CN105906667B - A kind of chemical substance with active anticancer and preparation method and application - Google Patents
A kind of chemical substance with active anticancer and preparation method and application Download PDFInfo
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- CN105906667B CN105906667B CN201610265097.8A CN201610265097A CN105906667B CN 105906667 B CN105906667 B CN 105906667B CN 201610265097 A CN201610265097 A CN 201610265097A CN 105906667 B CN105906667 B CN 105906667B
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- 239000000126 substance Substances 0.000 title claims abstract description 37
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims abstract description 49
- 229960004991 artesunate Drugs 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- -1 platinum (IV) compound Chemical class 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 80
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 11
- 230000003013 cytotoxicity Effects 0.000 abstract description 11
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- 239000003814 drug Substances 0.000 abstract description 9
- 239000003446 ligand Substances 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 230000013011 mating Effects 0.000 abstract description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 57
- 229910052697 platinum Inorganic materials 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 38
- 239000000843 powder Substances 0.000 description 32
- 239000007787 solid Substances 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 21
- 229960004316 cisplatin Drugs 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 229940125904 compound 1 Drugs 0.000 description 18
- 229940125782 compound 2 Drugs 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 9
- 229960001756 oxaliplatin Drugs 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 230000031700 light absorption Effects 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 7
- 238000000862 absorption spectrum Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 5
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 235000001405 Artemisia annua Nutrition 0.000 description 4
- 240000000011 Artemisia annua Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229930101531 artemisinin Natural products 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000013467 fragmentation Methods 0.000 description 4
- 238000006062 fragmentation reaction Methods 0.000 description 4
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 4
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- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 235000003826 Artemisia Nutrition 0.000 description 2
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 2
- 190014017285 Satraplatin Chemical group 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 244000030166 artemisia Species 0.000 description 2
- 235000009052 artemisia Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
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- 125000004185 ester group Chemical group 0.000 description 2
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- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000860 cochlear nerve Anatomy 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 230000001939 inductive effect Effects 0.000 description 1
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- 238000009434 installation Methods 0.000 description 1
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- 201000005202 lung cancer Diseases 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of chemical substances with active anticancer and preparation method and application, belong to chemical synthetic drug technical field.Solve the problems, such as how to provide the chemical substance that a kind of cytotoxicity is low, drug resistance is low, antitumor activity is high.The chemical substance with active anticancer of the present invention is structural formula such as formula (I) compound represented, it is either structural formula such as formula (II) compound represented or is the mixture of structural formula such as formula (I) compound represented and structural formula such as formula (II) compound represented.The chemical substance carries out mating reaction acquisition by Artesunate and platinum (IV) compound, both by introducing Artesunate ligand, reduce the cytotoxicity of platinum (IV) compound, the antitumor activity of platinum (IV) compound is improved again, and drug resistance is low, has extensive use in anticancer drug is prepared.
Description
Technical field
The present invention relates to chemical synthetic drug technical field more particularly to a kind of chemical substance with active anticancer and its
Preparation method and application.
Background technology
Since 1967 it is found that cis-platinum has active anticancer since, the research of Platinum Anti-tumor Drugs and application obtain
Permanent development at present screens thousands of a platinum series compounds, wherein there is tens compounds to enter clinic
Research has several granted into market.
Wherein, platinum (II) (representing divalent platinum) has been obtained for widely using in chemotherapy, such as cis- dichloro diamino
Platinum (II), also referred to as cis-platinum (cisplatin) are closed, is the divalent platinum of quantity maximum for a kind of periodical nonspecific drug
Class drug can be combined to form cross key with DNA, so as to destroy the copy function of DNA.Clinical practice proves that cis-platinum has anticancer
Spectrum is wide, and effect is strong, has a synergistic effect with a variety of antineoplastics, and the features such as without crossing drug resistant, is widely used in oophoroma, forefront
The treatment of the entity tumors such as gland cancer, carcinoma of testis, lung cancer, nasopharyngeal carcinoma, cancer of the esophagus, malignant lymphoma, breast cancer.However cis-platinum has
Severe digestive tract reaction, bone marrow suppression, auditory nerve toxicity and easily kidney is caused it is irreversible damage etc. toxic side effects limitation
The raising of its therapeutic index.Meanwhile low aqueous solubility and high toxicity are also asking for other divalent platinum medicine generally existings
Topic.In addition to this, in physiological conditions, platinum (II) has higher reactivity, therefore with relatively low stability, often in platinum
It is (II) most of to be combined and inactivation with bioactive molecules such as GSH, metallothioneins before reaching targeted cancerous cells,
And cancer cell often there is the congenital or day after tomorrow can obtain drug resistance in platinum (II).Above-mentioned various reasons limit platinum (II) change
Close the application of object.
It has been investigated that platinum (IV) (representing tetravalence platinum) compound is more on a vertical axis compared with platinum (II) compound
Two ligands spatially form octahedral structure, thus with kinetic inertness, have relatively low reactivity, smaller poison
Side effect.In addition by modifying the structures of vertical axes, thus it is possible to vary the reduction potential of platinum (IV) compound, so as to item in the cell
Platinum (II) is reduced under part rapidly, plays anticancer therapeutic.Lipophilic modification can also enhance lipophilicity, improve the efficiency of cellular uptake,
Improve curative effect.
Up to the present, most representational tetravalence platinum medicine is Satraplatin, be can be taken orally.The medicine by
Bristol-Squibb companies of the U.S., Johnson Matthey companies of Britain and Cancer Institute joint development, in 1992 into
Enter clinical test, enter the clinic III phases.But in terms of curative effect, compared with cis-platinum, carboplatin, Satraplatin, which is removed, has mouth
The outer advantage of clothes activity does not protrude, and antitumor activity needs to be further improved.
Qinghaosu (artemisinin) be China detached from composite family artemisia (artemisia) artemisia annua for the first time, identify it is anti-
Malaria drug finds that qinghaosu is significant in efficacy to rescuing and treating encephalic malaria and pernicious malaria etc. through largely studying and observing.
Hereafter derivative that is a series of active and dissolving in oil or water is developed, and Artesunate (Artesunate, Art) is
One of derivative of qinghaosu.Other than good anti-malarial acts on, in recent years, research finds qinghaosu and its derivative anti-
Also there is good application prospect in terms of tumour, alternative killing tumor cell, inducing apoptosis of tumour cell inhibit tumour life
The effect of growing, and toxic side effect is small, and also having with some drugs and act synergistically, can enhance anticancer drug promotes tumour cell
To the sensibility of chemotherapeutics, the side effect of anticancer drug is reduced, delays the generation of drug resistance.
Invention content
In view of this, the purpose of the present invention is how to provide a kind of chemical substance with active anticancer and preparation method thereof
With application, the cytotoxicity of the chemical substance is low, drug resistance is low, antitumor activity is high.
The present invention provides a kind of chemical substance with active anticancer, which is structural formula as shown in formula (I)
Compound is either structural formula such as formula (II) compound represented or is structural formula such as formula (I) compound represented and structure
The mixture of formula such as formula (II) compound represented：
In formula (I) and formula (II),For with one kind in lower structure：
The present invention also provides a kind of preparation methods of the chemical substance with active anticancer, include the following steps：
A) platinum (II) compound with hydrogen peroxide is reacted, obtains platinum (IV) compound；
Platinum (II) compound is(cis-platinum Cisplatin),It is (difficult to understand
Husky profit platinum Oxaliplatin)(pyAA-Pt-Cl2) or(CHAA-Pt-Cl2)；
B) under the conditions of anhydrous and oxygen-free, by step A) obtained platinum (IV) compound with Artesunate in item existing for condensing agent
It is reacted under part, obtains the chemical substance with active anticancer.
Preferably, the step B) in, the molar ratio of platinum (IV) compound and Artesunate is 1:(0.8~1.2), sweet wormwood
The molar ratio of amber ester and condensing agent is 1:(1~1.2) obtains structural formula such as formula (I) compound represented.
Preferably, the step B) in, the molar ratio of platinum (IV) compound and Artesunate is 1:(1.5~3), sweet wormwood amber
The molar ratio of ester and condensing agent is 1:(1~1.2) obtains structural formula such as formula (II) compound represented.
Preferably, the step A) in, the volume of hydrogen peroxide is (5mL~15mL) with the molar ratio of platinum (II) compound:
(1mmol~3mmol).
Preferably, the step A) in, platinum (II) compound is carried out with reacting for hydrogen peroxide under the conditions of being protected from light.
Preferably, the step A) in, the reaction temperature of platinum (II) compound and hydrogen peroxide is room temperature, the reaction time 5
~10h.
Preferably, the step B) in, condensing agent N, N'- dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole
(HOBT) or N- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl).
Preferably, the step B) in, the solvent of reaction is N, N '-dimethyl formamide (DMF).
Preferably, the step B) in, the temperature of reaction is 0 DEG C~20 DEG C, and the time is 16h~for 24 hours.
The present invention also provides application of the above-mentioned chemical substance with active anticancer in anticancer drug is prepared.
Compared with prior art, the beneficial effects of the invention are as follows：
1st, the chemical substance with active anticancer of the invention, core are that structural formula is formula (I) and the change shown in formula (II)
Object is closed, which is platinum (IV) complex using Artesunate as axial ligand, passes through Artesunate and platinum (IV) compound
Mating reaction acquisition is carried out, both by introducing Artesunate ligand, reduces the cytotoxicity of platinum (IV) compound, and improve
The antitumor activity of platinum (IV) compound, and drug resistance is low.Through cytotoxicity experiment the result shows that, platinum (IV) provided by the invention
Complex is to cancer cell (such as MCF-7 Human Breast Cancer Cells, HeLa Cells, human hepatoma HepG2 cell's human lung adenocarcinoma
A549 cells) there is good fragmentation effect, also there is good fragmentation effect to the human lung adenocarcinoma A549/DDP cells of cisplatin resistance,
And cytotoxicity is low, can be used as antitumor drug application.
2nd, the preparation method of the chemical substance with active anticancer of the invention is simple and practicable, without special installation with
Technique, it is at low cost, suitable for industrialized production.
Description of the drawings
Fig. 1 is the infrared absorption spectra of compound 1 prepared by the embodiment of the present invention 1；
Fig. 2 is the nuclear magnetic resonance H spectrograms of compound 1 prepared by the embodiment of the present invention 1；
Fig. 3 is the mass spectrogram of compound 1 prepared by the embodiment of the present invention 1；
Fig. 4 is the infrared absorption spectra of compound 2 prepared by the embodiment of the present invention 5；
Fig. 5 is the nuclear magnetic resonance H spectrograms of compound 2 prepared by the embodiment of the present invention 5；
Fig. 6 is the mass spectrogram of compound 2 prepared by the embodiment of the present invention 5.
Specific embodiment
In order to further appreciate that the present invention, the preferred embodiments of the invention are retouched With reference to embodiment
It states, but it is to be understood that these descriptions are only for the feature and advantage that further illustrate the present invention rather than to patent of the present invention
It is required that limitation.
The chemical substance with active anticancer of the present invention is the change of the compound or formula (II) structure of formula (I) structure
The mixture of the compound of the compound and formula (II) structure of object or formula (I) structure is closed, wherein, the compound of formula (I) structure
Compound with formula (II) structure is that (formula (I) and formula (II) structure exist using Artesunate as platinum (IV) complex of axial ligand
It is given hereinbefore, details are not described herein again) cytotoxicity of the chemical substance is low, drug resistance is low, antitumor activity is high.
The preparation method of the above-mentioned chemical substance with active anticancer, step are as follows：
A) platinum (II) compound is stirred to react with hydrogen peroxide under the conditions of being protected from light, reaction temperature is room temperature, the reaction time
For 5~10h, after reaction, purification (purification process generally filters) obtains yellow powder, as platinum (IV) compound；
Wherein, platinum (II) compound is cis-platinum Cisplatin, oxaliplatin Oxaliplatin, pyAA-Pt-Cl2Or
CHAA-Pt-Cl2, the present invention has no particular/special requirement to its source, can be general commercially available；Hydrogen peroxide is without particular/special requirement, preferably
30% hydrogen peroxide；The volume of hydrogen peroxide is preferably (5mL~15mL) with the molar ratio of platinum (II) compound:(1mmol~
3mmol)；
Step A) reaction equation it is following (in formula, M1、M2、M3、M4Substituent group is represented, with specific reference to platinum (II) compound
Structure determination, platinum (II) compound have above provided, and details are not described herein again)：
B) under the conditions of anhydrous and oxygen-free, by step A) obtained platinum (IV) compound with Artesunate in item existing for condensing agent
Esterification is carried out under part, obtains the chemical substance with active anticancer, with specific reference to reactant ratio difference, products therefrom is not
Together, can preferably be divided into B1), B2), B3) three kinds of situations：
B1 formula (I) structure compound represented) is prepared：Under the conditions of anhydrous and oxygen-free, by step A) obtained platinum (IV) chemical combination
Object is reacted with Artesunate under the conditions of existing for condensing agent, and the molar ratio of platinum (IV) compound and Artesunate is 1:
(0.8~1.2), preferably 1:The molar ratio of (1~1.2), Artesunate and condensing agent is 1:(1~1.2) after reaction, carries
It is pure, obtain white solid powder, as formula (I) structure compound represented；
B2 formula (II) structure compound represented) is prepared：Under the conditions of anhydrous and oxygen-free, by step A) obtained platinum (IV) chemical combination
Object is reacted with Artesunate under the conditions of existing for condensing agent, and the molar ratio of platinum (IV) compound and Artesunate is 1:
(1.5~3), preferably 1:The molar ratio of (1.5-2.5), Artesunate and condensing agent is 1:(1~1.2) after reaction, carries
It is pure, obtain white solid powder, i.e. formula (II) structure compound represented；
B3 the mixture of formula (I) structure compound represented and formula (II) structure compound represented, anhydrous and oxygen-free) are prepared
Under the conditions of, by step A) obtained platinum (IV) compound reacts with Artesunate under the conditions of existing for condensing agent, platinum
(IV) compound and the molar ratio of Artesunate are less than 1:1.2 are more than 1:1.5, the molar ratio of Artesunate and condensing agent is 1:(1
~1.2) it, after reaction, purifies, obtains white solid powder, i.e. formula (I) structure compound represented and formula (II) structure institute
The mixture for the compound shown；
Wherein, shown in Artesunate structure such as formula (III),
Condensing agent is preferably DCC, HOBT or EDC.HCl, and source has no particular/special requirement, can be general commercially available；Reaction
Solvent is preferably DMF, and platinum (IV) compound, there is no limit for the sequence of Artesunate and condensing agent dissolving in a solvent；Reaction
Temperature is preferably 0 DEG C~20 DEG C；The time of reaction is preferably 16h~for 24 hours；Purification process preferably first drains the solvent in system,
Then by surplus materials acetone solution, and insoluble matter is filtered out, then ether settles after filtrate is concentrated, and solid is obtained by filtration simultaneously
Vacuum is drained, you can obtains product.
The chemical substance with active anticancer of the present invention can still obtain and cis-platinum phase while cytotoxicity is reduced
When active anticancer, and drug resistance is low, can be applied in anticancer drug is prepared.
In order to further illustrate the present invention, with reference to embodiment to the chemicals provided by the invention with active anticancer
Matter and preparation method thereof is described in detail.Ventilation in embodiment 1-14 is not particularly limited, such as using inert gas
Argon gas.
Embodiment 1
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(185.6mg, 0.9mmol) is placed in dried polymerization bottle, and ventilation three times, then adds in the dried DMF of 5ml thereto,
0.5h is stirred at 20 DEG C, adds in Artesunate (307.5mg 0.8mmol), and reaction 16h is sufficiently stirred at 10 DEG C.Then it takes out
DMF in dry system by surplus materials acetone solution, and filters out insoluble matter, and ether settles after filtrate is concentrated, and filters institute
It obtains solid and vacuum is drained to obtain compound 1, be white solid powder 317.3mg.
Reaction equation is as follows：
The compound 1 of preparation is characterized using infrared absorption spectrum, nuclear magnetic resonance and electrospray ionization mass spectrum, is characterized
The result is shown in Figure 1, Fig. 2 and Fig. 3.Fig. 1 is the infrared absorption spectra of compound 1 prepared by the embodiment of the present invention 1, wherein, 1643cm-1
And 1746cm-1Stretching vibration peak of the absorption peak at place for the corresponding carbonyl C=O of Artesunate, 831cm-1、881cm-1With
1115cm-1The absorption peak at place be its-O-O- stretching vibration peak, 3250cm-1The absorption peak at place shakes for the flexible of cis-platinum amino ligands
Dynamic peak, 3500cm-1Locate as its-OH stretching vibration peak, Fig. 1 illustrates that Artesunate is successfully made coordination with cis-platinum, is changed
Close object 1；Fig. 2 is the nuclear magnetic resonance H spectrograms of compound 1 prepared by the embodiment of the present invention 1, wherein, the suction at 5.54-5.60ppm
Peak is received as the proton hydrogen peak of methine being connected with bridging oxygen on Artesunate, the absorption peak at 5.64-5.71ppm places is Artesunate
The proton hydrogen peak of the methine of upper connection ester group；Absorption peak at 5.73-6.17ppm is cis-platinum ammonia ligand proton hydrogen peak, it is seen that
The peak ownership of each proton hydrogen is clear and definite, and ratio is coincide, so as to again demonstrate the successful synthesis of compound 1；Fig. 3 is of the invention real
The mass spectrogram of the compound 1 of the preparation of example 1 is applied, maximum absorption peak m/z=699 is the molecular ion peak of compound 1, with it
Molecular weight coincide.
Fig. 1, Fig. 2 and Fig. 3 are demonstrated in the present invention, the successful preparation of compound 1.
Embodiment 2
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides (226.8,
It 1.1mmol) is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 5ml, stirred at 20 DEG C thereto
1h adds in Artesunate (384.4mg, 1mmol), and reaction 18h is sufficiently stirred at 10 DEG C.Then the DMF in system is drained,
By surplus materials acetone solution, and insoluble matter is filtered out, ether settles after filtrate is concentrated, solid and vacuum obtained by filtering
It drains to obtain compound 1, is white solid powder 335mg.
Reaction equation such as embodiment 1.
Embodiment 3
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(237.1mg, 1.15mmol) is placed in dried polymerization bottle, and ventilation three times, then adds in the dried DMF of 7ml thereto,
1h is stirred at 10 DEG C, adds in Artesunate (422.9mg, 1.11mmol), and reaction 18h is sufficiently stirred at 10 DEG C.Then it takes out
DMF in dry system by surplus materials acetone solution, and filters out insoluble matter, and ether settles after filtrate is concentrated, and filters institute
It obtains solid and vacuum is drained to obtain compound 1, be white solid powder 330mg.
Reaction equation such as embodiment 1.
Embodiment 4
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(247.4mg, 1.2mmol) and Artesunate (422.9mg, 1.1mmol) are placed in dried polymerization bottle, are taken a breath three times,
Then the dried DMF of 5ml are added in thereto, and reaction 16h is sufficiently stirred at 10 DEG C.Then the DMF in system is drained, it will
Surplus materials acetone solution, and insoluble matter is filtered out, ether settles after filtrate is concentrated, solid and vacuum pumping obtained by filtering
It is dry to obtain compound 1, it is white solid powder 330mg.
Reaction equation such as embodiment 1.
Embodiment 5
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(434.5mg, 2.1mmol), I-hydroxybenzotriazole (283.8mg, 2.1mmol) and Artesunate (768.8mg, 2mmol)
It is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 10ml, and fully stirred at 10 DEG C thereto
Mix reaction 16h.Then the DMF in system is drained, by surplus materials acetone solution, and insoluble matter is filtered out, filtrate is concentrated
Ether settles afterwards, and solid simultaneously drain by vacuum obtained by filtering, obtains compound 2, is white solid powder 650mg.
Reaction equation is as follows：
The compound 2 of preparation is characterized using infrared absorption spectrum, nuclear magnetic resonance and electrospray ionization mass spectrum, is characterized
As a result see Fig. 4, Fig. 5 and Fig. 6.Fig. 4 is the infrared absorption spectra of compound 2 prepared by the embodiment of the present invention 5, wherein, 1651cm-1
And 1745cm-1Stretching vibration peak of the absorption peak at place for the corresponding carbonyl C=O of Artesunate, 831cm-1、881cm-1With
1115cm-1The absorption peak at place be its-O-O- stretching vibration peak, 3250cm-1The absorption peak at place shakes for the flexible of cis-platinum amino ligands
Dynamic peak, and its 3500cm-1Place's-OH stretching vibration peaks disappear, and Fig. 4 illustrates that Artesunate is successfully made coordination with cis-platinum, obtains
Compound 2；Fig. 5 is the nuclear magnetic resonance H spectrograms of compound 2 prepared by the embodiment of the present invention 5, wherein, at 5.54-5.60ppm
Absorption peak be the proton hydrogen peak of methine being connected with bridging oxygen on Artesunate, the absorption peak at 5.64-5.71ppm places is sweet wormwood
The proton hydrogen peak of the methine of ester group is connected on amber ester；Absorption peak at 6.25-6.67ppm is cis-platinum ammonia ligand proton hydrogen peak,
It can be seen that the peak ownership of each proton hydrogen is clear and definite, and ratio is coincide, so as to again demonstrate the successful synthesis of compound 2；Fig. 6 is this hair
The mass spectrogram of compound 2 prepared by bright embodiment 5, maximum absorption peak m/z=1066 are the molecular ion of compound 2
Peak coincide with its molecular weight.
Fig. 4, Fig. 5 and Fig. 6 are demonstrated in the present invention, the successful preparation of compound 2.
Embodiment 6
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(639.2mg, 3.1mmol), I-hydroxybenzotriazole (419mg, 3.1mmol) and Artesunate (1153.2mg, 3mmol)
It is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 15ml, and be sufficiently stirred at 5 DEG C thereto
React 16h.Then the DMF in system is drained, by surplus materials acetone solution, and insoluble matter is filtered out, after filtrate is concentrated
Ether settles, and solid simultaneously drain by vacuum obtained by filtering, obtains compound 2, is white solid powder 700mg.
Reaction equation such as embodiment 5.
Embodiment 7
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(536.1mg, 2.6mmol), I-hydroxybenzotriazole (351.3mg, 2.6mmol) and Artesunate (961mg, 2.5mmol)
It is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 15ml, and fully stirred at 10 DEG C thereto
Mix reaction 18h.Then the DMF in system is drained, by surplus materials acetone solution, and insoluble matter is filtered out, filtrate is concentrated
Ether settles afterwards, and solid simultaneously drain by vacuum obtained by filtering, obtains compound 2, is white solid powder 720mg.
Reaction equation such as embodiment 5.
Embodiment 8
Cis-platinum (600mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, after room temperature is protected from light stirring 8h,
It is filtered to remove hydrogen peroxide and obtains Cisplatin (IV)-(OH)2Yellow powder.
By obtained Cisplatin (IV)-(OH)2(334mg, 1mmol), N, N'- dicyclohexylcarbodiimides (268mg,
2.6mmol), I-hydroxybenzotriazole (175.7mg, 2.6mmol) and Artesunate (576.3mg, 2.5mmol) are placed in dry
In the polymerization bottle of dry mistake, ventilation three times, then adds in the dried DMF of 10ml, and be sufficiently stirred reaction at 5 DEG C thereto
24h.Then the DMF in system is drained, by surplus materials acetone solution, and filters out insoluble matter, ether after filtrate is concentrated
Sedimentation, solid simultaneously drain by vacuum obtained by filtering, obtains compound 2, is white solid powder 750mg.
Reaction equation such as embodiment 5.
Embodiment 9
By CHAA-Pt-Cl2(764mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, and room temperature, which is protected from light, to be stirred
After mixing 8h, it is filtered to remove hydrogen peroxide and obtains CHAA-Pt (IV)-(OH)2Yellow powder.
By obtained CHAA-Pt (IV)-(OH)2(410mg, 1mmol), N, N'- dicyclohexylcarbodiimides (226.8,
It 1.1mmol) is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 5ml, stirred at 20 DEG C thereto
1h adds in Artesunate (384.4mg, 1mmol) and reaction 16h is sufficiently stirred at 10 DEG C.Then the DMF in system is drained,
By surplus materials acetone solution, and insoluble matter is filtered out, ether settles after filtrate is concentrated, and solid is obtained by filtration and vacuum is taken out
It is dry, obtain white solid powder 330mg.
Reaction equation is as follows：
Embodiment 10
By CHAA-Pt-Cl2(764mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, and room temperature, which is protected from light, to be stirred
After mixing 8h, it is filtered to remove hydrogen peroxide and obtains CHAA-Pt (IV)-(OH)2Yellow powder.
By obtained CHAA-Pt (IV)-(OH)2(410mg, 1mmol), N, N'- dicyclohexylcarbodiimides (639.2mg,
3.1mmol), I-hydroxybenzotriazole (419mg, 3.1mmol) and Artesunate (1153.2mg, 3mmol) are dissolved in 5ml and do
In dry DMF, and it is sufficiently stirred reaction at 5 DEG C for 24 hours.Then the DMF in system is drained, by surplus materials acetone solution,
And insoluble matter is filtered out, ether settles after filtrate is concentrated, and solid is obtained by filtration and vacuum is drained, obtains white solid powder
700mg。
Reaction equation is as follows：
Embodiment 11
Oxaliplatin (795mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, room temperature is protected from light stirring 8h
Afterwards, it is filtered to remove hydrogen peroxide and obtains Oxaliplatin (IV)-(OH)2Yellow powder.
By obtained Oxaliplatin (IV)-(OH)2(431mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(226.8,1.1mmol) are placed in dried polymerization bottle, and ventilation three times, then adds in the dried DMF of 5ml thereto, and 20
1h is stirred at DEG C, add in Artesunate (384.4mg, 1mmol) and reaction 16h is sufficiently stirred at 10 DEG C.Then system is drained
In DMF, by surplus materials acetone solution, and filter out insoluble matter, after filtrate is concentrated ether settle, solid is obtained by filtration
And vacuum is drained, and obtains white solid powder 320mg.
Reaction equation is as follows：
Embodiment 12
Oxaliplatin (795mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, room temperature is protected from light stirring 8h
Afterwards, it is filtered to remove hydrogen peroxide and obtains Oxaliplatin (IV)-(OH)2Yellow powder.
By obtained Oxaliplatin (IV)-(OH)2(431mg, 1mmol), N, N'- dicyclohexylcarbodiimides
(639.2mg, 3.1mmol), I-hydroxybenzotriazole (419mg, 3.1mmol) and Artesunate (1153.2mg, 3mmol) are molten
In the DMF that solution is dried in 5ml, and it is sufficiently stirred reaction at 5 DEG C for 24 hours.Then the DMF in system is drained, surplus materials is used
Acetone solution, and insoluble matter is filtered out, ether settles after filtrate is concentrated, and solid is obtained by filtration and vacuum is drained, obtains white
Solid powder 750mg.
Reaction equation is as follows：
Embodiment 13
By PyAA-Pt-Cl2(752mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, and room temperature, which is protected from light, to be stirred
After mixing 8h, it is filtered to remove hydrogen peroxide and obtains PyAA-Pt (IV)-(OH)2Yellow powder.
By obtained PyAA-Pt (IV)-(OH)2(410mg, 1mmol), N, N'- dicyclohexylcarbodiimides (226.8,
It 1.1mmol) is placed in dried polymerization bottle, ventilation three times, then adds in the dried DMF of 5ml, stirred at 20 DEG C thereto
1h adds in Artesunate (384.4mg, 1mmol) and reaction 16h is sufficiently stirred at 10 DEG C.Then the DMF in system is drained,
By surplus materials acetone solution, and insoluble matter is filtered out, ether settles after filtrate is concentrated, and solid is obtained by filtration and vacuum is taken out
It is dry, obtain white solid powder 300mg.
Reaction equation is as follows：
Embodiment 14
By PyAA-Pt-Cl2(752mg, 2mmol) is placed in flask, adds 30% hydrogen peroxide 10mL, and room temperature, which is protected from light, to be stirred
After mixing 8h, it is filtered to remove hydrogen peroxide and obtains PyAA-Pt (IV)-(OH)2Yellow powder.
By obtained PyAA-Pt (IV)-(OH)2(410mg, 1mmol), N, N'- dicyclohexylcarbodiimides (639.2mg,
3.1mmol), I-hydroxybenzotriazole (419mg, 3.1mmol) and Artesunate (1153.2mg, 3mmol) are dissolved in 5ml and do
In dry DMF, and it is sufficiently stirred reaction at 5 DEG C for 24 hours.Then the DMF in system is drained, by surplus materials acetone solution,
And insoluble matter is filtered out, ether settles after filtrate is concentrated, and solid is obtained by filtration and vacuum is drained, obtains white solid powder
650mg。
Reaction equation is as follows：
Embodiment 15
Compound 2 prepared by the compound 1 and embodiment 5 prepared to the embodiment of the present invention 1 carries out cytotoxicity test, point
Not using MCF-7, HeLa, A549, HepG2, A549/DDP cell as model, the compound 1 and embodiment that are provided with embodiment 1
5 compounds 2 provided are used as object to be detected, after the object to be detected is acted on cell, observe the survival rate situation of cell,
The cytotoxicity of platinum complex of the present invention is investigated in tetrazolium bromide (MTT) method, concrete operation step is as follows：
1) above-mentioned logarithmic phase cell is collected, adjusts the concentration of cell suspension, is added in 96 orifice plates, 100 μ l are added in per hole, often
Hole cell number about 5,000；
2) above-mentioned test specimen is placed in CO2In a concentration of 5% cell incubator, at 37 DEG C, under the conditions of saturated humidity
12h is cultivated, makes cell fully adherent；
3) compound 1 is diluted according to certain gradient multiple, concentration is respectively 108 μM, 54 μM, 27 μM, 13.5 μM, 6.75
μM, 3.375 μM, 1.6875 μM, then adding in has in 96 orifice plates of cell, and each concentration sets three multiple holes, incubation time setting
For for 24 hours, 48h, 72h；
4) the MTT solution (5mg/ml, i.e. 0.5%MTT) of 20 μ l is added in per hole, continues to cultivate 4h, sucks culture medium, per hole
Add the DMSO of 150 μ l, shaking table low speed concussion 10min that crystallization is made fully to dissolve；
5) light absorption value in each hole is detected at microplate reader 490nm；
6) while zeroing hole (culture medium, MTT, DMSO) and control group (cell, culture medium, MTT, DMSO) are set under
Face formula calculates cell viability：
Wherein, Abs (sample) is the light absorption value of sample sets cell；Abs (blank) is liquid in blank control group culture hole
The light absorption value of body；Abs (control) is the light absorption value of untreated experimental group cell.
Experimental result is shown in Table 1.
Comparative example 1
Cytotoxicity test is carried out to cis-platinum, respectively using MCF-7, HeLa, A549, HepG2, A549/DDP cell as mould
Type using cis-platinum as object to be detected, after the object to be detected is acted on cell, observes the survival rate situation of cell.With thiazole
Blue (MTT) method, investigates the cytotoxicity of cis-platinum, and concrete operation step is as follows：
1) above-mentioned logarithmic phase cell is collected, adjusts the concentration of cell suspension, is added in 96 orifice plates, 100 μ l are added in per hole, often
Hole cell number about 5,000；
2) above-mentioned test specimen is placed in CO2In a concentration of 5% cell incubator, at 37 DEG C, under the conditions of saturated humidity
12h is cultivated, makes cell fully adherent；
3) cis-platinum is diluted according to certain gradient multiple, concentration is respectively 108 μM, 54 μM, 27 μM, 13.5 μM, 6.75 μM,
3.375 μM, 1.6875 μM, then adding in has in 96 orifice plates of cell, and each concentration sets three multiple holes, and incubation time is set as
24h,48h,72h；
4) the MTT solution (5mg/ml, i.e. 0.5%MTT) of 20 μ l is added in per hole, continues to cultivate 4h, sucks culture medium, per hole
Add the DMSO of 150 μ l, shaking table low speed concussion 10min that crystallization is made fully to dissolve；
5) light absorption value in each hole is detected at microplate reader 490nm；
6) while zeroing hole (culture medium, MTT, DMSO) and control group (cell, culture medium, MTT, DMSO) are set under
Face formula calculates cell viability：
Wherein, Abs (sample) is the light absorption value of sample sets cell；Abs (blank) is liquid in blank control group culture hole
The light absorption value of body；Abs (control) is the light absorption value of untreated experimental group cell.
Experimental result is shown in Table 1.
1 cis-platinum of table and compound 1 handle different cells the IC of different time50It is worth (μM)
Table 1 is in the embodiment of the present invention 15 and comparative example 1, compound 1, compound 2, cis-platinum respectively to MCF-7, HeLa,
A549, HepG2, A549/DDP cell processing for 24 hours, the IC of 48h, 72h50Value Data summarizes.As shown in Table 1, it is provided by the invention
Platinum (IV) complex is to cancer cell such as MCF-7 Human Breast Cancer Cells, human cervical carcinoma Hela cell, human pulmonary epithelial cells, with
And human hepatoma HepG2 cell has good fragmentation effect, can still be obtained while system toxicity is reduced suitable with cis-platinum
Active anticancer, also have good fragmentation effect to the human lung adenocarcinoma A549/DDP cells of cisplatin resistance, have very low drug resistance
Property.
By above-described embodiment and comparative example it is found that platinum complex provided by the invention have higher antitumor activity and compared with
Low cytotoxicity.
The explanation of above example is only intended to facilitate the understanding of the method and its core concept of the invention.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvement and modification are also fallen within the protection scope of the claims of the present invention.
Claims (10)
1. a kind of chemical substance with active anticancer, which is characterized in that the chemical substance is change of the structural formula as shown in formula (I)
Conjunction object is either structural formula such as formula (II) compound represented or is structural formula such as formula (I) compound represented and structural formula
Such as the mixture of formula (II) compound represented：
In formula (I) and formula (II),For with one kind in lower structure：
2. a kind of preparation method of the chemical substance with active anticancer, which is characterized in that include the following steps：
A) platinum (II) compound with hydrogen peroxide is reacted, obtains platinum (IV) compound；
Platinum (II) compound is
B) under the conditions of anhydrous and oxygen-free, by step A) obtained platinum (IV) compound with Artesunate under the conditions of existing for condensing agent
It is reacted, obtains the chemical substance with active anticancer.
3. the preparation method of the chemical substance according to claim 2 with active anticancer, which is characterized in that the step
B in), the molar ratio of platinum (IV) compound and Artesunate is 1:The molar ratio of (0.8~1.2), Artesunate and condensing agent is
1:(1~1.2) obtains structural formula such as formula (I) compound represented.
4. the preparation method of the chemical substance according to claim 2 with active anticancer, which is characterized in that the step
B in), the molar ratio of platinum (IV) compound and Artesunate is 1:The molar ratio of (1.5~3), Artesunate and condensing agent is 1:
(1~1.2) obtains structural formula such as formula (II) compound represented.
5. the preparation method of the chemical substance with active anticancer according to claim 2-4 any one, feature exist
In the step A) in, the volume of hydrogen peroxide is (5mL~15mL) with the molar ratio of platinum (II) compound:(1mmol~
3mmol)。
6. the preparation method of the chemical substance with active anticancer according to claim 2-4 any one, feature exist
In the step A) in, platinum (II) compound is carried out with reacting for hydrogen peroxide under the conditions of being protected from light.
7. the preparation method of the chemical substance with active anticancer according to claim 2-4 any one, feature exist
In the step A) in, the reaction temperature of platinum (II) compound and hydrogen peroxide is room temperature, and the reaction time is 5~10h.
8. the preparation method of the chemical substance with active anticancer according to claim 2-4 any one, feature exist
In the step B) in, condensing agent N, N'- dicyclohexylcarbodiimide, I-hydroxybenzotriazole or N- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides, the solvent of reaction is N, N '-dimethyl formamide.
9. the preparation method of the chemical substance with active anticancer according to claim 2-4 any one, feature exist
In the step B) in, the temperature of reaction is 0 DEG C~20 DEG C, and the time is 16h~for 24 hours.
10. application of the chemical substance described in claim 1 with active anticancer in anticancer drug is prepared.
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