucosaminidase prepared with step 3 and glaucocalyxin A are for raw material, by condensation reaction, obtain glucose-derivative Ia-Ic, IIa-IIc of target product glaucocalyxin A.
5. method according to claim 4, is characterized in that, the method comprises the following steps:
Step 1, the preparation of full acetylated acetylbromoglycose and full acetylated nitrine glucose: glucose and sodium acetate are in molar ratio for 1:1.0-1:2.0 mixes, reflux 2-3h in diacetyl oxide, reaction terminates rear cooling, add frozen water and separate out white solid, filter, with the distilled water wash of 5-6 times amount, drying, obtains full acetylated glucose; The full acetylated glucose of gained is dissolved in methylene dichloride, drip hydrogen bromide-acetic acid solution, room temperature reaction 20-30h, add frozen water afterwards and terminate reaction, dichloromethane extraction, organic layer uses distilled water, saturated sodium bicarbonate, brine It successively, and dry, concentrating under reduced pressure, obtains full acetylated acetylbromoglycose; The full acetylated acetylbromoglycose of gained is dissolved in organic solvent, adds sodiumazide, and 60-90 DEG C of reaction 5-12h, is cooled to room temperature, adds frozen water and separates out solid, filter, dry, obtains full acetylated nitrine glucose;
Step 2, preparation containing the benzaldehyde derivative of terminal acetylene or carboxyl:: substituted hydroxy phenyl aldehyde and 3-propargyl bromide are 1:1-1:2 stirring and dissolving in organic solvent in molar ratio, add the Anhydrous potassium carbonate of 0.6-1 molar equivalent, the potassiumiodide of catalytic amount, 40-60 DEG C of reaction 6-10 hour, the isopyknic distilled water of reaction solution is added after reaction terminates, extraction into ethyl acetate, extraction liquid anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating purification, petroleum ether-ethyl acetate system wash-out, obtains the benzaldehyde derivative containing terminal acetylene;
Substituted hydroxy phenyl aldehyde is placed in 5% sodium hydroxide solution, and adjust ph is 8-9, dropwise adds the chloroacetic unsaturated carbonate potassium solution of 1.4-1.6 times amount, add the potassiumiodide of catalytic amount again, reflux to solution is continue reaction 2-4 hour after safran, stopped reaction, system is cooled to room temperature, concentrated hydrochloric acid regulator solution pH value is 1-2, Precipitation, suction filtration, the distilled water wash of 5-6 times amount repeatedly, 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, gained is that 1:1.0-1:1.5 is dissolved in organic solvent with mol ratio containing the benzaldehyde derivative of terminal acetylene, the copper sulfate of catalytic amount is added under condition of ice bath, L-AA sodium, 0-5h is reacted under room temperature condition, add the distilled water of 1.5-2 times of reaction solution volume, extraction into ethyl acetate, use distilled water successively, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure, column chromatographic isolation and purification, petroleum ether-ethyl acetate system wash-out, must containing the substituted benzaldehyde acetyl glucosaminidase of triazole group,
Step 4, the preparation of glaucocalyxin A glucose-derivative: in step 3 gained phenyl aldehyde acetyl glucosaminidase and glaucocalyxin A with mol ratio be 1:0.5 ?1:1.5 be dissolved in organic solvent, react under acidic conditions 1 ?5h, add dichloromethane extraction, wash with saturated sodium bicarbonate, saturated aqueous common salt successively, anhydrous MgSO
4drying, filters, concentrated, column chromatographic isolation and purification, petrol ether/ethyl acetate system wash-out, obtain end product Ia ?Ic, IIa ?IIc.
6. method according to claim 5, is characterized in that, in described step 1: described organic solvent is tetrahydrofuran (THF), DMF, methyl-sulphoxide, acetonitrile, Isosorbide-5-Nitrae-dioxane, methylene dichloride or chloroform;
In described step 2: described organic solvent is tetrahydrofuran (THF), DMF, methyl-sulphoxide, acetonitrile or Isosorbide-5-Nitrae-dioxane.
7. method according to claim 5, it is characterized in that, in described step 3, described organic solvent is tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, acetonitrile, Isosorbide-5-Nitrae-dioxane, propyl carbinol, n-butanol-water, methylene dichloride, chloroform or acetonitrile.
8. method according to claim 5, is characterized in that, in described step 4, described acidic conditions is mineral acid, organic acid or aprotic acid.
9., containing the preparation of the derivative described in any one of claim 1-3, it is characterized in that, described preparation is made up of this derivative and pharmaceutically acceptable carrier.
10. the application in the medicine of preparation treatment tumour of the derivative described in any one of claim 1-3 or preparation according to claim 9, described tumour is preferably liver cancer, cervical cancer, leukemia, choriocarcinoma and lung cancer.
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