CN106083965B - Triazole norcantharidin derivative of structure containing lactoside and the preparation method and application thereof - Google Patents
Triazole norcantharidin derivative of structure containing lactoside and the preparation method and application thereof Download PDFInfo
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- CN106083965B CN106083965B CN201610398106.0A CN201610398106A CN106083965B CN 106083965 B CN106083965 B CN 106083965B CN 201610398106 A CN201610398106 A CN 201610398106A CN 106083965 B CN106083965 B CN 106083965B
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- lactoside
- triazole
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- -1 Triazole norcantharidin derivative Chemical class 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 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 claims abstract description 18
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 9
- 239000008101 lactose Substances 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 230000008676 import Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 150000003852 triazoles Chemical class 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000003949 imides Chemical class 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 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 5
- 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
- 238000003756 stirring Methods 0.000 claims description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000706 filtrate Substances 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
- 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
- 230000003292 diminished effect Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000003456 ion exchange resin Substances 0.000 claims description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 3
- 239000007788 liquid Substances 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
- 238000001291 vacuum drying Methods 0.000 claims description 3
- RDKDZVKTUNMUMT-BHVWUGLYSA-N 1-[(3R,4R,5S,6R)-2,3,4-trihydroxy-6-(hydroxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]ethanone Chemical compound C(C)(=O)C1(O)[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO RDKDZVKTUNMUMT-BHVWUGLYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 2
- 238000001035 drying 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 238000005341 cation exchange Methods 0.000 claims 1
- 230000006837 decompression Effects 0.000 claims 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 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
- 206010009944 Colon cancer Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 201000007270 liver cancer Diseases 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
- 210000000214 mouth Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 206010061523 Lip and/or oral cavity 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 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
- 239000003814 drug Substances 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
- JAABVEXCGCXWRR-UHFFFAOYSA-N norcantharidin Chemical compound C1CC2C3C(=O)OC(=O)C3C1O2 JAABVEXCGCXWRR-UHFFFAOYSA-N 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000001953 recrystallisation Methods 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of triazole norcantharidin derivative of structure containing lactoside 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, is reacted with the full acetyl group lactose of 1- nitrine-and imports lactoside structure, to synthesize 1,2,3- triazole norcantharidin derivative of structure containing lactoside, 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 one kind triazole Norcantharidin of structure containing lactoside and spread out
Biology 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 be to provide a kind of triazole norcantharidin derivative of structure containing lactoside and
Preparation method and application.
The technical solution adopted by the present invention is as follows：
One kind triazole norcantharidin derivative of structure containing lactoside and the preparation method and application thereof, structural formula is such as
Under：
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 lactose, it is ingenious that 1,3- dipole-diople interaction methods is applied to introduce
1,2,3- triazole and lactoside 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 lactoside Norcantharidin derivative
The preparation method of object, 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), lactoside triazole structure is imported：
By N- phenyl substituted dehydronorcantharidiimide imide (3) and the full acetyl group lactose of 1- nitrine-under room temperature under nitrogen protection
(4) it is mixed in methanol, carries out addition reaction, 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 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 (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 the full acetyl group lactose of 1- nitrine-is as follows：Bromo is added in 50 milliliters of round-bottomed flasks
Acetyl lactose, sodium azide and anhydrous DMF, nitrogen protection.It is stirred overnight at room temperature, system color is light yellow by leucismus.Acutely
Under stirring, system is poured into 200 milliliters of water, a large amount of solids occurs, is filtered, cold water, which washes out, to desalt and DMF, dry, obtains
The full acetyl group lactose (4) of 1- nitrine-.
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 lactoside Norcantharidin derivative
Application of the object 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
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 lactoside, obtains the triazole norcantharidin derivative of structure containing lactoside.Above compound is directed to human liver cancer
The tumors strain such as cell, cancer cell of oral cavity, stomach cancer cell, ovarian cancer cell, leukaemia cell, colon-cancer cell, especially for white blood
Sick 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), lactoside triazole structure is imported：
By N- phenyl substituted dehydronorcantharidiimide imide (3) and the full acetyl group lactose of 1- nitrine-under room temperature under nitrogen protection
(4) it is mixed in methanol, carries out addition reaction, 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 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 lactoside
Molecular formula：C26H32N4O13
Physico-chemical parameter：Yellow solid, m.p.215-217 DEG C
Structural confirmation：
1H NMR(DMSO‐d6):δ=7.50-7.19 (m, 5H, 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), 4.00 (d, J=9.60Hz, 1H, H6), 3.43 (d,
J=7.20Hz, 1H, H3), 3.28 (d, J=7.20Hz, 1H, H2), 5.21-4.21,3.61-3.28 (m, 21H, 14 ×
Lactosyl‐H,7×OH)；
IR(KBr)ν:3478 (N-C=O), 2,985 2942 (ArH), 1782,1742,1715 (C=O), 1614 (N=N),
1232 (C-O-C), 1216 (C-N), 1167 (N-N) cm‐1；
Anal.calcd.for C26H32N4O13.C,51.32；H,5.30；N,9.25.
Application Example：The antitumor activity of the triazole norcantharidin derivative of structure containing lactoside (compound 5)
It measures.
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, is diluted, tumour cell Bel-7402 (human liver cancer cell), (carcinoma of mouth is thin by KB
Born of the same parents), SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia cell), ECA109 (colon-cancer cell) exist
It is planted on 96 orifice plates into 4000/200 holes μ L/, is added compound 2 μ L per hole, final concentration of 12.0 μM, 6.0 μM, 3.0 μM, 1.5 μ
M, jointly in 37 DEG C, 5%CO2It is incubated 72 hours in cell incubator, with DMSO (1%) for blank control.After 72 hours, it is added
The MTT of final concentration of 0.25mg/mL is placed in 37 DEG C, 5%CO24 hours in cell incubator, solvent is blotted later, is added per hole
100 μ l DMSO measure absorbance (OD values) with enzyme linked immunological instrument at 570nm, and the data obtained is for calculating IC50Value.It measures not
With influence of the compound effects time difference to human tumor cells period and apoptosis under concentration.
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 lactoside50Value
。
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 lactoside, structural formula are as follows：
In formula：
。
2. a kind of preparation method of the triazole of structure containing lactoside norcantharidin derivative as described in claim 1,
It is characterized in that, includes 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 lactoside triazole structure：
N- phenyl substituted dehydronorcantharidiimide imide and the full acetyl group lactose of 1- nitrine-are mixed in first under room temperature under nitrogen protection
In alcohol, addition reaction is carried out, ice-water bath is cooled to 0 DEG C after reflux 2 hours, and the methanol that sodium methoxide is slowly added dropwise under nitrogen protection is molten
Liquid；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 cation exchange tree
Fat regulation system to neutrality, filtering washs ion exchange resin for several times with methanol, and it is solid to obtain yellow after filtrate decompression removing methanol
Body, methanol recrystallizes after column chromatography, and vacuum drying obtains the target compound triazole Norcantharidin of structure containing lactoside and spreads out
Biology.
3. a kind of preparation method of the triazole of structure containing lactoside norcantharidin derivative according to claim 2,
It is characterized in that：Step（1）In, dehydronorcantharidiimide element obtained by the reaction need to be filtered under diminished pressure.
4. a kind of preparation method of the triazole of structure containing lactoside norcantharidin derivative according to claim 2,
It is characterized in that：Step（3）In, the synthetic method of the full acetyl group lactose of 1- nitrine-is as follows：Bromine is added in 50 milliliters of round-bottomed flasks
For acetyl lactose, sodium azide and anhydrous DMF, nitrogen protection；It is stirred overnight at room temperature, system color is light yellow by leucismus；It is acute
Under strong stirring, system is poured into 200 milliliters of water, a large amount of solids occurs, is filtered, cold water, which washes out, to desalt and DMF, dry, obtains
To the full acetyl group lactose of 1- nitrine-.
5. a kind of triazole norcantharidin derivative of structure containing lactoside described in claim 1 is preparing antitumor drug
The application of aspect.
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