CN105924486B - Triazole norcantharidin derivative of structure containing maltoside and the preparation method and application thereof - Google Patents
Triazole norcantharidin derivative of structure containing maltoside and the preparation method and application thereof Download PDFInfo
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- CN105924486B CN105924486B CN201610395205.3A CN201610395205A CN105924486B CN 105924486 B CN105924486 B CN 105924486B CN 201610395205 A CN201610395205 A CN 201610395205A CN 105924486 B CN105924486 B CN 105924486B
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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
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
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Abstract
The invention discloses a kind of triazole norcantharidin derivative of structure containing maltoside 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 the full acetyl group maltose of 1- nitrine-and imports maltoside structure, to synthesize structure containing maltoside 1,2; 3- triazole norcantharidin derivatives, the compound have 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 Norcantharidin of structure containing maltoside
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 derivative of structure containing maltoside.
The technical solution adopted by the present invention is as follows：
A kind of triazole norcantharidin derivative of structure containing maltoside, structural formula are as follows：
In formula：
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 1- nitrine-full acetyl group maltose, it is ingenious that 1,3- dipole-diople interaction methods is applied to draw
Enter 1,2,3- triazoles and maltoside structure, so as to effectively improve the activity of Norcantharidin.
The second aspect of the present invention purpose is to provide the above-mentioned triazole of structure containing the maltoside Norcantharidin of one kind and spreads out
The preparation method of biology, which is characterized in that include the following steps：
(1), the synthesis of dehydronorcantharidiimide element：
Maleic anhydride is finely ground, ether is added, stirring under room temperature instills furans, be stirred at room temperature 24 to dissolving
~48 hours, furans occurred Diels-Alder with maleic anhydride and reacts, and it is plain (1) that dehydronorcantharidiimide is made；
(2), the synthesis of N- phenyl substituted dehydronorcantharidiimide imide：
Dehydronorcantharidiimide element is dissolved in acetone solvent, the acetone soln of aniline is added dropwise under stiring, after reacting 1 hour
Manganese acetate, triethylamine and aceticanhydride is added, reacts 8 hours at room temperature；Precipitation after drying is dissolved in dimethylformamide, ice
It is stirred to react with dicyclohexylcarbodiimide 10 hours in water-bath, filtrate is placed in ice 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 the full acetyl group malt of 1- nitrine-under room temperature under nitrogen protection
Sugared (4) are mixed in methanol, carry out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours, is slowly added dropwise under nitrogen protection
The methanol solution of sodium methoxide；After being added dropwise, it is warmed to room temperature that the reaction was continued 10~12 hours, TLC, which is monitored to raw material point, to disappear, and uses
732 superacicd styrene cation exchange resin regulation systems to neutrality, filtering washs ion exchange resin for several times with methanol, filters
Liquid obtains yellow solid after methanol is removed under reduced pressure, and methanol recrystallizes after column chromatography, and vacuum drying obtains target compound and contains maltose
Glycosides structure triazole norcantharidin derivative (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 (2), the synthetic method of the full acetyl group maltose of 1- nitrine-is as follows：Bromine is added in 50 milliliters of round-bottomed flasks
For acetyl maltose, sodium azide and anhydrous DMF, nitrogen protection.It is stirred overnight at room temperature, system color is light yellow by leucismus.
It being 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, dry,
Obtain the full acetyl group maltose (4) of 1- nitrine-.
Reaction of the present invention is as follows：
The third aspect of the present invention purpose is to provide the aforementioned triazole of structure containing the maltoside Norcantharidin of one kind and spreads out
Application of the biology in terms of preparing antitumor drug.Pass through experimental verification：Above compound, it is thin for different tumor strain such as human liver cancers
Born of the same parents, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell etc., all have inhibiting effect, wherein right
There is more preferably inhibiting rate and selectivity in HL-60 (leukaemia cell), antitumor drug can be prepared separately, can also be used as work
Property ingredient and other antitumor drugs prepare anti-tumor compositions, there is 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 maltoside, obtains the triazole norcantharidin derivative of structure containing maltoside；Above compound is directed to people
The tumors strain such as liver cancer cells, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell, especially for
Leukaemia cell has 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), maltoside triazole structure is imported：
By N- phenyl substituted dehydronorcantharidiimide imide (3) and the full acetyl group malt of 1- nitrine-under room temperature under nitrogen protection
Sugared (4) are mixed in methanol, carry out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours, is slowly added dropwise under nitrogen protection
The methanol solution of sodium methoxide.After being added dropwise, it is warmed to room temperature that the reaction was continued 10~12 hours, TLC, which is monitored to raw material point, to disappear, and uses
732 superacicd styrene cation exchange resin regulation systems to neutrality, filtering washs ion exchange resin for several times with methanol, filters
Liquid obtains yellow gummy solid after methanol is removed under reduced pressure, and is recrystallized with methanol after column chromatography, vacuum drying obtains target compound
(5)。
Compound (5) title：The triazole norcantharidin derivative of structure containing maltoside
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)v：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 work of the triazole norcantharidin derivative of structure containing maltoside (compound 5)
Property measure.
By above-described embodiment prepare compound (5), respectively with different tumor strains (tumour cell Bel-7402, KB,
SGC7901, H08901, 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), HO8901 (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 maltoside50Value
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, before having extraordinary commercial Application
Scape.
Claims (5)
1. a kind of triazole norcantharidin derivative of structure containing maltoside, structural formula are as follows：
In formula：
。
2. a kind of preparation method of the triazole of structure containing maltoside norcantharidin derivative as described in claim 1,
It is characterized by comprising the following steps：
（1）, dehydronorcantharidiimide element synthesis：
Maleic anhydride is finely ground, ether is added, stirring under room temperature instills furans, it is small to be stirred at room temperature 24 ~ 48 to dissolving
When, furans occurs Diels-Alder with maleic anhydride and reacts, and dehydronorcantharidiimide element is made；
（2）, N- phenyl substituted dehydronorcantharidiimide imides synthesis：
Dehydronorcantharidiimide element is dissolved in acetone solvent, the acetone soln of aniline is added dropwise under stiring, reaction is added after 1 hour
Manganese acetate, triethylamine and aceticanhydride react 8 hours at room temperature；Precipitation after drying is dissolved in dimethylformamide, ice-water bath
In be stirred to react 10 hours with dicyclohexylcarbodiimide, filtrate is placed in ice water and is crystallized, then is recrystallized to give product；
（3）, import maltoside triazole structure：
N- phenyl substituted dehydronorcantharidiimide imide and the full acetyl group maltose of 1- nitrine-are mixed under room temperature under nitrogen protection
In methanol, addition reaction is carried out, ice-water bath is cooled to 0 DEG C after reflux 2 hours, and the methanol of sodium methoxide is slowly added dropwise under nitrogen protection
Solution；After being added dropwise, it is warmed to room temperature that the reaction was continued 10 ~ 12 hours, TLC, which is monitored to raw material point, to disappear, with 732 strong acid benzene
Ethylene cation exchange resin regulation system to neutrality, filtering washs ion exchange resin for several times with methanol, and filtrate decompression removes
Yellow solid is obtained after methanol, methanol recrystallizes after column chromatography, and vacuum drying obtains three nitrogen of target compound structure containing maltoside
Azole norcantharidin derivative.
3. a kind of preparation side of the triazole of structure containing maltoside 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 maltoside norcantharidin derivative according to claim 2
Method, it is characterised in that：Step（3）In, the synthetic method of the full acetyl group maltose of 1- nitrine-is as follows：In 50 milliliters of round-bottomed flasks
Bromoacetyl maltose, sodium azide and anhydrous DMF, nitrogen protection is added；It is stirred overnight at room temperature, system color is shallow by leucismus
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 the full acetyl group maltose of 1- nitrine-.
5. a kind of triazole norcantharidin derivative of structure containing maltoside described in claim 1 is preparing antineoplastic
The application in object space face.
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| 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 |
| 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 |
| 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 |
| 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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