CN106083967A - Containing galactoside structure triazole norcantharidin derivative and preparation method and application - Google Patents

Containing galactoside structure triazole norcantharidin derivative and preparation method and application Download PDF

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Publication number
CN106083967A
CN106083967A CN201610392600.6A CN201610392600A CN106083967A CN 106083967 A CN106083967 A CN 106083967A CN 201610392600 A CN201610392600 A CN 201610392600A CN 106083967 A CN106083967 A CN 106083967A
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galactoside
methanol
room temperature
reaction
norcantharidin derivative
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CN106083967B (en
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邓莉平
王玮
胡纯琦
许燕飞
张耀红
任小荣
左树峰
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Jewim Pharmaceutical Shandong Co ltd
Shandong Ruishun Pharmaceutical Co ltd
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University of Shaoxing
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00Processes for the preparation of sugar derivatives

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

The invention discloses a kind of containing galactoside structure triazole norcantharidin derivative and preparation method and application, this preparation method with 1,3 dipole-diople interaction methods C in norcantharidin structure5And C6Position introduces 1,2,3 triazoles, importing galactoside structure is reacted with triacetyl arabinose azide, thus synthesize containing galactoside structure triazole norcantharidin derivative, this compound has multiple biological activity, can be used for preparing antitumor drug.

Description

Containing galactoside structure triazole norcantharidin derivative and preparation method thereof With application
Technical field:
The invention belongs to pharmaceutical technology field, be specifically related to a kind of structure triazole demethylcantharidin Han galactoside Element derivant and preparation method and application.
Background technology:
Norcantharidin, chemical name: 7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic anhydride, CAS:[5442-12-6; 29745-04-8], chemical structural formula is as follows:
Cantharidin is the active ingredient of research malignant tumor medicine.Modern study proves, primary hepatocarcinoma is had necessarily by it Curative effect, and have leukocyte increasing, do not suppress the advantages such as immune system, therefore, there is the highest medicinal study and be worth, cause people Extensive concern.But the toxicity of cantharidin is relatively big, synthesizes the most complicated, recent studies have shown that, has lacked 2,3 in norcantharidin Two methyl of position, norcantharidin not only maintains stronger anti-tumor activity and unique function of increasing leukocyte, and Toxicity is substantially reduced, and substantially eliminates cantharidin and urinary system telson is swashed side effect.
Therefore, relevant with a cantharidin backbone modification synthetic work being significant is to remove prosposition methyl Replace.This structural change does not interferes with cantharidin active anticancer and toxicity decreases, and synthesis step simplifies.
Summary of the invention:
A first aspect of the present invention purpose is to provide a kind of derivative containing galactoside structure triazole norcantharidin Thing.
The technical scheme that the present invention takes is as follows:
A kind of structure triazole norcantharidin derivative Han galactoside, its structural formula is as follows:
This compound relevant experimental data is as follows:
Applicant is found by research: the oxygen in norcantharidin five-membered ring can replace with nitrogen or sulfur, some substituent groups Can be substituted on nitrogen and sulfur, simultaneously at C5And C6Upper replacement can also change pharmacologically active.Determined by further experiment: make With triacetyl arabinose azide, norcantharidin being carried out structure of modification, ingenious application 1,3 dipole-diople interaction method is drawn Entering 1,2,3-triazoles and galactoside structure, such that it is able to be effectively improved the activity of norcantharidin.
A second aspect of the present invention purpose is to provide a kind of above-mentioned containing galactoside structure triazole norcantharidin The preparation method of derivant, it is characterised in that comprise the following steps:
(1), dehydronorcantharidiimide element synthesis: maleic anhydride is finely ground, add ether, stir under room temperature condition to Dissolving, instill furan, be stirred at room temperature 24~48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare and go First dehydrogenation cantharidin (1);
(2), the synthesis of N-phenyl substituted dehydronorcantharidiimide imide: dehydronorcantharidiimide element is dissolved in acetone solvent In, under agitation drip the acetone soln of aniline, add manganese acetate, triethylamine and acetic anhydride after reacting 1 hour, at room temperature react 8 hours;Dried precipitation is dissolved in dimethylformamide, little with dicyclohexylcarbodiimide stirring reaction 10 in ice-water bath Time, filtrate is placed in frozen water and is crystallized, then be recrystallized to give product (3);
(3), galactoside triazole structure is imported: by N-phenyl substituted dehydronorcantharidiimide acyl under room temperature under nitrogen protection Imines and triacetyl arabinose azide (4) are mixed in methanol, carry out additive reaction, and after refluxing 2 hours, ice-water bath is cold But to 0 DEG C, the methanol solution of Feldalat NM under nitrogen protection, it is slowly added dropwise.After dropping, it is warmed to room temperature continuation reaction 3~4 little Time, TLC monitoring disappears to raw material point, by 732 superacicd styrene cation exchange resin regulation system to neutral, filters, uses first For several times, filtrate decompression obtains yellow solid, methanol recrystallization after column chromatography to alcohol washing ion exchange resin after removing methanol, vacuum is done Dry obtain target compound (5).
Further:
In step (1), the precipitation that reaction obtains needs filtration under diminished pressure;
In step (2), the precipitation that reaction obtains needs vacuum drying;Ice-water bath should cool the temperature to 0 DEG C;Recrystallization is applied Methanol.
In step (3), the synthetic method of triacetyl arabinose azide is as follows: add bromine in 50 milliliters of round-bottomed flasks For acetyl arabinose, Hydrazoic acid,sodium salt and dry DMF, nitrogen is protected.Stirred overnight at room temperature, system color is pale yellow by leucismus Color.Being stirred vigorously down, system poured in 200 milliliters of water, a large amount of solid, sucking filtration occur, cold water washes out and desalts and DMF, dry Dry, obtain triacetyl arabinose azide (4).
The reaction that the present invention relates to is as follows:
A third aspect of the present invention purpose is to provide a kind of aforementioned containing galactoside structure triazole norcantharidin Derivant application in terms of preparing antitumor drug.Pass through experimental verification: above-claimed cpd, for different tumor strain such as people's hepatocarcinoma Cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cell etc., be respectively provided with inhibitory action, wherein For HL-60 (leukaemia), there is more preferably suppression ratio and selectivity, can be manufactured separately antitumor drug, can also conduct Anti-tumor compositions prepared by active component and other antitumor drug, has extraordinary prospects for commercial application.
The principle of the present invention and having the beneficial effect that:
Applicant is found by research: 1,2,3-triazoles compounds itself has various activity, by 1,2,3-triazoles base Introduce some bioactive molecule and can be remarkably reinforced its property of medicine;We also import on the basis of introducing triazole on C-5 or C-6 specifically Containing galactoside structure, obtain containing galactoside structure triazole norcantharidin derivative.Above-claimed cpd pin To tumor strains such as human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cells, particularly For leukaemia, there is significant antiproliferative activity.
Below in conjunction with embodiment, the present invention is described further, but embodiment should not be construed as the model limiting the present invention Enclose.
Detailed description of the invention:
Embodiment 1:
(1), the synthesis of dehydronorcantharidiimide element:
15mL ether, 4.00g (40mmol) powder maleic anhydride it is sequentially added in 100mL conical flask.Etc. suitable After anhydride maleique dissolves, under stirring, add 2.76g (40.5mmol) furan.Ambient temperatare is put 24-48 hour the most again, will be anti- Should completely after the product that obtains carry out filtration under diminished pressure and obtain norcantharidin crystallization.
(2), the synthesis of N-phenyl substituted dehydronorcantharidiimide imide:
Take 3.32g (20mmol) norcantharidin to be dissolved in 30mL acetone, acetone soln and aniline are joined reaction In conical flask, it is seen that have substantial amounts of precipitation to generate.After reaction at normal temperatures 8 hours, precipitation is filtered out final vacuum and is dried, molten Solution, in 20mL dimethylformamide, is cooled to 0 DEG C.It is placed in ice-water bath, adds 3.09g (15mmol) dicyclohexyl carbon two sub- Amine, stirring reaction 10 hours.Then cool down, filter, filtrate is poured in 50mL frozen water, separate out solid.Filtered, washing, Finally obtain product (3) by recrystallizing methanol.
(3), galactoside triazole structure is imported: by N-substituted dehydronorcantharidiimide imide under room temperature under nitrogen protection Being mixed in methanol with triacetyl arabinose azide, carry out additive reaction, after refluxing 2 hours, ice-water bath is cooled to 0 DEG C, The methanol solution of Feldalat NM it is slowly added dropwise under nitrogen protection.After dropping, being warmed to room temperature continuation reaction 3~4 hours, TL C supervises Survey and disappear to raw material point, by 732 superacicd styrene cation exchange resin regulation system to neutral, filter, with methanol wash from For several times, filtrate decompression obtains yellow solid after removing methanol to sub-exchange resin, uses methanol recrystallization after column chromatography, and vacuum drying obtains Target compound (5).
Compound (5) title: containing galactoside structure triazole norcantharidin derivative
Molecular formula: C19H20N4O7
Physico-chemical parameter: yellow solid, m.p.141 142.5 DEG C
Structural confirmation:
1H NMR(DMSO‐d6): δ=7.51 7.19 (m, 5H, Ar H), 5.15 (d, J=9.60Hz, 1H, H5), 4.74 (d, J=17.60Hz, 1H, H4), 4.56 (d, J=17.60Hz, 1H, H1), 4.00 (d, J=9.60Hz, 1H, H6), 3.43 (d, J=7.20Hz, 1H, H3), 3.29 (d, J=7.20Hz, 1H, H2), 5.46 (d, J=8.80Hz, 1H, C1 ' H), 5.34 (m, J =8.80Hz, 1H, C2 ' OH), 5.08 (d, J=6.00Hz, 1H, C4 ' OH), 5.46 (d, J=4.50Hz, 1H, C3 ' OH), 4.06 (d, J=8.80Hz, 1H, C5 ' H), 3.78 (3H, m, C2 ' H, C3 ' H, C4 ' H), 3.56 (1H, m, C5 ' H);
IR (KBr) ν: 3478 (N C=O), 2,985 2942 (ArH), 1782,1742,1715 (C=O), 1612 (N=N), 1229 (C O C), 1212 (C N), 1161 (N N) cm‐1
Anal.calcd.for C19H20N4O7.C,54.81;H,4.84;N,13.46.
Application Example: the antitumor of the structure triazole norcantharidin derivative containing galactoside (compound 5) Determination of activity.
Compound (5) prepared by above-described embodiment, respectively with different tumor strains (tumor cell Bel-7402, KB, SGC7901, HO8901, HL-60, ECA109) it is experimental subject, test compound (5) is made for the vitro inhibition of different tumor strains With: experiment uses tetramethyl azo azoles salt trace enzyme reaction colorimetry (mtt assay), and activity half-inhibition concentration represents (IC50)。
Specific experiment step is as follows:
By compound 5 with DMSO dissolve, dilution, tumor cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity), SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia), ECA109 (colon-cancer cell) are in 96 holes Planting into 4000/200 μ L/ holes on plate, every hole adds compound 2 μ L, final concentration of 12.0 μMs, 6.0 μMs, 3.0 μMs, 1.5 μMs, is total to It is same as 37 DEG C, 5%CO2Cell culture incubator is hatched 72 hours, with DMSO (1%) as blank.After 72 hours, add the denseest Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 5%CO2In cell culture incubator 4 hours, blotting solvent afterwards, every hole adds 100 μ L DMSO, measures absorbance (OD value) with enzyme linked immunological instrument at 570nm, and the data obtained is used for calculating IC50Value.Measure different dense The compound effects time under Du is different on human tumor cells cycle and the impact of apoptosis.
The test-compound of variable concentrations carries out scalping with 96 orifice plates, according to the suppression ratio of gained, calculates IC50Value, result See table.
Table 1, the IC to six kinds of tumor cell lines of the structure triazole norcantharidin derivative containing galactoside50Value
By upper table data it can be seen that the compound prepared of the present invention, suppression is respectively provided with for six kinds of tumor cell lines Effect, wherein has prominent suppression ratio and selectivity for HL-60 (leukaemia), antineoplastic agent can be manufactured separately Thing, anti-tumor compositions can also be prepared, before there is extraordinary commercial Application as active component and other antitumor drug Scape.

Claims (6)

1. a structure triazole norcantharidin derivative Han galactoside, its structural formula is as follows:
2. the preparation method containing galactoside structure triazole norcantharidin derivative, it is characterised in that include Following steps:
(1), the synthesis of dehydronorcantharidiimide element: maleic anhydride is finely ground, and addition ether, under room temperature condition, stirring is to the most molten Solving, instill furan, be stirred at room temperature 24 ~ 48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare nor- Dehydrogenation cantharidin;
(2), the synthesis of N-phenyl substituted dehydronorcantharidiimide imide: dehydronorcantharidiimide element is dissolved in acetone solvent, The lower acetone soln dripping aniline of stirring, adds manganese acetate, triethylamine and acetic anhydride after reacting 1 hour, at room temperature reaction 8 is little Time;Dried precipitation is dissolved in dimethylformamide, with dicyclohexylcarbodiimide stirring reaction 10 hours in ice-water bath, Filtrate is placed in frozen water and is crystallized, then be recrystallized to give product;
(3), galactoside triazole structure is imported: by N-phenyl substituted dehydronorcantharidiimide imide under room temperature under nitrogen protection Being mixed in methanol with triacetyl arabinose azide, carry out additive reaction, after refluxing 2 hours, ice-water bath is cooled to 0 DEG C, The methanol solution of Feldalat NM it is slowly added dropwise under nitrogen protection;After dropping, it is warmed to room temperature continuation reaction 3 ~ 4 hours, TLC Monitor and disappear to raw material point, by cation exchange resin regulation system to neutral, filter, wash ion exchange resin number with methanol Secondary, filtrate decompression obtains yellow solid, methanol recrystallization after column chromatography after removing methanol, vacuum drying obtains target compound.
A kind of preparation side containing galactoside structure triazole norcantharidin derivative the most according to claim 2 Method, it is characterised in that: in step (1), the precipitation that reaction obtains needs filtration under diminished pressure.
A kind of preparation side containing galactoside structure triazole norcantharidin derivative the most according to claim 2 Method, it is characterised in that: in step (2), the precipitation that reaction obtains needs vacuum drying;Ice-water bath should cool the temperature to 0 DEG C;Heavily tie Brilliant application methanol.
A kind of preparation side containing galactoside structure triazole norcantharidin derivative the most according to claim 2 Method, it is characterised in that: in step (3), the synthetic method of triacetyl arabinose azide is as follows: in 50 milliliters of round-bottomed flasks Adding bromoacetyl arabinose, Hydrazoic acid,sodium salt and dry DMF, nitrogen is protected;Stirred overnight at room temperature, system color is by leucismus Light yellow;Be stirred vigorously down, system poured in 200 milliliters of water, a large amount of solid, sucking filtration occur, cold water wash out desalt and DMF, is dried, obtains triacetyl arabinose azide.
6. a structure triazole norcantharidin derivative Han the galactoside application in terms of preparing antitumor drug.
CN201610392600.6A 2016-06-06 2016-06-06 Triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof Active CN106083967B (en)

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