CN106083967B - Triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof - Google Patents
Triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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Abstract
The invention discloses a kind of triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof, preparation method C in Norcantharidin structure with 1,3- dipole-diople interactions method5And C6Position introduces 1,2,3- triazoles, it is reacted with triacetyl arabinose azide and imports Arabinoside structure, to synthesize the triazole norcantharidin derivative of structure containing Arabinoside, which has multiple biological activities, can be used for preparing antitumor drug.
Description
Technical field：
The invention belongs to pharmaceutical technology fields, are specifically related to a kind of triazole demethylcantharidin of structure containing Arabinoside
Plain derivative and the preparation method and application thereof.
Background technology：
Norcantharidin, chemical name：7- Yang Zaerhuans [2.2.1]Heptane -2,3- dicarboxylic anhydride, CAS:[5442-12-6；
29745-04-8], chemical structural formula is as follows：
Cantharidin is the effective ingredient for studying malignant tumor medicine.Modern study proves that having centainly to primary carcinoma of liver
Curative effect, and the advantages that have increasing leukocyte, do not inhibit immune system, therefore, there is very high medicinal study to be worth, cause people
Extensive concern.But cantharidin is more toxic, and synthesis is very complicated, recent studies have shown that, 2,3 have been lacked in Norcantharidin
Two methyl of position, Norcantharidin not only maintain stronger antitumor activity and unique function of increasing leukocyte, but also
Toxicity substantially reduces, and substantially eliminates cantharidin and swashs side effect to urinary system telson.
Therefore, a synthetic work being of great significance related with cantharidin backbone modification is to remove 2,3 methyl
Substitution.The change of this structure does not interfere with cantharidin active anticancer and toxicity decreases, and synthesis step simplifies.
Invention content：
The first aspect of the present invention purpose is to provide a kind of triazole Norcantharidin of structure containing Arabinoside derivative
Object.
The technical solution adopted by the present invention is as follows：
A kind of triazole norcantharidin derivative of structure containing Arabinoside, structural formula are as follows：
The compound relevant experimental data is as follows：
Applicant is had found by studying：Oxygen in Norcantharidin five-membered ring can with nitrogen or it is thio replace, some substituent groups
It can be substituted on nitrogen and sulphur, while in C5And C6Upper substitution can also change pharmacological activity.It is determined by further experiment：Make
Structure of modification is carried out to Norcantharidin with triacetyl arabinose azide, it is ingenious that 1,3- dipole-diople interaction methods is applied to draw
Enter 1,2,3- triazoles and Arabinoside structure, so as to effectively improve the activity of Norcantharidin.
The second aspect of the present invention purpose is to provide a kind of above-mentioned triazole of structure containing Arabinoside Norcantharidin
The preparation method of derivative, which is characterized in that include the following steps：
(1), the synthesis of dehydronorcantharidiimide element：Maleic anhydride is finely ground, be added ether, stir under room temperature to
Dissolving instills furans, is stirred at room temperature 24~48 hours, and furans occurs Diels-Alder with maleic anhydride and reacts, and is made and goes
First dehydrogenation cantharidin (1)；
(2), the synthesis of N- phenyl substituted dehydronorcantharidiimide imide：Dehydronorcantharidiimide element is dissolved in acetone solvent
In, the acetone soln of aniline is added dropwise under stiring, reaction is added manganese acetate, triethylamine and aceticanhydride after 1 hour, reacts at room temperature
8 hours；Precipitation after drying is dissolved in dimethylformamide, it is small with dicyclohexylcarbodiimide to be stirred to react 10 in ice-water bath
When, filtrate is placed in ice water and is crystallized, then is recrystallized to give product (3)；
(3), Arabinoside triazole structure is imported：By N- phenyl substituted dehydronorcantharidiimide acyls under room temperature under nitrogen protection
Imines and triacetyl arabinose azide (4) are mixed in methanol, carry out addition reaction, ice-water bath is cold after reflux 2 hours
But the methanol solution of sodium methoxide is slowly added dropwise to 0 DEG C, under nitrogen protection.After being added dropwise, it is 3~4 small to be warmed to room temperature that the reaction was continued
When, TLC, which is monitored to raw material point, to disappear, and with 732 superacicd styrene cation exchange resin regulation systems to neutrality, first is used in filtering
Alcohol washs ion exchange resin for several times, and filtrate decompression obtains yellow solid after removing methanol, and methanol recrystallizes after column chromatography, and vacuum is dry
It is dry to obtain target compound (5).
Further：
In step (1), precipitation obtained by the reaction need to be filtered under diminished pressure；
In step (2), precipitation obtained by the reaction needs to be dried in vacuo；Ice-water bath should cool the temperature to 0 DEG C；Recrystallization application
Methanol.
In step (3), the synthetic method of triacetyl arabinose azide is as follows：Bromine is added in 50 milliliters of round-bottomed flasks
For acetyl arabinose, sodium azide and anhydrous DMF, nitrogen protection.It is stirred overnight at room temperature, system color is pale yellow by leucismus
Color.It is vigorously stirred down, system is poured into 200 milliliters of water, a large amount of solids occur, filter, cold water, which washes out, to desalt and DMF, does
It is dry, obtain triacetyl arabinose azide (4).
Reaction of the present invention is as follows：
The third aspect of the present invention purpose is to provide a kind of aforementioned triazole of structure containing Arabinoside Norcantharidin
Application of the derivative in terms of preparing antitumor drug.Pass through experimental verification：Above compound, for different tumor strain such as human liver cancers
Cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell etc., all have inhibiting effect, wherein
There is more preferably inhibiting rate and selectivity for HL-60 (leukaemia cell), antitumor drug can be prepared separately, can also be used as
Active constituent prepares anti-tumor compositions with other antitumor drugs, has extraordinary prospects for commercial application.
It the principle of the present invention and has the beneficial effect that：
Applicant is had found by studying：The more various activity of tool of 1,2,3-triazoles class compound itself, by 1,2,3-triazoles base
Its pharmacological property can be remarkably reinforced by introducing certain bioactive molecules；Specifically we also import on the basis of introducing triazole on C-5 or C-6
Structure containing Arabinoside, obtains the triazole norcantharidin derivative of structure containing Arabinoside.Above compound needle
To the tumors strain such as human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell, especially
For leukaemia cell, there is significant antiproliferative activity.
The present invention is described further with reference to embodiments, but embodiment should not be construed as limiting the model of the present invention
It encloses.
Specific implementation mode：
Embodiment 1：
(1), the synthesis of dehydronorcantharidiimide element：
15mL ether, 4.00g (40mmol) powdered maleic anhydride are sequentially added in 100mL conical flasks.Etc. suitable
After anhydride maleique dissolving, it is added with stirring 2.76g (40.5mmol) furans.Then it places 24-48 hours at room temperature again, it will be anti-
The product obtained after answering completely is filtered under diminished pressure to obtain Norcantharidin crystallization.
(2), the synthesis of N- phenyl substituted dehydronorcantharidiimide imide：
It takes 3.32g (20mmol) Norcantharidin to be dissolved in 30mL acetone, acetone soln and aniline is added to reaction
In conical flask, it is seen that there is a large amount of precipitation to generate.After reacting 8 hours at normal temperatures, it is dried in vacuo after precipitation is filtered out, it is molten
Solution is cooled to 0 DEG C in 20mL dimethylformamides.It is placed in ice-water bath, it is sub- that 3.09g (15mmol) dicyclohexyls carbon two is added
Amine is stirred to react 10 hours.Then it cools down, filters, filtrate is poured in 50mL ice water, solid is precipitated.It is filtered, is washed,
Finally product (3) is obtained with recrystallizing methanol.
(3), Arabinoside triazole structure is imported：By N- substituted dehydronorcantharidiimide imides under room temperature under nitrogen protection
It being mixed in methanol with triacetyl arabinose azide, carries out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours,
The methanol solution of sodium methoxide is slowly added dropwise under nitrogen protection.After being added dropwise, it is warmed to room temperature that the reaction was continued 3~4 hours, TLC prisons
Survey to raw material point and disappear, with 732 superacicd styrene cation exchange resin regulation systems to neutrality, filtering, with methanol wash from
For several times, filtrate decompression obtains yellow solid to sub-exchange resin after removing methanol, is recrystallized with methanol after column chromatography, vacuum drying obtains
Target compound (5).
Compound (5) title：The triazole norcantharidin derivative of structure containing Arabinoside
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 triazole norcantharidin derivative of structure containing Arabinoside (compound 5) it is antitumor
Determination of activity.
By above-described embodiment prepare compound (5), respectively with different tumor strains (tumour cell Bel-7402, KB,
SGC7901, HO8901, HL-60, ECA109) it is experimental subjects, test compound (5) makees the external inhibition of different tumor strains
With：Experiment uses the micro enzyme reaction colorimetric method (mtt assay) of tetramethyl azo azoles salt, activity to indicate (IC with half-inhibition concentration50)。
Steps are as follows for specific experiment：
Compound 5 is dissolved with DMSO, dilute, tumour cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity),
SGC7901 (stomach cancer cell), H08901 (ovarian cancer cell), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) are in 96 holes
It is planted on plate into 4000/200 holes μ L/, 2 μ L of often hole addition compound, 6.0 μM, 3.0 μM, 1.5 μM, are total to by final concentration of 12.0 μM
It is same as 37 DEG C, 5%CO2It is incubated 72 hours in cell incubator, with DMSO (1%) for blank control.After 72 hours, it is added dense eventually
Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 5%CO24 hours in cell incubator, solvent is blotted later, and 100 μ are added per hole
L DMSO measure absorbance (OD values) with enzyme linked immunological instrument at 570nm, and the data obtained is for calculating IC50Value.It measures different dense
Influence of the compound effects time difference to human tumor cells period and apoptosis under degree.
The test-compound of various concentration carries out scalping with 96 orifice plates, according to the inhibiting rate of gained, calculates IC50Value, as a result
It see the table below.
The IC of table 1, the triazole six kinds of tumor cell lines of norcantharidin derivative pair of structure containing Arabinoside50Value
It can be seen that by upper table data：Compound prepared by the present invention all has inhibition for six kinds of tumor cell lines
Antineoplastic can be prepared separately wherein having inhibiting rate outstanding and selectivity for HL-60 (leukaemia cell) in effect
Object can also be used as active constituent and other antitumor drugs prepare anti-tumor compositions, have extraordinary prospects for commercial application.
Claims (5)
1. a kind of triazole norcantharidin derivative of structure containing Arabinoside, structural formula are as follows：
。
2. a kind of preparation side of the triazole of structure containing Arabinoside norcantharidin derivative as described in claim 1
Method, which is characterized in that include the following steps：
（1）, dehydronorcantharidiimide element synthesis：Maleic anhydride is finely ground, ether is added, is stirred under room temperature to molten
Solution instills furans, is stirred at room temperature 24 ~ 48 hours, and furans occurs Diels-Alder with maleic anhydride and reacts, and is made and goes first
Dehydrogenation cantharidin；
（2）, N- phenyl substituted dehydronorcantharidiimide imides synthesis：Dehydronorcantharidiimide element is dissolved in acetone solvent,
The lower acetone soln that aniline is added dropwise of stirring, reaction are added manganese acetate, triethylamine and aceticanhydride after 1 hour, it is small to react 8 at room temperature
When；Precipitation after drying is dissolved in dimethylformamide, is stirred to react with dicyclohexylcarbodiimide 10 hours in ice-water bath,
Filtrate is placed in ice water and is crystallized, then is recrystallized to give product；
（3）, import Arabinoside triazole structure：By N- phenyl substituted dehydronorcantharidiimide imides under room temperature under nitrogen protection
It being mixed in methanol with triacetyl arabinose azide, carries out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours,
The methanol solution of sodium methoxide is slowly added dropwise under nitrogen protection；After being added dropwise, it is warmed to room temperature that the reaction was continued 3 ~ 4 hours, TLC
Monitoring to raw material point disappears, and with cation exchange resin regulation system to neutrality, filtering washs ion exchange resin number with methanol
Secondary, filtrate decompression obtains yellow solid after removing methanol, and methanol recrystallizes after column chromatography, and vacuum drying obtains target compound.
3. a kind of preparation side of the triazole of structure containing Arabinoside norcantharidin derivative according to claim 2
Method, it is characterised in that：Step（1）In, dehydronorcantharidiimide element obtained by the reaction need to be filtered under diminished pressure.
4. a kind of preparation side of the triazole of structure containing Arabinoside norcantharidin derivative according to claim 2
Method, it is characterised in that：Step（3）In, the synthetic method of triacetyl arabinose azide is as follows：In 50 milliliters of round-bottomed flasks
Bromoacetyl arabinose, sodium azide and anhydrous DMF, nitrogen protection is added；It is stirred overnight at room temperature, system color is by leucismus
It is light yellow；Be vigorously stirred down, system poured into 200 milliliters of water, a large amount of solids occur, filter, cold water washing except desalting and
DMF, it is dry, obtain triacetyl arabinose azide.
5. a kind of triazole norcantharidin derivative of structure containing Arabinoside as described in claim 1 is preparing anti-swell
Application in terms of tumor medicine.
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