CN106518941A - Glycosyl beta-elemene derivatives, preparation method and application thereof - Google Patents

Glycosyl beta-elemene derivatives, preparation method and application thereof Download PDF

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CN106518941A
CN106518941A CN201610952610.0A CN201610952610A CN106518941A CN 106518941 A CN106518941 A CN 106518941A CN 201610952610 A CN201610952610 A CN 201610952610A CN 106518941 A CN106518941 A CN 106518941A
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elemene
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CN106518941B (en
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王坚毅
王勉
陈政君
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Guangxi University
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Abstract

The invention discloses glycosyl beta-elemene derivatives having general formulae I, II and III. Researches indicate that the glycosyl beta-elemene derivatives have good biological water solubility and good anti-cancer activities, can be applied to malignant tumor treatment as an anti-cancer medicine for realizing real-time tumor monitoring and treatment, and have important scientific meaning to researches and application of beta-elemene in the field of medicine. Furthermore, the invention provides a method for preparing the corresponding compounds. The method applies a click chemical reaction technology, and is simple and scientific in synthesis.

Description

Glycosyl beta-elemene derivatives and its preparation method and application
Technical field
The present invention relates to pharmaceutical technology field, more particularly to glycosyl beta-elemene derivatives and its preparation method and application.
Background technology
Beta-elemene is that two class of country that China's research worker is extracted from zingiberaceous plant RADIX CURCUMAE rhizome first resists Cancer drug, its by anticancer propagation, cancer cell specific induction of apoptosis, anticancer angiogenesis, containment cancer cell metastasis, Telomerase activation and inverse cancer cell drug resistance etc. is affected to play antitumor action, its antitumaous effect determined curative effect, poison are secondary to be made With it is little, can by a plurality of approach improve body's immunity and to some it is easy produce drug resistance malignant tumor Also there are preferable curative effect, the active anticancer with wide spectrum and good antitumor application thereof prospect.But, due to beta-elemene indissoluble Yu Shui, bioavailability are low, the shortcomings of be unable to monitor in real time treatment tumor so as to present in concentration and on the time it is stronger according to Lai Xing, seriously limits its clinical practice.Therefore, transformed simultaneous to improve beta-elemene water solublity and biology to its compound Capacitive has important scientific meaning.
The structure of beta-elemene is as follows：
The content of the invention
The technical problem to be solved in the present invention is to provide glycosyl beta-elemene derivatives and its preparation method and application, specifically Be three classes can monitor in real time treatment tumor glycosyl beta-elemene derivatives and its synthetic method and anti-tumor aspect should With.
For solving above-mentioned technical problem, the present invention is employed the following technical solutions：
Glycosyl beta-elemene derivatives, with below general formula：
In formula I, II, III,For polyhydroxy glycosyl.
In formula I, II, III,
Compounds of formula I is：
Compounds of formula II is：
Compounds of formula III is：
Rhodamine B cyclization is obtained glimmering by cyclization by the preparation method of above-mentioned glycosyl beta-elemene derivatives first The Rhodamine Derivatives of optical quenching, then carry out nucleophilic displacement of fluorine from different terminal acetylene compounds anti-under sodium hydride catalysis respectively The Rhodamine Derivatives containing different terminal acetylenes should be obtained, such compound again respectively with full acetyl glycosyl nitrine, Azide Beta-elemene is clicked on chemical reaction and deacetylation through copper (I) catalysis and obtains target compound.
Full acetyl glycosyl nitrine is the polyhydroxy glycosyl nitrine after acetylation protection.
Application of the above-mentioned glycosyl beta-elemene derivatives in terms of the cancer therapy drug of monitor in real time treatment tumor is prepared.
Polyhydric glucide is the important nutrient substance of the mankind, with stronger hydrophilic, and environmental protection.Cause This, introduces hydrophilic glucide in beta-elemene, is to improve the good mentality of designing of beta-elemene water solublity.And rhodamine Class compound has that high quantum production rate, high extinction coefficient, fabulous light stability, excitation wavelength are longer, detection sensitivity is high, valency Many advantages, such as lattice are cheap, and (the quenching after closed loop under alkalescence condition of fluorescence " on-off " effect is shown under condition of different pH Fluorescence, sends fluorescence after open loop under acid condition)；In addition, there are some researches show, tumor cell is in slant acidity (extracellular pH 6.2- 6.9, intracellular pH 4.5-5.5), the rhodamine compound of closed loop can discharge strong fluorescence in open loop in tumor cell.Cause This, introduces rhodamine in beta-elemene and will be expected to realize the purpose that monitor in real time treats tumor.
For this purpose, being insoluble in the shortcomings of water, bioavailability are low, be unable to monitor in real time treats tumor for beta-elemene, send out A person of good sense according to the property of tumor cell slant acidity by hydrophilic glucide and the rhodamine with hyperfluorescence property introduce β- In elemene structure, design has synthesized the glycosyl beta-elemene derivatives with formula I, II, III.Research shows, the sugar of gained Base beta-elemene derivatives water solublity is preferable, active anticancer is good, and the cancer therapy drug that can be implemented as monitor in real time treatment tumor should For the treatment of malignant tumor, there is important scientific meaning to research of the beta-elemene in field of medicaments with application.Meanwhile, send out A person of good sense establishes the preparation method of respective compound, and the method uses click chemistry reaction technology, and synthesis is simple, science.
Compared with prior art, it is of the invention to have the prominent advantages that：
(1) present invention introduces glycosyl 1,2,3-triazoles and rhodamine B simultaneously in beta-elemene, has synthesized glycosyl 1,2,3- tri- Azoles rhodamine beta-elemene derivatives, synthesize a class good water solubility, the beta-elemene of achievable monitor in real time treatment tumor and spread out It is biological；
(2) present invention introduces group be glycosyl 1,2,3-triazoles, glucide is the important nutrient substance of the mankind, is had Stronger hydrophilic, and environmental protection；
(3) present invention introduces rhodamine fluorescent dyes low price, quantum yield height, good light stability, excitation wavelength It is longer, the interference of Intrinsic fluorescence can be reduced；
(4) to can apply to pharmaceutical technology field pernicious swollen for glycosyl 1,2,3-triazoles rhodamine beta-elemene derivatives of the present invention The treatment of tumor.
Description of the drawings
Fig. 1 is the fluorometric investigation curve chart of glycosyl beta-elemene derivatives pH responses of the present invention, in figure：Each song from top to bottom Line represents the fluorescence intensity of compound under different pH condition respectively.
Fig. 2 is the synthetic line figure one of glycosyl beta-elemene derivatives of the present invention.
Fig. 3 is the synthetic line figure two of glycosyl beta-elemene derivatives of the present invention.
Specific embodiment
The glycosyl beta-elemene derivatives of the present invention reaction scheme can synthesize as shown in Fig. 1 and Fig. 2, concrete preparation method For：Rhodamine B cyclization is obtained the Rhodamine Derivatives of fluorescent quenching first by cyclization, then under sodium hydride catalysis Nucleophilic substitution is carried out from different terminal acetylene compounds respectively and obtains the Rhodamine Derivatives containing different terminal acetylenes, should Class compound again respectively with full acetyl glycosyl nitrine, Azide beta-elemene through copper (I) catalysis click on chemical reaction and Deacetylation obtains target compound.
For a better understanding of the present invention, with reference to embodiment further elucidate beta-elemene derivatives of the present invention and its The content of preparation method.
Embodiment 1
Rhodamine B (10g) is dissolved in methanol (20mL) adds ethanolamine (25mL), Ar protections to place under 75 DEG C of oil baths afterwards Red disappearance is back to, cold cut to room temperature adds 100mL deionized waters, CH2Cl2Extraction, saturated common salt water washing are anhydrous Na2SO4Be dried, filter, concentration, silica column purification (PE/EA=4: 1), obtain pale solid 1 (3.84g, 35%).1H NMR (600MHz, CDCl3) δ 7.92 (dd, J=5.6,3.0Hz, 1H), 7.46 (dd, J=5.6,3.1Hz, 2H), 7.09 (dd, J= 5.2,3.2Hz, 1H), 6.51 (d, J=8.9Hz, 2H), 6.40 (d, J=2.4Hz, 2H), 6.31 (dd, J=8.9,2.4Hz, 2H), 3.51-3.47 (m, 2H), 3.36 (q, J=7.0Hz, 8H), 3.32-3.29 (m, 2H), 1.19 (t, J=7.1Hz, 12H) .13C NMR (151MHz, CDCl3) δ 170.10,153.92,153.28,148.90,132.69,130.45,128.51, 128.14,123.81,122.90,108.24,104.80,97.80,65.87,62.68,62.66,44.65,44.37,12.61.
Serinol (5g) is dissolved in into the dehydrated alcohol of 150mL, 100mL BOC anhydride (12g) ethanol solutions, room is added Temperature reaction 6h, rotation except solvent, then with normal heptane recrystallization obtain white solid 2 (9.6g, 91%).1H NMR (600MHz, DMSO) δ 4.51 (t, J=5.3Hz, 2H), 3.35 (m, 5H), 1.38 (s, 9H).
The KOH (3.05g) and anhydrous THF (15mL) suspension of powdery are cooled to into 0 DEG C, Ar protections.By compound 2 (2.06g) after being dissolved in anhydrous THF (10mL), it is added dropwise in reactant liquor, after adding, 0 DEG C of reaction 15min, is added dropwise over 4.7mL Propargyl bromide, 0 DEG C reaction 5min after be warming up to 35 DEG C reaction overnight, add deionized water (100mL), CH2Cl2Extraction, saturation food Salt water washing, anhydrous Na2SO4Be dried, filter, post separation is crossed in concentration, obtain yellow liquid 3 (2.467g, 88%).1H NMR (600MHz, CDCl3) δ 4.18 (d, J=2.3Hz, 4H), 3.94 (s, 1H), 3.65 (dd, J=9.3,4.4Hz, 2H), 3.59 (dd, J=8.9,6.1Hz, 2H), 2.45 (t, J=2.4Hz, 2H), 1.46 (s, 9H) .ESI-MS (m/z) 268.2 [M+H+].
Compound 3 (2.4g) is dissolved in the CH of 30mL dryings2Cl2, trifluoroacetic acid (15mL) is added dropwise at 0 DEG C, under Ar protections Room temperature reaction 3h, rotation is except solvent, after addition toluene (6 × 10mL) band is except unnecessary trifluoroacetic acid, the CH for adding 15mL to be dried2Cl2 With the DIPEA of 4.5mL, Ar protection, be added dropwise over after being cooled to 0 DEG C 30mL mixed liquors (1.2mL bromoacetyl bromides+ The CH that 30mL is dried2Cl2), room temperature reaction is warmed naturally to after adding overnight, adds 30mL CH2Cl2Dilution, deionization washing Wash, anhydrous Na2SO4Be dried, post separation (PE/EA=7: 1) is crossed in concentration, obtain weak yellow liquid 4 (1.78g, 68%).1H NMR (600MHz, CDCl3) δ 6.81 (d, J=8.5Hz, 1H), 4.26 (dtt, J=8.7,5.6,4.5Hz, 1H), 4.19 (dd, J= 2.4,0.9Hz, 4H), 3.89 (s, 2H), 3.69 (dd, J=9.4,4.5Hz, 2H), 3.62 (dd, J=9.5,5.6Hz, 2H), 2.47 (t, J=2.4Hz, 2H).
NaH (60%, 0.407g) and anhydrous THF (10mL) suspension are cooled to into 0 DEG C, Ar protections.By compound 1 (1.31g) after being dissolved in anhydrous THF (15mL), it is added dropwise under stirring in reactant liquor, 0 DEG C of reaction 30min after adding, then will be advance The solution (the anhydrous THF of 1.04g compound 4+5mL) of configuration is added dropwise in reaction system, places room temperature reaction overnight after adding. Add deionized water quenching reaction, CH2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, concentration, column chromatography Purification (PE/EA=4: 1), obtain pale solid 5 (1.3g, 68%).
1H NMR (600MHz, CDCl3) δ 7.95-7.91 (m, 1H), 7.48-7.44 (m, 2H), 7.13-7.07 (m, 2H), 6.46 (d, J=8.9Hz, 2H), 6.39 (d, J=2.5Hz, 2H), 6.29 (dd, J=8.9,2.5Hz, 2H), 4.30 (dt, J= 8.8,5.4Hz, 1H), 4.10 (d, J=2.4Hz, 4H), 3.68-3.62 (m, 6H), 3.42 (t, J=6.2Hz, 2H), 3.35 (q, J=7.1Hz, 8H), 3.07 (t, J=6.2Hz, 2H), 2.40 (t, J=2.3Hz, 2H), 1.18 (t, J=7.1Hz, 12H) .ESI-MS(m/z)693.4[M+H+].
Compound 5 (0.28g) is dissolved in into THF (2.5mL), Ar protections will be advance deionized water (2.5mL) molten under room temperature The sodium ascorbate (13.5mg) of solution and CuSO4·5H2During O (1.6mg) solution adds reactant liquor, repeatedly it is dividedly in some parts on a small quantity complete Acetyl galactose nitrine (0.15g), TCL monitoring reaction to product point it is most dense when terminate react (about 24h altogether), add deionization Water, CH2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, concentration is crossed post separation, obtains light red solid 6 (0.19g, 44%).1H NMR (600MHz, CDCl3) δ 7.93 (ddd, J=10.2,8.5,3.7Hz, 2H), 7.46 (dd, J= 5.6,3.1Hz, 2H), 7.15-7.09 (m, 2H), 6.47-6.44 (m, 2H), 6.39 (t, J=2.4Hz, 2H), 6.30-6.27 (m, 2H), 5.87 (dd, J=9.3,3.4Hz, 1H), 5.62 (td, J=9.8,4.4Hz, 1H), 5.56 (d, J=3.2Hz, 1H), 5.29-5.25 (m, 1H), 4.67 (d, J=3.9Hz, 2H), 4.34-4.28 (m, 1H), 4.26-4.20 (m, 2H), 4.17-4.12 (m, 1H), 4.07-4.04 (m, 2H), 3.69-3.58 (m, 6H), 3.49 (dddd, J=13.0,9.5,6.4,3.2Hz, 1H), 3.39-3.33 (m, 9H), 3.12 (dt, J=9.5,6.0Hz, 1H), 3.05-2.99 (m, 1H), 2.43-2.41 (m, 1H), 2.24 (s, 3H), 2.06 (s, 3H), 2.03 (d, J=0.9Hz, 3H), 1.90 (d, J=4.2Hz, 3H), 1.18 (t, J=7.0Hz, 12H).
The mixed liquor of the beta-elemene and 2mL of 2.58mL is placed into ice bath and is cooled to less than 5 DEG C, dropwise added under magnetic agitation Enter the liquor natrii hypochloritises (more than Deca duration 4h) of 13.5mL, place room temperature reaction 2h after adding, add CH2Cl2Extraction, goes Ion water washing, anhydrous Na2SO4It is dried, filters, concentration, silicagel column careful separation (petroleum ether) obtains the 7-1 and 7-2 of 1.1g Mixed liquor (based on 7-1).
The mixed liquor (0.85g) of the 7-1 for obtaining and 7-2 is dissolved under 5mL DMSO, room temperature and is dividedly in some parts NaN3 (0.36g), room temperature reaction 3h, reactant liquor is poured in the deionized water of 40mL, CH2Cl2Extraction (4 × 15mL), saturated aqueous common salt Washing, anhydrous Na2SO4It is dried, filters, post separation (petroleum ether) is crossed in concentration, and obtaining purer oily liquids 8 (still has micro The beta-elemene of 14 replacements, 0.44g, 50%).
Compound 6 (0.19g) and compound 8 (56mg) are dissolved in into THF (3mL), Ar protections, spent under room temperature in advance from Sodium ascorbate (13.5mg) and CuSO that sub- water (3mL) dissolves4·5H2During O (1.6mg) solution adds reactant liquor, room temperature reaction Overnight, deionized water, CH are added2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, post separation is crossed in concentration, Obtain light red solid 9 (0.18g, 77%).
Compound 9 (0.18g) is dissolved in into being dried in methanol solution of 5mL, adds sodium methoxide solution to adjust pH to 9-10, room Temperature reaction overnight, adds hydrogen ion exchange resin to adjust pH to neutrality, filters, and concentration is crossed post separation, obtains white solid 10 (0.12g, 76%).1H NMR (600MHz, CD3OD) δ 8.21 (d, J=15.3Hz, 1H), 7.91 (dd, J=7.5,3.9Hz, 1H), 7.80 (d, J=1.2Hz, 1H), 7.59-7.51 (m, 2H), 7.08-7.04 (m, 1H), 6.44 (s, 2H), 6.40-6.32 (m, 3H), 6.31-6.27 (m, 1H), 5.80 (dd, J=17.5,10.8Hz, 1H), 5.59 (dd, J=9.1,3.0Hz, 1H), 5.07 (d, J=2.3Hz, 1H), 5.00 (dd, J=12.8,9.3Hz, 2H), 4.90 (d, J=3.0Hz, 2H), 4.86 (s, 1H), 4.80 (s, 2H), 4.57 (dd, J=5.2,3.2Hz, 3H), 4.52 (s, 1H), 4.24 (dd, J=5.6,2.2Hz, 1H), 4.20 (t, J=9.3Hz, 1H), 4.02 (d, J=2.8Hz, 1H), 3.86 (t, J=5.8Hz, 1H), 3.76 (ddd, J=21.9, 13.0,6.3Hz, 3H), 3.67-3.54 (m, 6H), 3.49-3.34 (m, 10H), 3.10-2.97 (m, 2H), 1.96 (dt, J= 12.7,3.5Hz, 1H), 1.92 (d, J=3.4Hz, 1H), 1.68 (s, 3H), 1.61-1.48 (m, 3H), 1.42 (ddd, J= 13.7,11.6,6.8Hz, 3H), 1.20-1.12 (m, 11H), 1.05 (t, J=7.0Hz, 1H), 1.00 (s, 3H).13C NMR (151MHz, CD3OD) δ 170.75,169.10,153.74,153.38,153.35,149.89,149.09,148.66, 148.65,147.20,144.66,144.59,132.89,130.59,130.56,128.29,123.99,123.97,123.67, 122.56,122.52,112.08,112.03,111.57,109.23,108.23,108.13,104.66,104.54,97.65, 88.86,78.52,73.95,70.07,69.47,68.98,68.74,68.39,65.54,63.68,61.03,53.67, 52.41,48.50,44.01,42.07,39.57,39.37,39.13,32.81,26.78,23.98,15.72,11.58, 11.57.ESI-MS(m/z)1143.6[M+H+].HRMS(MALDI)calcd for C62H83N10O11：[M+H+] 1143.6237, found 1143.6245.
Embodiment 2
Compound 12 is obtained with the synthetic method similar to compound 6.1H NMR (600MHz, CDCl3)δ7.92-7.89 (m, 1H), 7.87 (s, 1H), 7.48-7.43 (m, 2H), 7.16-7.08 (m, 2H), 6.45 (ddd, J=8.6,5.9,2.6Hz, 2H), 6.39 (t, J=2.6Hz, 2H), 6.29 (ddd, J=8.2,5.5,2.6Hz, 2H), 5.86 (dd, J=9.3,2.7Hz, 1H), 5.49 (q, J=9.4Hz, 1H), 5.44-5.40 (m, 1H), 5.38 (d, J=2.8Hz, 1H), 5.15 (dd, J=10.4, 7.9Hz, 1H), 4.99 (dd, J=10.4,3.5Hz, 1H), 4.65 (d, J=2.9Hz, 2H), 4.55 (dd, J=7.9,2.1Hz, 1H), 4.49 (d, J=12.2Hz, 1H), 4.32-4.27 (m, 1H), 4.18-4.12 (m, 3H), 4.06-4.03 (m, 2H), 4.03-3.98 (m, 1H), 3.93 (dt, J=10.5,6.1Hz, 2H), 3.69 (dd, J=14.8,3.5Hz, 1H), 3.65-3.61 (m, 3H), 3.61-3.57 (m, 2H), 3.48 (dd, J=14.0,6.9Hz, 1H), 3.39-3.32 (m, 10H), 3.11 (dt, J= 9.4,6.0Hz, 1H), 3.03-2.98 (m, 1H), 2.41 (dd, J=2.3,1.7Hz, 1H), 2.18 (s, 3H), 2.11 (s, 3H), 2.09 (d, J=0.6Hz, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.87 (d, J=4.5Hz, 3H), 1.18 (td, J=7.0,1.3Hz, 12H).
Compound 13 is obtained with the synthetic method similar to compound 9, next step reaction is directly carried out.
Compound 14 is obtained with the synthetic method similar to compound 10.1H NMR (600MHz, CD3OD) 8.20 (d, J=of δ 19.2Hz, 1H), 7.91-7.85 (m, 1H), 7.76 (d, J=1.6Hz, 1H), 7.57-7.50 (m, 2H), 7.06 (dd, J= 5.3,1.5Hz, 1H), 6.54-6.21 (m, 6H), 5.79 (dd, J=17.5,10.8Hz, 1H), 5.64 (dd, J=9.2, 2.2Hz, 1H), 5.06 (d, J=3.9Hz, 1H), 5.01-4.92 (m, 2H), 4.88 (t, J=1.1Hz, 1H), 4.85 (s, 2H), 4.81-4.76 (m, 2H), 4.59-4.53 (m, 3H), 4.50 (d, J=2.9Hz, 2H), 4.42 (dd, J=7.7,3.6Hz, 1H), 4.21 (dt, J=10.9,5.4Hz, 1H), 4.00 (t, J=9.0Hz, 1H), 3.89 (d, J=2.4Hz, 2H), 3.84 (d, J= 3.0Hz, 1H), 3.82-3.70 (m, 5H), 3.63-3.54 (m, 7H), 3.53-3.48 (m, 2H), 3.46-3.32 (m, 9H), 3.08-2.92 (m, 2H), 1.98-1.87 (m, 2H), 1.67 (t, J=6.2Hz, 3H), 1.60-1.46 (m, 3H), 1.46-1.37 (m, 3H), 1.15 (td, J=7.0,2.8Hz, 11H), 1.05-1.01 (m, 1H), 0.98 (d, J=1.0Hz, 3H) .ESI-MS (m/z)1305.7[M+H+].HRMS calcd for C68H93N10O16：[M+H+] 1305.67655, found 1305.67712.
Embodiment 3
5g trishydroxymethylaminomethane is dissolved in into the mixed solution of 30mL methanol and 30mL tert-butyl alcohols composition, stirring is lower to be added BOC anhydride (11.75g) tert-butyl alcohol (50mL) solution, overnight, rotation adds ethyl acetate refrigerated overnight, mistake except solvent to room temperature reaction Filter obtain white solid 15 (8.5g, 93%).1H NMR (600MHz, DMSO-d6) δ 4.49 (s, 3H), 3.52 (s, 6H), 1.37 (s, 9H).
The KOH (2.3g) of powdery and DMF (10mL) suspension being dried are cooled to into 0 DEG C, Ar protections.By compound 15 (1.5g) after being dissolved in anhydrous THF (10mL), it is added dropwise in reactant liquor, after adding, 0 DEG C of reaction 10min, is added dropwise over 3.3mL's Propargyl bromide, is warming up to 35 DEG C of reactions overnight after 0 DEG C of reaction 5min, adds deionized water (100mL), CH2Cl2Extraction, saturated common salt Water washing, anhydrous Na2SO4Be dried, filter, post separation (PE: EA=15: 1-8: 1) is crossed in concentration, obtain yellow liquid 16 (1.4g, 61%).1H NMR (600MHz, CDCl3) δ 5.32 (s, 1H), 4.17 (d, J=2.3Hz, 6H), 3.81 (s, 6H), 2.45 (t, J =2.3Hz, 3H), 1.44 (s, 9H).
Compound 16 (1.27g) is dissolved in the CH of 15mL dryings2Cl2, at 0 DEG C, it is added dropwise over trifluoroacetic acid (6mL), Ar protections Lower room temperature reaction 3h, rotation add what 10mL was dried except solvent after adding toluene (6 × 10mL) band except unnecessary trifluoroacetic acid CH2Cl2With the DIPEA of 1.7mL, Ar protections, 20mL mixed liquors (0.41mL bromines after being cooled to 0 DEG C, are added dropwise over The CH that acetyl bromide+20mL is dried2Cl2), room temperature reaction is warmed naturally to after adding overnight, adds 30mL CH2Cl2Dilution, go from Sub- water washing, anhydrous Na2SO4Be dried, post separation (PE/EA=7: 1) is crossed in concentration, obtain weak yellow liquid 17 (0.92g, 68%).1H NMR (600MHz, CDCl3) δ 6.70 (s, 1H), 4.18 (d, J=2.4Hz, 6H), 3.87 (s, 6H), 3.82 (s, 2H), 2.47 (t, J=2.3Hz, 3H).13C NMR (151MHz, CDCl3) δ 165.39,79.40,74.81,68.14,59.76, 58.70,29.47.
NaH (60%, 0.2175g) and anhydrous THF (5mL) suspension are cooled to into 0 DEG C, Ar protections.By compound 1 (0.643g) after being dissolved in anhydrous THF (5mL), it is added dropwise in reactant liquor, 0 DEG C of reaction 30min after adding, then will be pre-configured with Solution (the anhydrous THF of 0.592g compound 17+5mL) is added dropwise in reaction system, places room temperature reaction overnight after adding.Add Deionized water quenching reaction, CH2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, post separation is crossed in concentration (PE/EA=1: 4), obtain light red solid 18 (0.733g, 72.8%).1H NMR (600MHz, CDCl3) δ 7.94-7.91 (m, 1H), 7.47-7.42 (m, 2H), 7.11-7.06 (m, 1H), 6.82 (s, 1H), 6.46 (d, J=8.9Hz, 2H), 6.39 (d, J= 2.3Hz, 2H), 6.29 (dd, J=8.9,2.5Hz, 2H), 4.11 (d, J=2.4Hz, 6H), 3.85 (s, 6H), 3.55 (s, 2H), 3.42 (t, J=6.6Hz, 2H), 3.35 (q, J=7.1Hz, 8H), 3.06 (t, J=6.6Hz, 2H), 2.40 (t, J=2.3Hz, 3H), 1.18 (t, J=7.1Hz, 12H).13C NMR (151MHz, CDCl3) 6169.47,168.35,153.67,153.20, 148.83,132.41,130.94,128.88,128.01,123.76,122.89,108.13,105.44,97.69,79.74, 74.54,70.39,68.27,68.12,64.62,59.17,58.58,44.38,39.06,12.61.ESI-MS (m/z) 761.4 [M+H+].
Compound 18 (1.04g) is dissolved in into THF (10mL), Ar protections will be advance deionized water (10mL) molten under room temperature The sodium ascorbate (1.1g) of solution and CuSO4·5H2During O (12.6mg) solution adds reactant liquor, full second is repeatedly dividedly in some parts on a small quantity Acyl galactose nitrine (1.5g), TCL monitoring reaction to product point it is denseer when terminate react (about 30h altogether), add deionized water, CH2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, concentration is crossed post separation and obtains light red solid 19 (0.23g, 15%) and light red solid 20 (0.395g, 19%).
Compound 19 (0.23g) and compound 8 (0.125g) are dissolved in into THF (4mL), Ar protections will be used under room temperature in advance Sodium ascorbate (32mg) and CuSO that deionized water (4mL) dissolves4·5H2During O (20mg) solution adds reactant liquor, room temperature is anti- Deionized water, CH should be added overnight2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, post point is crossed in concentration From, obtain light red solid 21 (0.22g, 67%).
Compound 21 (0.2g) is dissolved in into being dried in methanol solution of 5mL, adds sodium methoxide solution to adjust pH to 9-10, room Temperature reaction overnight, adds hydrogen ion exchange resin to adjust pH to neutrality, filters, and concentration is crossed post separation, obtains white solid 22 (0.13g, 72.5%).1H NMR (600MHz, CD3OD) δ 8.16 (s, 1H), 7.93-7.76 (m, 3H), 7.58-7.43 (m, 2H), 7.11-7.00 (m, 1H), 6.60-6.19 (m, 6H), 5.79 (dd, J=17.5,10.9Hz, 2H), 5.57 (d, J= 9.1Hz, 1H), 5.05 (s, 2H), 5.01 (d, J=6.2Hz, 4H), 4.88 (s, 2H), 4.84 (s, 2H), 4.79 (s, 4H), 4.55 (dd, J=25.4,12.2Hz, 8H), 4.18 (t, J=9.3Hz, 1H), 4.00 (d, J=2.8Hz, 1H), 3.84 (t, J= 5.9Hz, 1H), 3.80-3.69 (m, 9H), 3.42 (s, 2H), 3.35 (dd, J=13.4,6.5Hz, 8H), 2.99 (d, J= 5.2Hz, 2H), 2.02-1.88 (m, 4H), 1.67 (s, 6H), 1.55 (dt, J=17.6,12.6Hz, 6H), 1.48-1.37 (m, 6H), 1.14 (t, J=7.0Hz, 10H), 1.03 (t, J=7.0Hz, 2H), 0.98 (s, 6H).13C NMR (151MHz, CD3OD)δ 170.27,168.89,153.84,153.30,149.92,149.02,148.75,147.21,144.73,144.68,132.74, 130.57,128.38,128.18,124.00,123.64,122.48,111.91,111.60,109.24,108.16,104.80, 97.62,88.92,78.60,73.94,70.12,69.70,68.96,67.93,67.88,67.67,65.23,64.02, 63.87,61.03,59.68,53.66,52.40,44.02,42.06,39.58,39.39,32.79,26.81,24.03, 15.73,11.62.ESI-MS (m/z) 1456.8 [M+].HRMS(MALDI)calcd for C81H110N13O12：[M+H+] 1456.8391, found 1456.8391.
Embodiment 4
Compound 20 (0.35g) and compound 8 (0.086g) are dissolved in into THF (4mL), Ar protections will be used under room temperature in advance Sodium ascorbate (20mg) and CuSO that deionized water (4mL) dissolves4·5H2O (12mg), during solution adds reactant liquor, room temperature is anti- Deionized water, CH should be added overnight2Cl2Extraction, saturated common salt water washing, anhydrous Na2SO4It is dried, filters, post point is crossed in concentration From, obtain light red solid 23 (0.29g, 71%).
Compound 23 (0.25g) is dissolved in into being dried in methanol solution of 6mL, adds sodium methoxide solution pH to be adjusted to 9-10, Room temperature reaction overnight, adds hydrogen ion exchange resin to adjust pH to neutrality, filters, and concentration is crossed post separation, obtains white solid 24 (0.15g, 74%).1H NMR (600MHz, CD3OD) δ 8.19 (d, J=4.4Hz, 2H), 7.92-7.87 (m, 1H), 7.84 (s, 1H), 7.56-7.50 (m, 2H), 7.06 (tt, J=5.5,2.8Hz, 1H), 6.44 (d, J=2.4Hz, 2H), 6.41 (dd, J= 8.9,3.8Hz, 2H), 6.37-6.31 (m, 2H), 5.80 (dd, J=17.5,10.8Hz, 1H), 5.62 (d, J=9.2Hz, 2H), 5.06 (s, 1H), 5.02 (d, J=8.3Hz, 2H), 4.90 (d, J=1.1Hz, 1H), 4.80 (d, J=1.3Hz, 2H), 4.56 (dd, J=33.8,16.4Hz, 8H), 4.23 (t, J=9.3Hz, 2H), 4.03 (d, J=3.1Hz, 2H), 3.88 (t, J= 5.9Hz, 2H), 3.77 (ddd, J=17.8,12.2,5.0Hz, 12H), 3.47 (s, 2H), 3.42-3.34 (m, 10H), 3.02 (dd, J=8.2,5.7Hz, 2H), 2.02-1.88 (m, 2H), 1.68 (s, 3H), 1.62-1.52 (m, 3H), 1.48-1.38 (m, 3H), 1.16 (t, J=7.1Hz, 11H), 1.04 (dd, J=8.2,5.9Hz, 1H), 1.00 (s, 3H).13C NMR (151MHz, CD3OD) δ 170.41,169.02,153.83,153.31,149.94,149.04,148.72,147.23,144.70,144.57, 132.81,130.51,128.38,128.22,124.05,123.64,122.67,122.51,111.93,111.58,109.22, 108.21,104.73,97.62,88.82,78.54,73.92,70.08,69.64,69.00,68.02,67.84,67.60, 65.35,63.97,63.78,61.04,59.73,53.68,52.39,44.02,42.03,39.57,39.39,39.00, 32.79,26.80,24.01,15.71,13.38,11.60.ESI-MS (m/z) 1416.7 [M+H+].HRMS(MALDI)calcd for C72H98N13O17：[M+H+] 1416.7198, found 1416.7196.
Embodiment 5
Compound 25 and 26 is obtained with the synthetic method similar to compound 19 and 20.Compound 261H NMR and13C NMR is：1H NMR (600MHz, CDCl3) δ 7.90-7.86 (m, 2H), 7.84 (s, 1H), 7.45 (dd, J=5.3,3.3Hz, 2H), 7.09 (dd, J=5.7,2.6Hz, 1H), 6.83 (s, 1H), 6.45 (d, J=8.7Hz, 2H), 6.38 (s, 2H), 6.28 (d, J=8.4Hz, 2H), 5.91 (dd, J=9.3,1.8Hz, 2H), 5.52 (t, J=9.4Hz, 2H), 5.43 (t, J=9.1Hz, 2H), 5.37 (d, J=3.2Hz, 2H), 5.14 (dd, J=10.0,8.3Hz, 2H), 4.99 (dd, J=10.4,3.3Hz, 2H), 4.65-4.61 (m, 4H), 4.56 (d, J=7.9Hz, 2H), 4.50 (d, J=12.9Hz, 2H), 4.19-4.14 (m, 3H), 4.14-4.09 (m, 3H), 4.06-4.02 (m, 2H), 4.01-3.97 (m, 4H), 3.92 (dd, J=12.6,5.8Hz, 2H), 3.84-3.80 (m, 2H), 3.80-3.75 (m, 4H), 3.51 (q, J=14.7Hz, 2H), 3.46-3.37 (m, 2H), 3.34 (q, J =6.9Hz, 8H), 3.07-2.98 (m, 2H), 2.39 (t, J=2.3Hz, 1H), 2.17 (s, 6H), 2.09 (s, 6H), 2.08- 2.06 (m, 18H), 1.98 (s, 6H), 1.83 (s, 3H), 1.81 (s, 3H), 1.16 (t, J=7.0Hz, 12H).13C NMR (151MHz, CDCl3) δ 170.40,170.33,170.17,170.09,169.68,169.66,169.60,169.18, 169.05,169.02,168.46,153.62,153.19,148.87,145.66,132.57,130.81,128.80,128.14, 123.83,122.79,121.89,121.76,108.15,101.12,97.69,85.28,85.26,79.75,75.76, 75.69,74.82,72.84,70.97,70.79,70.51,70.35,69.09,68.73,68.69,68.22,68.11, 66.66,64.81,64.78,64.76,61.89,60.84,59.43,58.38,56.81,44.37,39.09,21.79, 20.80,20.74,20.65,20.64,20.62,20.51,20.20,20.16,12.57.ESI-MS (m/z) 2084.8 [M+H+].
Compound 27 is obtained with the synthetic method similar to compound 21.1H NMR (600MHz, CDCl3)δ7.89-7.81 (m, 2H), 7.61 (d, J=11.2Hz, 2H), 7.44 (ddd, J=5.7,4.9,3.6Hz, 2H), 7.10 (dd, J=5.6, 2.5Hz, 1H), 6.81 (s, 1H), 6.44 (d, J=8.9Hz, 2H), 6.39 (d, J=2.5Hz, 2H), 6.30-6.24 (m, 2H), 5.90 (d, J=9.4Hz, 1H), 5.82-5.76 (m, 2H), 5.56 (t, J=9.5Hz, 1H), 5.43 (t, J=9.3Hz, 1H), 5.38 (d, J=3.3Hz, 1H), 5.16 (dd, J=10.3,7.9Hz, 1H), 5.08 (s, 2H), 5.01-4.96 (m, 5H), 4.91 (d, J=2.4Hz, 2H), 4.89 (d, J=2.4Hz, 2H), 4.83 (d, J=3.9Hz, 4H), 4.61-4.56 (m, 8H), 4.18 (dd, J=12.2,5.4Hz, 1H), 4.14 (q, J=7.1Hz, 5H), 4.08 (t, J=9.5Hz, 1H), 4.00-3.96 (m, 1H), 3.93 (d, J=6.7Hz, 1H), 3.80 (dd, J=9.0,2.8Hz, 3H), 3.76 (dd, J=9.7,6.3Hz, 2H), 3.51 (s, 2H), 3.40 (t, J=6.5Hz, 2H), 3.34 (q, J=7.0Hz, 8H), 3.03 (t, J=6.5Hz, 2H), 2.18 (s, 3H), 2.10 (s, 3H), 2.08 (s, 6H), 2.07 (s, 3H), 2.06 (s, 3H), 1.98 (d, J=5.9Hz, 4H), 1.96 (d, J=3.9Hz, 1H), 1.91 (s, 2H), 1.82 (s, 3H), 1.69 (s, 6H), 1.65 (d, J=8.9Hz, 2H), 1.58 (dd, J=24.0,12.8Hz, 4H), 1.48-1.40 (m, 6H), 1.17 (t, J=7.1Hz, 12H), 1.00 (s, 6H) .ESI-MS (m/ z)1914.0[M+H+].
Compound 28 is obtained with the synthetic method similar to compound 22.1H NMR (600MHz, CD3OD) δ 8.17 (s, 1H), 7.87 (dd, J=20.0,4.5Hz, 3H), 7.54 (tt, J=13.0,6.7Hz, 2H), 7.08 (dd, J=6.4,1.1Hz, 1H), 6.41 (ddd, J=14.9,11.3,2.0Hz, 4H), 6.36-6.31 (m, 2H), 5.81 (dd, J=17.5,10.8Hz, 2H), 5.67 (d, J=9.2Hz, 1H), 5.07 (s, 2H), 5.03 (s, 4H), 4.90 (d, J=1.0Hz, 2H), 4.87 (s, 2H), 4.81 (s, 4H), 4.63-4.55 (m, 6H), 4.53 (s, 3H), 4.45 (d, J=7.7Hz, 1H), 4.02 (t, J=9.1Hz, 1H), 3.92 (d, J=2.5Hz, 2H), 3.86 (d, J=3.1Hz, 1H), 3.84-3.80 (m, 2H), 3.78 (s, 2H), 3.75 (t, J=10.5Hz, 6H), 3.65-3.59 (m, 2H), 3.53 (dd, J=9.7,3.2Hz, 1H), 3.45 (s, 2H), 3.38 (dd, J=13.8,6.8Hz, 10H), 3.01 (t, J=5.9Hz, 2H), 2.02-1.91 (m, 4H), 1.69 (s, 6H), 1.64-1.57 (m, 4H), 1.54 (t, J=10.0Hz, 2H), 1.44 (ddd, J=14.3,13.5,7.7Hz, 6H), 1.16 (t, J=7.0Hz, 11H), 1.01 (s, 6H), 0.92 (t, J=7.0Hz, 1H).13C NMR (151MHz, CD3OD) 6170.33,168.94, 153.85,153.31,149.92,149.04,148.74,147.21,132.76,130.54,128.35,128.19,123.99, 123.63,122.95,122.46,111.91,111.57,109.21,108.16,104.74,103.73,97.61,88.00, 78.33,78.19,75.74,75.44,73.45,72.30,71.16,68.91,67.88,65.28,64.00,61.12, 60.15,59.69,53.66,52.40,44.01,42.07,39.57,39.38,32.79,26.80,24.00,15.70, 11.58.ESI-MS(m/z)1618.9[M+H+].HRMS(MALDI)calcd for C87H120N13O17：[M+H+] 1618.8920, found 1618.8917.
Embodiment 6
Compound 29 is obtained with the synthetic method similar to compound 23, the reaction of next step is directly carried out.1H NMR (600MHz, CDCl3) δ 7.92-7.82 (m, 3H), 7.60 (s, 1H), 7.44 (dd, J=8.7,5.3Hz, 2H), 7.10 (d, J= 6.0Hz, 1H), 6.82 (d, J=9.3Hz, 1H), 6.47 (dd, J=24.2,14.1Hz, 2H), 6.40-6.24 (m, 3H), 5.92 (dd, J=9.2,4.6Hz, 2H), 5.79 (dd, J=17.7,10.6Hz, 1H), 5.58-5.51 (m, 2H), 5.44 (t, J= 9.1Hz, 2H), 5.38 (d, J=2.2Hz, 2H), 5.18-5.12 (m, 2H), 5.08 (s, 1H), 5.03-4.95 (m, 4H), 4.90 (dd, J=14.1,1.9Hz, 2H), 4.82 (s, 2H), 4.65-4.54 (m, 10H), 4.52 (d, J=12.3Hz, 2H), 4.16 (ddd, J=22.6,15.0,8.1Hz, 7H), 4.07 (t, J=9.4Hz, 2H), 4.01 (d, J=4.3Hz, 2H), 3.93 (t, J =6.5Hz, 2H), 3.78 (ddd, J=23.1,15.5,9.1Hz, 6H), 3.50 (dd, J=13.9,4.3Hz, 2H), 3.38 (ddd, J=19.9,13.6,6.8Hz, 8H), 3.20-3.12 (m, 1H), 3.07-2.95 (m, 2H), 2.18 (s, 6H), 2.08 (d, J=8.0Hz, 24H), 1.99 (s, 6H), 1.82 (s, 3H), 1.79 (s, 3H), 1.69 (s, 3H), 1.61-1.57 (m, 4H), 1.44 (s, 3H), 1.17 (t, J=6.9Hz, 11H), 1.04 (t, J=7.0Hz, 1H), 1.00 (s, 3H) .ESI-MS (m/z) 2351.9[M+Na+].
Compound 30 is obtained with the synthetic method similar to compound 24.1H NMR (600MHz, CD3OD) δ 8.16 (s, 2H), 7.89 (dd, J=10.5,5.8Hz, 1H), 7.81 (s, 1H), 7.55-7.48 (m, 2H), 7.06-7.01 (m, 1H), 6.56-6.23 (m, 6H), 5.78 (dd, J=17.5,10.8Hz, 1H), 5.69 (d, J=9.2Hz, 2H), 5.04 (s, 1H), 4.99 (d, J=7.9Hz, 2H), 4.88 (s, 2H), 4.84 (d, J=1.1Hz, 1H), 4.78 (d, J=5.2Hz, 2H), 4.60 (s, 1H), 4.55 (s, 1H), 4.51 (d, J=20.7Hz, 6H), 4.46 (d, J=7.6Hz, 2H), 4.05 (t, J=8.9Hz, 2H), 3.91 (s, 4H), 3.87 (d, J=3.0Hz, 2H), 3.84-3.81 (m, 3H), 3.80 (s, 1H), 3.78 (d, J= 8.6Hz, 3H), 3.74 (dd, J=15.4,7.6Hz, 9H), 3.67-3.64 (m, 2H), 3.63-3.60 (m, 2H), 3.55 (dd, J =9.7,3.1Hz, 2H), 3.46 (s, 2H), 3.35 (dd, J=13.6,6.6Hz, 8H), 2.99 (s, 2H), 1.98-1.92 (m, 2H), 1.66 (s, 3H), 1.60-1.49 (m, 3H), 1.46-1.36 (m, 3H), 1.14 (t, J=7.1Hz, 11H), 1.03 (t, J =7.1Hz, 1H), 0.98 (s, 3H).13C NMR (151MHz, CD3OD) δ 170.47,169.04,153.84,153.31, 149.93,149.06,148.71,147.22,144.69,144.48,132.86,130.46,128.37,128.26,124.04, 123.64,123.17,123.12,122.56,111.95,111.62,109.26,108.20,104.65,103.75,97.63, 87.87,78.49,78.13,75.69,75.44,73.41,72.26,71.18,69.67,68.96,68.12,67.69, 65.39,63.97,63.79,61.19,60.22,59.76,53.68,52.38,46.07,44.03,42.04,39.58, 39.39,32.79,26.80,24.04,15.74,11.63.ESI-MS (m/z) 1740.8 [M+H+].HRMS(MALDI)calcd for C84H118N13O27：[M+H+] 1740.8255, found 1740.8255.
Fluorometric investigation
Target compound is made into into 2.5 × 10-4The solution of mol/L, carries out fluorometric investigation.
The preparation of Britton-Robinson buffer solution：0.04mol/ is in phosphoric acid, boric acid, acetic acid each sample concentration In the 100mL mixed liquors of L, the NaOH solution of different volumes 0.2mol/L is added, and being made into pH respectively is：2.31、3.25、3.93、 4.35th, 4.81,5.15,5.74,6.25,6.40,6.82,7.19,7.5 Britton-Robinson buffer solution.
The fluorometric investigation of pH responses：The parameter of first fluorescence spectrophotometer is set to：Excitation wavelength is 565nm, and sweep limitss are 575-700nm, scanning speed are middling speed, and the sampling interval is 1.0, and the slit of excitation wavelength is 3nm, and the slit of launch wavelength is 1.5nm, response time are automatic.Then, after shake up the test solution for preparing again, take during 4mL is put into fluorescence pond and start to survey Examination.
As shown in figure 1, the target compound of the present invention is Rhodamine Derivatives, with similar fluorescence property.In pH it is In the range of 4.5-5.5, the less fluorescence intensities of pH are stronger, illustrate that the fluorescent probe of present invention synthesis is in potential tumor cell The fluorescent switch probe of response pH, can be used to monitor the change of cellular pH.
Biological activity test
Glycosyl 1,2,3-triazoles beta-elemene derivatives of the present invention are determined using presto blue reagents to give birth to hepatoma carcinoma cell Long inhibitory action carries out preliminary assessment.Specific experiment step is as follows：
(1) preparation of cell culture medium：DMEM culture medium contains 10% inactivated fetal bovine serum and 1% penicillin/streptomycin.
(2) culture of cell：Respectively HepG2 cells are inoculated in cell culture medium, in 37 DEG C, 5%CO2In incubator Culture.
(3) preparation of compound sample：Compound DMSO is dissolved so as to which concentration is 10mM.It is dilute with cell culture medium Releasing suitable concn carries out cytoactive test.
(4) determine inhibitory action of the compound sample to growth of tumour cell
HepG2 cell lines are digested with pancreatin, 5 × 10 are diluted to culture medium4/ mL, is added in 96 orifice plates, often 100 μ L of hole, are positioned over 37 DEG C, cultivate 24 hours in 5%CO2 incubators.Former culture medium is discarded, is added containing compound sample per hole Culture medium per 100 μ L of hole, be positioned over 37 DEG C, cultivate 48 hours in 5%CO2 incubators.Add per hole in Tissue Culture Plate 10 μ L presto blue, are incubated 2 hours in 37 DEG C, 5%CO2 incubators, determined with microplate reader and inhale at 570nm and 600nm Luminosity, calculates the IC of compound sample50, wherein elemene is used as positive control, ICI.e.Measurement result is as shown in table 1：
1 compound biological activity test result of table
As seen from the above table, compound 10,14,24 and 30 of the invention has excellent resisting liver cancer activity, and its effect is better than Elemene, with preferable application prospect.
In sum, the invention provides three classes can monitor in real time treatment tumor glycosyl 1,2,3-triazoles beta-elemene spread out In pharmaceutical technology field, biology, such compound realize that the research of monitor in real time treatment tumor is anticipated with important science with application Justice.

Claims (8)

1. glycosyl beta-elemene derivatives, it is characterised in that with below general formula：
In formula I, II, III,For polyhydroxy glycosyl.
2. glycosyl beta-elemene derivatives according to claim 1, it is characterised in that：
In formula I, II, III,
3. glycosyl beta-elemene derivatives according to claim 2, it is characterised in that compounds of formula I is：
4. glycosyl beta-elemene derivatives according to claim 2, it is characterised in that compounds of formula II is：
5. glycosyl beta-elemene derivatives according to claim 2, it is characterised in that compounds of formula III is：
6. the preparation method of glycosyl beta-elemene derivatives described in claim 1, it is characterised in that：First will by cyclization Rhodamine B cyclization obtains the Rhodamine Derivatives of fluorescent quenching, then sodium hydride catalysis under respectively from different terminal acetylenes Compound carries out nucleophilic substitution and obtains the Rhodamine Derivatives containing different terminal acetylenes, such compound again respectively with full second Acyl glycosyl nitrine, Azide beta-elemene are clicked on chemical reaction and deacetylation through copper (I) catalysis and obtain target Compound.
7. the preparation method of glycosyl beta-elemene derivatives according to claim 6, it is characterised in that：The full acetyl sugar Base nitrine is the polyhydroxy glycosyl nitrine after acetylation protection.
8. glycosyl beta-elemene derivatives described in claim 1 prepare monitor in real time treatment tumor cancer therapy drug in terms of should With.
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