CN105906678B - Fluorine substitution triazole norcantharidin derivative of structure containing glucoside and preparation method and application - Google Patents
Fluorine substitution triazole norcantharidin derivative of structure containing glucoside and preparation method and application Download PDFInfo
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- CN105906678B CN105906678B CN201610395573.8A CN201610395573A CN105906678B CN 105906678 B CN105906678 B CN 105906678B CN 201610395573 A CN201610395573 A CN 201610395573A CN 105906678 B CN105906678 B CN 105906678B
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- 229930182478 glucoside Natural products 0.000 title claims abstract description 20
- 150000008131 glucosides Chemical class 0.000 title claims abstract description 19
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 18
- 239000011737 fluorine Substances 0.000 title claims abstract description 17
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 15
- -1 triazole norcantharidin derivative Chemical class 0.000 title claims abstract description 15
- 125000001153 fluoro group Chemical group F* 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract 2
- 230000008676 import Effects 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 150000003949 imides Chemical class 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 150000002240 furans Chemical class 0.000 claims description 5
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003456 ion exchange resin Substances 0.000 claims description 4
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 230000003292 diminished effect Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- WFBHLGOLOWZMBJ-GVYWOMJSSA-N (4r,5s,6r,7r)-1-bromo-4,5,6,7,8-pentahydroxyoctane-2,3-dione Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)C(=O)CBr WFBHLGOLOWZMBJ-GVYWOMJSSA-N 0.000 claims description 2
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229940071125 manganese acetate Drugs 0.000 claims description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical group C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 abstract description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 150000000177 1,2,3-triazoles Chemical class 0.000 abstract description 4
- 230000003993 interaction Effects 0.000 abstract description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 abstract 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical class C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 150000003852 triazoles Chemical class 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 229940095758 cantharidin Drugs 0.000 description 4
- 229930008397 cantharidin Natural products 0.000 description 4
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000623906 Lytta vesicatoria Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AORTZIIKTZPIQU-UHFFFAOYSA-N 3-butyl-4-methyloxolane-2,5-dione Chemical compound CCCCC1C(C)C(=O)OC1=O AORTZIIKTZPIQU-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- JAABVEXCGCXWRR-UHFFFAOYSA-N norcantharidin Chemical compound C1CC2C3C(=O)OC(=O)C3C1O2 JAABVEXCGCXWRR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of fluorine substitution triazole norcantharidin derivative of structure containing glucoside and preparation method and application, preparation method C in Norcantharidin structure with 1,3 dipole-diople interaction method5And C6Position introduces 1,2,3 triazoles; acetyl group α D glucose responses complete with 1 nitrine import glucoside structure; so as to synthesize the fluorine substitution triazole norcantharidin derivative of structure containing glucoside, which has multiple biological activities, available for preparing antitumor drug.
Description
Technical field：
The invention belongs to pharmaceutical technology fields, are specifically related to a kind of fluorine substitution triazole of structure containing glucoside and go first
Cantharidin derivative and preparation method and application.
Background technology：
Norcantharidin, chemical name：7- oxabicyclos [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 have to primary carcinoma of liver centainly
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 the toxicity of cantharidin is larger, 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, the synthetic work that is 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 Norcantharidin of structure containing glucoside
Derivative.
The technical solution that the present invention takes is as follows：
A kind of fluorine replaces the triazole norcantharidin derivative of structure containing glucoside, and structural formula is 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 1- nitrine-full acetyl group-alpha-D-glucose, it is ingenious to apply 1,3- dipole-diople interaction sides
Method introduces 1,2,3- triazoles and glucoside 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 glucoside and removes first spot
The preparation method of Chinese blister beetle element derivative, which is characterized in that include the following steps：
(1), the synthesis of dehydronorcantharidiimide element：
Maleic anhydride is finely ground, ether is added in, 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- p-fluorophenyls substituted dehydronorcantharidiimide imide：
Dehydronorcantharidiimide element is dissolved in acetone solvent, the acetone soln of para-fluoroaniline (2), reaction are added dropwise under stiring
Manganese acetate, triethylamine and aceticanhydride are added in after 1 hour, is reacted 8 hours at room temperature；Dried precipitation is dissolved in dimethyl formyl
In amine, it is stirred to react in ice-water bath with dicyclohexylcarbodiimide 10 hours, filtrate is placed in ice water and is crystallized, then tied again
Crystalline substance obtains product (3)；
(3), glucoside triazole structure is imported：
Under room temperature under nitrogen protection by N- p-fluorophenyls substituted dehydronorcantharidiimide imide and 1- nitrine-full acetyl group-α-
D-Glucose (4) is mixed in methanol, carries out addition reaction, and ice-water bath is cooled to 0 DEG C after reflux 2 hours, and nitrogen protection is lower slow
The slow methanol solution that sodium methoxide is added dropwise；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
It loses, with 732 superacicd styrene cation exchange resin regulation systems 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 (5).
Further：
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 applies methanol.
In the step (3), the synthetic method of 1- nitrine-full acetyl group-alpha-D-glucose is as follows：50 milliliters of round bottoms are burnt
Bromoacetyl glucose, sodium azide and anhydrous DMF, nitrogen protection are added in bottle.It is stirred overnight at room temperature, system color is by white
Become light yellow.Be vigorously stirred down, system poured into 200 milliliters of water, a large amount of solids occur, filter, cold water wash out desalt and
DMF, it is dry, obtain 1- nitrine-full acetyl group-alpha-D-glucose (4).
Reaction of the present invention is as follows：
The third aspect of the present invention purpose is to provide a kind of aforementioned fluorine substitution triazole of structure containing glucoside and removes first spot
Application of the Chinese blister beetle element derivative in terms of antitumor drug is prepared.Pass through experimental verification：Above compound, for different knurl strain such as people
Liver cancer cells, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell etc., are respectively provided with inhibiting effect,
Wherein there is more preferably inhibiting rate and selectivity for HL-60 (leukaemia cell), antitumor drug can be prepared separately, can also
Anti-tumor compositions are prepared as active constituent and 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：1,2,3-triazoles class compound in itself more has various activity, 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, so as to change its pharmacological property.Specifically we introduce on C-5 or C-6
Glucoside structure has also been imported on the basis of triazole, has obtained the fluorine substitution triazole Norcantharidin of structure containing glucoside
Derivative.Above compound is for human liver cancer cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, intestines
The knurls strain such as 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 embodiment：
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- p-fluorophenyls substituted dehydronorcantharidiimide imide：
3.32g (20mmol) Norcantharidin is taken to be dissolved in 30mL acetone, acetone soln and para-fluoroaniline are added to
It reacts in conical flask, it is seen that have a large amount of precipitation generation.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, adds in 3.09g (15mmol) dicyclohexyl
Carbodiimide is stirred to react 10 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), glucoside triazole structure is imported：By N- p-fluorophenyl substituted dehydronorcantharidiimides under room temperature under nitrogen protection
Acid imide and 1- nitrine-full acetyl group-alpha-D-glucose are mixed in methanol, carry out addition reaction, ice-water bath after reflux 2 hours
0 DEG C is cooled to, 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
Hour, TLC, which is monitored to raw material point, to disappear, and with 732 superacicd styrene cation exchange resin regulation systems to neutrality, filters, uses
For several times, filtrate decompression obtains yellow solid to methanol washing ion exchange resin after removing methanol, is recrystallized after column chromatography with methanol, very
Sky is dried to obtain target compound (5).
Compound (5) title：Fluorine replaces the triazole norcantharidin derivative of structure containing glucoside
Molecular formula：C20H21FN4O8
Physico-chemical parameter：Yellow solid, m.p.171-172 DEG C
Structural confirmation：
1H NMR(DMSO-d6):δ=7.53-7.21 (m, 4H, 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), 3.30 (d, J=7.20Hz, 1H, H2), 5.08-3.08 (m, 11H, 7 × Glucosyl-H, 4 ×
OH)；
IR(KBr)ν:3478 (N-C=O), 2,985 2942 (ArH), 1782,1742,1715 (C=O), 1612 (N=N),
1229 (C-O-C), 1216 (C-N), 1160 (N-N) cm-1；
Anal.calcd.for C20H21FN4O8.C,51.72；H,4.58；N,12.07.
Application Example：The fluorine substitution triazole norcantharidin derivative of structure containing glucoside (compound 5) resists
Tumor promotion measures.
By above-described embodiment prepare compound (5), respectively with different knurl strains (tumour cell Bel-7402, KB,
SGC7901, HO8901, HL-60, ECA109) it is experimental subjects, test compound (5) inhibits to make for the external of different knurl strains
With：Experiment represents (IC using the micro enzyme reaction colorimetric method (mtt assay) of tetramethyl azo azoles salt, activity with half-inhibition concentration50)。
Specific experiment step is as follows：
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 μ L/ holes, 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, add in dense eventually
The MTT for 0.25mg/mL is spent, is placed in 37 DEG C, 5%CO24 hours in cell incubator, solvent is blotted later, and 100 μ are added in per hole
L DMSO, absorbance (OD values) is measured with enzyme linked immunological instrument at 570nm, and the data obtained is used to calculate 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, glucoside structure triazole norcantharidin derivative are to the IC of six kinds of tumor cell lines50Value
It can be seen that by upper table data：Compound prepared by the present invention is respectively provided with inhibition for six kinds of tumor cell lines
Wherein having prominent inhibiting rate and selectivity for HL-60 (leukaemia cell), antineoplastic can be prepared separately 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 fluorine replaces the triazole norcantharidin derivative of structure containing glucoside, structural formula is as follows：
。
2. a kind of preparation of fluorine substitution triazole norcantharidin derivative of structure containing glucoside as described in claim 1
Method includes the following steps：
（1）, dehydronorcantharidiimide element synthesis：
Maleic anhydride is finely ground, ether is added in, 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 are added in, is reacted 8 hours at room temperature；Dried precipitation is dissolved in dimethylformamide, ice
It is stirred to react in water-bath with dicyclohexylcarbodiimide 10 hours, filtrate is placed in ice water and is crystallized, then be recrystallized to give
Product；
（3）, import glucoside triazole structure：
By N- p-fluorophenyls substituted dehydronorcantharidiimide imide and 1- nitrine-full acetyl group-α-D- Portugals under room temperature under nitrogen protection
Grape sugar is mixed in methanol, carries out addition reaction, and ice-water bath is cooled to 0 DEG C after reflux 2 hours, and first is slowly added dropwise under nitrogen protection
The methanol solution of sodium alkoxide；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, with sun
Ion exchange resin regulation system to neutrality, filtering washs ion exchange resin for several times with methanol, after filtrate decompression removes methanol
Yellow solid is obtained, methanol recrystallizes after column chromatography, and vacuum drying obtains target compound.
3. a kind of system of fluorine substitution triazole norcantharidin derivative of structure containing glucoside 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 system of fluorine substitution triazole norcantharidin derivative of structure containing glucoside according to claim 2
Preparation Method, it is characterised in that：Step（3）In, the synthetic method of 1- nitrine-full acetyl group-alpha-D-glucose is as follows：50 milliliters of circles
Bromoacetyl glucose, sodium azide and anhydrous DMF are added in the flask of bottom, nitrogen protection is stirred overnight at room temperature, system color
It 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 removes
Salt and DMF, it is dry, obtain 1- nitrine-full acetyl group-alpha-D-glucose.
5. a kind of fluorine substitution triazole norcantharidin derivative of structure containing glucoside described in claim 1 is anti-in preparation
Application in terms of tumour medicine.
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