CN105924486A - Maltoside structure-containing triazole demethylcantharidin derivative and preparation method and application thereof - Google Patents

Maltoside structure-containing triazole demethylcantharidin derivative and preparation method and application thereof Download PDF

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Publication number
CN105924486A
CN105924486A CN201610395205.3A CN201610395205A CN105924486A CN 105924486 A CN105924486 A CN 105924486A CN 201610395205 A CN201610395205 A CN 201610395205A CN 105924486 A CN105924486 A CN 105924486A
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maltoside
methanol
room temperature
derivative
triazole
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CN105924486B (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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Shenyang Sunshine Pharmaceutical Co ltd
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University of Shaoxing
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a maltoside structure-containing triazole demethylcantharidin derivative and a preparation method and application thereof. The preparation method comprises the following steps: introducing 1, 2, 3-triazole into C5 and C6 positions of a demethylcantharidin structure by a 1, 3-dipolar cycloaddition method, and reacting with 1-azide-acetyl maltose to introduce a maltoside structure so as to synthesize the maltoside structure-containing 1, 2, 3-triazole demethylcantharidin derivative. The maltoside structure-containing triazole demethylcantharidin derivative has a variety of biological activities and can be applied to preparation of antitumor medicines.

Description

Containing maltoside 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 norcantharidin Han maltoside 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 structure triazole norcantharidin derivative Han maltoside.
The technical scheme that the present invention takes is as follows:
A kind of structure triazole norcantharidin derivative Han maltoside, its structural formula is as follows:
In formula:
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 1 nitrine full acetyl group maltose, norcantharidin being carried out structure of modification, ingenious application 1,3 dipole-diople interaction method is drawn Entering 1,2,3-triazoles and maltoside 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 structure triazole norcantharidin containing maltoside and spreads out Biological preparation method, it is characterised in that comprise the following steps:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24 ～48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare dehydronorcantharidiimide element (1)；
(2), the synthesis of N-phenyl substituted dehydronorcantharidiimide imide:
Dehydronorcantharidiimide element is dissolved in acetone solvent, under agitation drips the acetone soln of aniline, after reacting 1 hour Add manganese acetate, triethylamine and acetic anhydride, at room temperature reaction 8 hours；Dried precipitation is dissolved in dimethylformamide, ice With dicyclohexylcarbodiimide stirring reaction 10 hours in water-bath, filtrate is placed in frozen water and is crystallized, then be recrystallized to give Product (3)；
(3), maltoside triazole structure is imported:
By N-phenyl substituted dehydronorcantharidiimide imide (3) and 1 nitrine full acetyl group Fructus Hordei Germinatus under room temperature under nitrogen protection Sugar (4) is mixed in methanol, carries out additive reaction, and after refluxing 2 hours, ice-water bath is cooled to 0 DEG C, is slowly added dropwise under nitrogen protection The methanol solution of Feldalat NM；After dropping, being warmed to room temperature continuation reaction 10～12 hours, TLC monitoring disappears to raw material point, uses 732 superacicd styrene cation exchange resin regulation system, to neutral, filter, with methanol washing ion exchange resin for several times, and filter Liquid decompression obtains yellow solid, methanol recrystallization after column chromatography after removing methanol, vacuum drying obtains target compound containing maltose Glycosides structure triazole norcantharidin derivative (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 (2), the synthetic method of 1 nitrine full acetyl group maltose is as follows: add bromine in 50 milliliters of round-bottomed flasks For acetyl maltose, Hydrazoic acid,sodium salt and dry DMF, nitrogen is protected.Stirred overnight at room temperature, system color is light yellow by leucismus. 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, is dried, Obtain 1 nitrine full acetyl group maltose (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 structure triazole norcantharidin containing maltoside and spreads out Biological application in terms of preparing antitumor drug.Pass through experimental verification: above-claimed cpd, thin for different tumor strain such as people's hepatocarcinoma Born of the same parents, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cell etc., be respectively provided with inhibitory action, the most right In HL-60 (leukaemia), there is more preferably suppression ratio and selectivity, can be manufactured separately antitumor drug, can also be as work Property composition and other antitumor drug prepare anti-tumor compositions, there is 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 maltoside structure, obtain containing maltoside structure triazole norcantharidin derivative；Above-claimed cpd is for people The tumor strains such as hepatoma carcinoma cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cell, especially for Leukaemia, has 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), maltoside triazole structure is imported:
By N-phenyl substituted dehydronorcantharidiimide imide (3) and 1 nitrine full acetyl group Fructus Hordei Germinatus under room temperature under nitrogen protection Sugar (4) is mixed in methanol, carries out additive reaction, and after refluxing 2 hours, ice-water bath is cooled to 0 DEG C, is slowly added dropwise under nitrogen protection The methanol solution of Feldalat NM.After dropping, being warmed to room temperature continuation reaction 10～12 hours, TLC monitoring disappears to raw material point, uses 732 superacicd styrene cation exchange resin regulation system, to neutral, filter, with methanol washing ion exchange resin for several times, and filter Liquid decompression obtains yellow gummy solid after removing methanol, uses methanol recrystallization, vacuum drying to obtain target compound after column chromatography (5)。
Compound (5) title: containing maltoside structure triazole norcantharidin derivative
Molecular formula: C26H32N4O13
Physico-chemical parameter: yellow solid, m.p.213 215 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), 5.62 4.54,3.62 3.06 (m, 21H, 14 × Maltosyl‐H,7×OH)；
IR (KBr) ν: 3478 (N C=O), 2,985 2942 (ArH), 1782,1742,1715 (C=O), 1614 (N=N), 1229 (C O C), 1212 (C N), 1161 (N N) cm‐1；
Anal.calcd.for C26H32N4O13.C,51.32；H,5.30；N,9.24.
Application Example: the antitumor of the structure triazole norcantharidin derivative containing maltoside (compound 5) is lived Property measure.
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 maltoside50Value
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 maltoside, its structural formula is as follows:
In formula:
。
2. the preparation method containing maltoside structure triazole norcantharidin derivative, it is characterised in that include with Lower step:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24 ~ 48 little Time, furan and maleic anhydride occur Diels-Alder to react, prepare dehydronorcantharidiimide element；
(2), the synthesis of N-phenyl substituted dehydronorcantharidiimide imide:
Dehydronorcantharidiimide element is dissolved in acetone solvent, under agitation drips the acetone soln of aniline, add after reacting 1 hour Manganese acetate, triethylamine and acetic anhydride, at room temperature reaction 8 hours；Dried precipitation is dissolved in dimethylformamide, ice-water bath In with dicyclohexylcarbodiimide stirring reaction 10 hours, filtrate is placed in frozen water and is crystallized, then be recrystallized to give product；
(3), maltoside triazole structure is imported:
Under room temperature under nitrogen protection, N-phenyl substituted dehydronorcantharidiimide imide and 1-nitrine-full acetyl group maltose are mixed in In methanol, carrying out additive reaction, after refluxing 2 hours, ice-water bath is cooled to 0 DEG C, is slowly added dropwise the methanol of Feldalat NM under nitrogen protection Solution；After dropping, being warmed to room temperature continuation reaction 10 ~ 12 hours, TLC monitoring disappears to raw material point, with 732 strong acid benzene Ethylene cation exchange resin regulation system, to neutral, filters, and with methanol washing ion exchange resin for several times, filtrate decompression removes Obtaining yellow solid, methanol recrystallization after column chromatography after methanol, vacuum drying obtains target compound nitrogen on maltoside structure three Azole norcantharidin derivative.
A kind of preparation side containing maltoside 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 maltoside 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 maltoside structure triazole norcantharidin derivative the most according to claim 2 Method, it is characterised in that: in step (3), the synthetic method of 1-nitrine-full acetyl group maltose is as follows: in 50 milliliters of round-bottomed flasks Adding bromoacetyl maltose, Hydrazoic acid,sodium salt and dry DMF, nitrogen is protected；Stirred overnight at room temperature, system color is shallow by leucismus Yellow；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, It is dried, obtains 1-nitrine-full acetyl group maltose.
6. a structure triazole norcantharidin derivative Han the maltoside application in terms of preparing antitumor drug.
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CN108558968A (en) * 2018-04-23 2018-09-21 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing glucose and the preparation method and application thereof
CN108570085A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing xylose and the preparation method and application thereof
CN108570086A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing arabinose and the preparation method and application thereof
CN108570087A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing galactolipin and the preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN108558968A (en) * 2018-04-23 2018-09-21 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing glucose and the preparation method and application thereof
CN108570085A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing xylose and the preparation method and application thereof
CN108570086A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing arabinose and the preparation method and application thereof
CN108570087A (en) * 2018-04-23 2018-09-25 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing galactolipin and the preparation method and application thereof
CN108558968B (en) * 2018-04-23 2019-08-16 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing glucose and the preparation method and application thereof
CN108570087B (en) * 2018-04-23 2019-08-16 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing galactolipin and the preparation method and application thereof
CN108570085B (en) * 2018-04-23 2019-08-20 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing xylose and the preparation method and application thereof
CN108570086B (en) * 2018-04-23 2019-08-20 绍兴文理学院元培学院 Maleimide derivatives of the triazole structure containing arabinose and the preparation method and application thereof

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