CN106008634B - Fluorine replaces triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof - Google Patents
Fluorine replaces triazole norcantharidin derivative of structure containing Arabinoside and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of fluorine to replace 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 arabinose structure 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, and in particular to a kind of fluorine substitution triazole of structure containing Arabinoside goes first
Cantharidin 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 fluorine substitution triazole demethylcantharidin of structure containing Arabinoside
Plain derivative.
The technical solution adopted by the present invention is as follows：
A kind of fluorine substitution 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 demethylcantharidin acid imide with the substitution of triacetyl arabinose azide fluorine, it is ingenious to apply 1,3- dipole-rings
Addition method introduces 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 fluorine substitution triazole of structure containing Arabinoside and goes first
The preparation method of cantharidin derivative, 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 (compound 1) that dehydronorcantharidiimide is made；
(2), the synthesis of N- p-fluorophenyls substituted dehydronorcantharidiimide imide：
Dehydronorcantharidiimide element is dissolved in acetone solvent, the acetone that para-fluoroaniline (compound 2) is added dropwise under stiring is molten
Liquid, reaction are added manganese acetate, triethylamine and aceticanhydride after 1 hour, react 8 hours at room temperature；Precipitation after drying is dissolved in two
In methylformamide, it is stirred to react with dicyclohexylcarbodiimide 10 hours in ice-water bath, filtrate is placed in ice water and is tied
Crystalline substance, then it is recrystallized to give product N- p-fluorophenyls substituted dehydronorcantharidiimide imide (compound 3)；
(3), Arabinoside triazole structure is imported：
Under room temperature under nitrogen protection by N- p-fluorophenyls substituted dehydronorcantharidiimide imide (compound 3) and triacetyl I
The sugared azide (compound 4) of uncle is mixed in methanol, carries out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours, nitrogen
The methanol solution of sodium methoxide is slowly added dropwise under gas shielded.After being added dropwise, it is warmed to room temperature that the reaction was continued 3~4 hours, TLC monitorings
It disappears to raw material point, with cation exchange resin regulation system to neutrality, filtering washs ion exchange resin for several times with methanol,
Filtrate decompression obtains yellow solid after removing methanol, and methanol recrystallizes after column chromatography, and vacuum drying obtains the substitution of target product fluorine and contains
Arabinoside structure triazole norcantharidin derivative (compound 5).
Reaction of the present invention is as follows：
Further：
The synthetic method of the triacetyl arabinose azide is as follows：
Bromoacetyl arabinose, sodium azide and anhydrous DMF, nitrogen protection are added in 50 milliliters of round-bottomed flasks.Room
Temperature is stirred overnight, and system color is light yellow by leucismus.It is vigorously stirred down, system is poured into 200 milliliters of water, occur a large amount of solid
Body filters, and cold water, which washes out, to desalt and DMF, dry, obtains triacetyl arabinose azide (compound 4)；
In the step (1), precipitation obtained by the reaction need to be filtered under diminished pressure；
In the step (2), precipitation obtained by the reaction needs to be dried in vacuo；Ice-water bath should cool the temperature to 0 DEG C；It ties again
Crystalline substance uses methanol.
In the step (3), cation exchange resin is 732 superacicd styrene cation exchange resins.
The third aspect of the present invention purpose is to provide a kind of aforementioned fluorine substitution triazole of structure containing Arabinoside and goes first
Application of the cantharidin derivative in terms of preparing antitumor drug.Pass through experimental verification：Above compound, such as different tumor strains
Human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell etc. all have inhibition and make
With, wherein there is more preferably inhibiting rate and selectivity for HL-60 (leukaemia cell), can be prepared separately antitumor drug,
Active constituent can be used as to prepare anti-tumor compositions with other antitumor drugs, 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；Further experimental study confirms：The introducing of fluorine atom can assign
The unique and beneficial physiochemical properties of machine molecule, to change its pharmacological property, current we introduce on C-5 or C-6
Structure containing Arabinoside has also been imported on the basis of triazole, is obtained the fluorine substitution triazole of structure containing Arabinoside and is gone first
Cantharidin derivative, after testing, above compound for human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell,
The tumors strain such as leukaemia cell, colon-cancer cell has significant antiproliferative activity especially for leukaemia cell.
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 dehydronorcantharidiimide element crystallization (1).
(2), the synthesis of N- p-fluorophenyls substituted dehydronorcantharidiimide imide：
It takes 3.32g (20mmol) Norcantharidin to be dissolved in 30mL acetone, acetone soln and para-fluoroaniline is added to
It reacts in conical flask, it is seen that there is a large amount of precipitation to generate.After reacting 8 hours at normal temperatures, precipitation is filtered out into rear vacuum and is done
It is dry, it is dissolved in 20mL dimethylformamides, is cooled to 0 DEG C.It is placed in ice-water bath, 3.09g (15mmol) dicyclohexyl is added
Carbodiimide is stirred to react 15 hours.Then it cools down, filters, filtrate is poured in 50mL ice water, solid is precipitated.It is filtered,
Washing, finally obtains product (3) with recrystallizing methanol.
(3), Arabinoside triazole structure is imported：
By N- p-fluorophenyls substituted dehydronorcantharidiimide imide and triacetyl arabinose nitrine under room temperature under nitrogen protection
Compound 4 is mixed in methanol, carries 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 3~4 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 is recrystallized with methanol after column chromatography, vacuum drying obtains target compound (5).
Compound (5) title：Fluorine replaces the triazole norcantharidin derivative of structure containing Arabinoside
Molecular formula：C19H19FN4O7
Physico-chemical parameter：Yellow solid, m.p.166-167.5 DEG C.
Structural confirmation：
1H NMR(DMSO‐d6):δ=7.53-7.22 (m, 4H, Ar-H), 5.16 (d, J=9.60Hz, 1H, H5), 4.74
(d, J=17.60Hz, 1H, H4), 4.56 (d, J=17.60Hz, 1H, H1), 4.02 (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), 3.77 (3H, m, C2 '-H, C3 '-H, C4 '-H), 3.58 (1H, m, C5 '-H)；
IR(KBr)ν:3482 (N-C=O), 2,984 2962 (ArH), 1782,1742,1715 (C=O), 1617 (N=N),
1229 (C-O-C), 1214 (C-N), 1161 (N-N) cm‐1；
Anal.calcd.for C19H19FN4O7.C,52.55；H,4.41；N,12.92.
Application Example：Fluorine replaces the triazole norcantharidin derivative of structure containing Arabinoside (compound 5)
Antitumor cytolytic 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), 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.
Table 1, fluorine replace the triazole of structure containing Arabinoside six kinds of tumor cell lines of norcantharidin derivative pair
IC50Value.
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 (6)
1. a kind of fluorine replaces the triazole norcantharidin derivative of structure containing Arabinoside, structural formula as follows：
。
2. a kind of system of fluorine substitution triazole norcantharidin derivative of structure containing Arabinoside as described in claim 1
Preparation Method, which is characterized in that include 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- p-fluorophenyl substituted dehydronorcantharidiimide imides synthesis：
Dehydronorcantharidiimide element is dissolved in acetone solvent, the acetone soln of para-fluoroaniline is added dropwise under stiring, after reacting 1 hour
Manganese acetate, triethylamine and aceticanhydride is added, reacts 8 hours at room temperature；It is dissolved in dimethylformamide after the precipitation of generation is dried
In, it is stirred to react with dicyclohexylcarbodiimide 10 hours in ice-water bath, filtrate is placed in ice water and is crystallized, then recrystallized
Obtain product N- p-fluorophenyl substituted dehydronorcantharidiimide imides；
（3）, import Arabinoside triazole structure：
By N- p-fluorophenyls substituted dehydronorcantharidiimide imide and triacetyl arabinose azide under room temperature under nitrogen protection
It is mixed in methanol, carries out addition reaction, ice-water bath is cooled to 0 DEG C after reflux 2 hours, and sodium methoxide is slowly added dropwise under nitrogen protection
Methanol solution；After being added dropwise, be warmed to room temperature that the reaction was continued 3~4 hours, TLC, which is monitored to raw material point, to disappear, with sun from
Sub-exchange resin regulation system to neutrality, filtering washs ion exchange resin for several times with methanol, and filtrate decompression obtains after removing methanol
Yellow solid, methanol recrystallizes after column chromatography, and vacuum drying obtains the target product fluorine substitution triazole of structure containing Arabinoside
Class norcantharidin derivative.
3. a kind of fluorine substitution triazole norcantharidin derivative of structure containing Arabinoside according to claim 2
Preparation 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 fluorine substitution triazole norcantharidin derivative of structure containing Arabinoside according to claim 2
Preparation method, it is characterised in that：Step（3）In, the synthetic method of the triacetyl arabinose azide is as follows：50 milliliters
Bromoacetyl arabinose, sodium azide and anhydrous DMF, nitrogen protection are added in round-bottomed flask；It is stirred overnight at room temperature, system
Color is light yellow by leucismus；It is vigorously stirred down, system is poured into 200 milliliters of water, a large amount of solids occur, filter, cold water washing
It is dry except desalting and DMF, obtain triacetyl arabinose azide.
5. a kind of fluorine substitution triazole norcantharidin derivative of structure containing Arabinoside according to claim 2
Preparation method, it is characterised in that：Step（3）In, cation exchange resin is 732 superacicd styrene cation exchange resins.
6. a kind of fluorine substitution triazole norcantharidin derivative of structure containing Arabinoside as described in claim 1 is being made
Application in terms of standby antitumor drug.
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| CN101812066A (en) * | 2010-03-04 | 2010-08-25 | 绍兴文理学院 | Pyrazolo N-substituted dehydronorcantharidin imide derivative as well as synthesis method, activity test method and application thereof |
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