CN104163823A - camptothecin and artesunate conjugate as well as preparation method and application thereof - Google Patents
camptothecin and artesunate conjugate as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104163823A CN104163823A CN201410181237.4A CN201410181237A CN104163823A CN 104163823 A CN104163823 A CN 104163823A CN 201410181237 A CN201410181237 A CN 201410181237A CN 104163823 A CN104163823 A CN 104163823A
- Authority
- CN
- China
- Prior art keywords
- camptothecine
- artesunate
- conjugate
- organic solvent
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 91
- 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 title claims abstract description 68
- 229960004991 artesunate Drugs 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title abstract 5
- 229940127093 camptothecin Drugs 0.000 title abstract 5
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title abstract 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract description 17
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims abstract description 13
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 206010006187 Breast cancer Diseases 0.000 claims description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 201000005619 esophageal carcinoma Diseases 0.000 claims description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 2
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 201000008261 skin carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 239000003814 drug Substances 0.000 description 9
- 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 8
- 229960004191 artemisinin Drugs 0.000 description 8
- 229930101531 artemisinin Natural products 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- 238000012423 maintenance Methods 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 102000002070 Transferrins Human genes 0.000 description 6
- 108010015865 Transferrins Proteins 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 150000002505 iron Chemical class 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- -1 iron ion Chemical class 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229960002190 topotecan hydrochloride Drugs 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 240000000011 Artemisia annua Species 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 101100045694 Caenorhabditis elegans art-1 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 101001109419 Homo sapiens RNA-binding protein NOB1 Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100022491 RNA-binding protein NOB1 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 101150043789 cpt2 gene Proteins 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a camptothecin and artesunate conjugate shown in formula , and a preparation method thereof comprises the following steps: dissolving camptothecin shown in a formula (II) and artesunate shown in a formula (III) in an organic solvent, stirring and reacting at 15-50 ℃ under the action of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine, tracking and monitoring by TLC (thin layer chromatography) until the reaction is not carried out any more, and carrying out post-treatment on a reaction solution to obtain a camptothecin and artesunate conjugate shown in a formula ; the camptothecin and artesunate conjugate can be used for preparing antitumor drugs;
Description
(1) technical field
The present invention relates to a kind of camptothecine and Artesunate conjugate and preparation method thereof, and in the application of preparing in antitumor drug.
(2) background technology
Camptothecine derives from Chinese Plants camplotheca acuminata, and due to the mechanism of action of its uniqueness, in cancer therapy drug research field, a large amount of camptothecin derivatives is synthesized and studies.Camptothecine extremely derivative has all played good inhibition for various cancer cells, for example: lung cancer, prostate cancer, mammary cancer, colorectal carcinoma, cancer of the stomach, ovarian cancer, melanoma, lymphoma etc.But that camptothecine is not applied to is clinical, because himself high toxicity and poor solvability.The another kind of Artemisinin extracting from composite family artemisia sweet wormwood has used more than 2000 year as anti-malaria medicaments always, and Artemisinin extremely derivative is considered to safely and effectively always.Research finds, Artemisinin can be combined with Transferrins,iron complexes in vivo, and himself chemical structure has comprised a peroxide bridge, when can form a free radical in the time that iron ion is combined, thus the restraining effect of playing.Transferrins,iron complexes is the functional protein of being responsible for transhipment iron ion in organism, and with respect to normal cell, cancer cells is higher to the demand of iron ion, this to such an extent as to Artemisinin can play better action effect to cancer cells.The for example transferrin content on breast cancer cell surface is Normocellular 5-15 times, and Transferrins,iron complexes is expressed on breast cancer cell, and breast cancer cell has absorbed a large amount of iron ions, and normal cell does not have.Therefore Artemisinin is because this compound can be combined with Transferrins,iron complexes in vivo to the selective action of cancer cells, and Transferrins,iron complexes can be to the high position transport of iron ion content.
Therefore the mechanism of utilizing Artemisinin to be combined with Transferrins,iron complexes, Artemisinin is used as to carrier to be used, and camptothecine has the restraining effect higher for various cancer cells, but the large feature of himself toxicity, we are by camptothecine and artemisinin derivative---Artesunate coupling, when making it there is better inhibition to cancer cells, reduce self toxicity.
(3) summary of the invention
The object of the invention is to provide a kind of camptothecine and Artesunate conjugate and preparation method thereof, and in the application of preparing in antitumor drug, camptothecine of the present invention and Artesunate conjugate all have inhibited proliferation in various degree to liver cancer cell (SMMC-7721), human breast cancer cell (MCF-7) etc.
For achieving the above object, the technical solution used in the present invention is:
Camptothecine and Artesunate conjugate shown in a kind of formula (I):
The preparation method of a kind of camptothecine of the present invention and Artesunate conjugate, described preparation method is: Artesunate shown in camptothecine shown in formula (II) and formula (III) is dissolved in organic solvent a, under the effect of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and DMAP (DMAP), in 15～50 DEG C of stirring reactions, TLC tracking monitor to reaction is no longer carried out, reaction solution aftertreatment, obtains the camptothecine shown in formula (I) and Artesunate conjugate.
The preparation method of camptothecine of the present invention and Artesunate conjugate, wherein said organic solvent a is the solvent that side reaction does not occur with it solubilized reaction substrate, as chloroform or methylene dichloride etc., is preferably chloroform; The volumetric usage of described organic solvent a can, as 1～10mL/mmol, be preferably 3～5mL/mmol taking the molar weight of camptothecine.
The preparation method of camptothecine of the present invention and Artesunate conjugate, wherein said camptothecine can be 1:1～10 with the ratio of the amount of substance that feeds intake of Artesunate, is preferably 1:3;
The ratio of the amount of substance that feeds intake of described camptothecine and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride can be 1:1～5, is preferably 1:3;
The quality consumption of described DMAP can, as 1～20mg/mmol, be preferably 5～10mg/mmol taking the molar weight of camptothecine.
The preparation method of camptothecine of the present invention and Artesunate conjugate, recommends feeding method as follows: under room temperature, first Artesunate to be dissolved in chloroform, after dissolving completely, add EDCI, stir 30 minutes, then add DMAP, continue to stir 30 minutes, finally add camptothecine, stirring reaction; And, preferably stirring reaction 3 hours at 25 DEG C.
The preparation method of camptothecine of the present invention and Artesunate conjugate, described post-treating method is:
After reaction finishes, in reaction solution, add organic solvent b, suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, and gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target compound, concentrate drying, obtains the camptothecine shown in formula (I) and Artesunate conjugate; Described organic solvent b is chloroform or methylene dichloride, and its volumetric usage is 2 times of organic solvent a volume.
Concrete, the preparation method of recommendering folder invention camptothecine and Artesunate conjugate is: under room temperature, Artesunate is dissolved in organic solvent a, after dissolving completely, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, stir 30 minutes, add again DMAP, continue to stir 30 minutes, finally add camptothecine, stirring reaction 3 hours at 25 DEG C, after reaction finishes, in reaction solution, add organic solvent b, suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target compound, concentrate drying, obtain the camptothecine shown in formula (I) and Artesunate conjugate, wherein, described organic solvent a is chloroform, and the volumetric usage of described organic solvent a is counted 3～5mL/mmol with the molar weight of camptothecine, described camptothecine is 1:3 with the ratio of the amount of substance that feeds intake of Artesunate, the ratio of the amount of substance that feeds intake of described camptothecine and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:3, the quality consumption of described DMAP is counted 5～10mg/mmol with the molar weight of camptothecine, in last handling process, described organic solvent b is chloroform or methylene dichloride, and its volumetric usage is 2 times of organic solvent a volume.
In the present invention, organic solvent a and organic solvent b all refer to organic solvent, and wherein, label a, b are just for distinguishing different operating step organic solvent used.
Camptothecine of the present invention and Artesunate conjugate can be used for preparing antitumor drug, and described camptothecine and Artesunate conjugate are 10～60mg/kg body weight as antitumor inhibitor to the quality consumption of common mouse.
Described tumour is as cerebral tumor, oral carcinoma, laryngocarcinoma, the esophageal carcinoma, lung cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, colorectal carcinoma, mammary cancer, ovarian cancer, carcinoma of the pancreas, bladder cancer, skin carcinoma, leukemia, sarcoma, the rectum cancer, glioma and HIV (human immunodeficiency virus) (HIV), but is not only confined to this.
Camptothecine of the present invention and Artesunate conjugate can also be made various formulations with the acceptable pharmaceutical excipient combination of human body, comprise solution, injection, tablet, capsule, ointment, gelifying agent etc.Camptothecine of the present invention and Artesunate conjugate can be together with conventional pharmaceutical excipients, and with the form of pharmaceutical composition, by oral, snuffing enters, the mode of stomach or administered parenterally is applied to patient.When oral, can be made into conventional solid preparation as tablet, pulvis, granula, capsule etc.; During for administered parenterally, can be made into solution, water or the oiliness suspension agent of injection; Externally used solution agent, lotion, liniment, ointment, paste, patch that percutaneous drug delivery is used; Gargle, sublingual tablet, suppository, film that mucosa delivery is used; Enema that rectal administration is used, suppository, rectal capsule bolt etc.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: the camptothecine and the Artesunate conjugate that the invention provides a kind of novelty, and this conjugate has anti-tumor activity, can be used in and prepare antitumor drug, camptothecine of the present invention and Artesunate conjugate have inhibited proliferation (referring to embodiment 3) in various degree, the IC of this conjugate to liver cancer cell (SMMC-7721), human breast cancer cell (MCF-7)
50basic and camptothecine maintains an equal level.And show by experimentation on animals, this conjugate has reduced (embodiment 4) to the injury of body to a great extent with respect to camptothecine.
(4) brief description of the drawings
Fig. 1 is the situation that camptothecine and Artesunate conjugate suppress proliferative activity o f tumor;
Fig. 2 is camptothecine and the impact of Artesunate conjugate on Mouse Weight;
In figure, the implication of each label is: CPT---camptothecine group, ART---Artesunate group, C-Q---conjugate group, Control---control group.
(5) embodiment
Below by specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
Embodiment 1: the preparation (1) of camptothecine and Artesunate conjugate
In 25mL round-bottomed flask, add Artesunate (15mmol) and methylene dichloride (10mL), 25 DEG C of stirring and dissolving, add again EDCI (15mmol), 25 DEG C are stirred 0.5h, then add DMAP (50mg), 25 DEG C are stirred 0.5h, finally add camptothecine (5mmol), 25 DEG C of stirring reaction 3h, obtain faint yellow suspension liquid, after reaction finishes, in reaction solution, add methylene dichloride (20mL), suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target components, after concentrate drying, obtain the camptothecine shown in formula (I) and Artesunate conjugate, productive rate 80%.
MP:194.8-195.3℃
1H-NMR(500MHz,CDCl3):8.3742(s,1H),8.2587(d,J＝8.5HZ,2H),7.9331(d,J＝8.15HZ,1H),7.8157(t,J＝7.5HZ,1H),7.6525(t,J＝7.4HZ,1H),7.2865(d,J＝5.5HZ,1H),5.679,(m,J＝9.85HZ,2H),5.4117,(d,J＝17.15HZ,1H),5.2991(s,1H),5.2606(d,J＝3.75HZ,1H),5.1177(s,1H),2.8763(m,J＝6,85HZ,2H),2.8623(m,J＝9.69HZ,2H),2.4341(m,J＝3.55HZ,2H),2.3180(m,J＝7.2125HZ,2H),1.9937(m,J＝9.8152HZ,3H),1.8264(m,J＝3.258HZ,1H),1.6931(m,J＝4.2625HZ,1H),1.6159(d,J＝5.33HZ,1H),1.5121(m,J＝4.48HZ,1H),1.3301(m,J＝7.45HZ,4H),0.9940(m,J＝7.475HZ,3H),0.9353(m,J＝7.2375HZ,5H),0.7791(d,J＝7.1HZ,3H)；
13C-NMR171.1203,170.6127(ArtC＝O),167.3167(CPT-16a),157.3081(CPT-21),152.4506(CPT-6),148.8204(CPT-15),146.2229(CPT-8),145.7012(CPT-13),131.0144(CPT-12),130.4693(CPT-3),129.7100(CPT-2),128.6331(CPT-7),128.1745(CPT-11),128.1107(CPT-10),127.8704(CPT-16),120.2405(CPT-9),104.2652(ART-12),96.3067(ART-4),92.2332(ART-5),91.2771(ART-6),79.8964(CPT-20),76.1379(CPT-14),51.4200(ART-1),49.9400(CPT-5),45.1595(ART-7),37.0777(ART-10),36.0987(ART-3),33.9923(ART-9),31.8131(CPT-19),31.6769(ART-11),28.8540,28.5795(ART-O＝C-C-C＝O-),25.7284(ART-15),24.4896(ART-2),21.8608(ART-8),20.1093(ART-14),11.9571(ART-13),7.5473(CPT-18),IR＝(Ar-H:2929.03,2875.63C＝O:1750.98,1663.72)HRMSm/z[M+H]
+:715.2840(Calcd?for?C
39H
43N
2O
11:715.2867).
Embodiment 2: the preparation (2) of camptothecine and Artesunate conjugate
In 25mL round-bottomed flask, add Artesunate (10mmol) and chloroform (20mL), 30 DEG C of stirring and dissolving, add again EDCI (10mmol), 30 DEG C are stirred 0.5h, then add DMAP (50mg), 25 DEG C are stirred 0.5h, finally add camptothecine (3mmol), 30 DEG C of stirring reaction 3h, obtain faint yellow suspension liquid, after reaction finishes, in reaction solution, add methylene dichloride (40mL), suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target components, after concentrate drying, obtain the camptothecine shown in formula (I) and Artesunate conjugate, productive rate 85%.
Embodiment 3: shown in formula (I), compound is to tumor cell proliferation inhibition activity
1) test materials
Liver cancer cell (SMMC-7721), human breast cancer cell (MCF-7), all purchased from typical case's culture collection council of Chinese Academy of Sciences cell bank.
Camptothecine and Artesunate standard substance are purchased from lark prestige bio tech ltd.
Cell maintenance medium is 2% serum-concentration substratum, and SMMC-7721 uses RPMI1640 substratum, and MCF-7 uses DMEM substratum.
Camptothecine prepared by embodiment 1 and Artesunate conjugate, camptothecine, Artesunate, dimethyl sulfoxide (DMSO) (DMSO) are diluted with cell maintenance medium respectively, every kind of sample does 6 concentration gradients: 0.032,0.16,0.8,4,20,100 μ mol/L, each concentration gradient is done 4 multiple holes.
2) detection method
By the human liver cancer cell in being logarithmic phase (SMMC-7721), human breast cancer cell (MCF-7), be configured to single cell suspension with corresponding nutrient solution, with 10
5the density in individual/hole is inoculated in 96 orifice plates, CO
2in cell culture incubator, cultivate after 24h for 37 DEG C, discard cell culture fluid, be divided into 5 groups: group 1 is experimental group (conjugate of preparing with cell maintenance medium dilution embodiment 1, concentration is 0.032,0.16,0.8,4,20,100 μ mol/L); Group 2 is blank group (only adding cell maintenance medium); Organize 3 negative control groups (adding the isocyatic DMSO of cell maintenance medium dilution); Organize 4 positive control groups (adding the isocyatic camptothecine standard substance of cell maintenance medium dilution), group 5 is positive control group (adding the isocyatic Artesunate standard substance of cell maintenance medium dilution) also.Every hole adds reference substance or the medicine of 100 μ L, CO
2in incubator, hatch after 48h for 37 DEG C, the MTT solution that every hole adds the 5mg/mL of 20 μ L, continues to hatch after 4h, discard liquid in hole, add 100 μ LDMSO, vibrate to the abundant dissolving of purple precipitation, the absorbance value (OD value) in each hole while being 492nm with microplate reader mensuration wavelength.Calculate the average OD value in multiple hole, the growth inhibition ratio according to average OD value computerized compound to cell: inhibiting rate=1-[(experimental group OD value-blank group OD value)/(negative control group OD value-blank group OD value)] × 100%.The results are shown in Figure shown in 1.
Measure compound shown in formula (I) to two kinds of tumour cells with mtt assay: the cell inhibitory effect activity of liver cancer cell (SMMC-7721), human breast cancer cell (MCF-7), suppresses activity to growth of tumour cell and sees Fig. 1.As seen from the figure, compound shown in formula (I) has all showed inhibition growth activity in various degree to two kinds of tumour cells.By the analysis to detected result, camptothecine of the present invention and Artesunate conjugate inhibiting rate and the camptothecine to tumour cell is close, higher than Artesunate inhibition.And experimental result demonstration, along with increasing of concentration, the inhibition of conjugate is progressively higher than camptothecine.
Embodiment 4: compound activity in vivo shown in formula (I) is evaluated
1) test materials
Camptothecine prepared by medicine: embodiment 1 and Artesunate conjugate, camptothecine, Artesunate, topotecan hydrochloride.Described medicine is first used respectively DMSO and dissolve with ethanol, use respectively again normal saline dilution, in the each drug solution of dilution gained, the volumetric concentration of DMSO is 5%, the volumetric concentration of ethanol is 5%, drug level regulates (volume injected is 200 μ L, and dosage is 0.023mmol/kg/2days) according to the body weight of mouse.
Test is bought from Shanghai Slac Experimental Animal Co., Ltd. with nude mice.
2) detection method
The female BALB/c nude mice in four to five week age has been chosen in this experiment, and when treating that nude mouse weighs 18 ± 2g, human breast cancer cell (MCF-7 cell) is inoculated in to nude mice oxter, and (cell concn of inoculated tumour is 1 × 10
7every mouse of individual cell).When the volume of nude mice tumour grows to 200mm
3, getting 35 successful mouse of tumor inoculation when the left and right, be divided at random 5 groups, is respectively camptothecine and Artesunate conjugate group, camptothecine group, Artesunate group, topotecan hydrochloride group, every group of 7 mouse.After overnight fasting, intraperitoneal administration, administration group is according to 0.023mmol/kg/2days dosed administration, volume injected is 200 μ L (regulating drug for injection concentration according to Mouse Weight), control group injecting normal saline 200 μ L, be administration every other day, be administered four times altogether, within the 8th day, put to death and get tumour and weigh.Tumour inhibiting rate result is as follows:
The tumour inhibiting rate of table 1 different pharmaceutical to human breast cancer cell
| ? | Topotecan hydrochloride | Camptothecine | Artesunate | Conjugate |
| Tumour inhibiting rate (%) | 70.21±1.32 | 45.31±1.34 | 40.21±0.34 | 50.19±1.31 |
From table tumor suppression experimental result we can draw conjugate tumour inhibiting rate higher than Artesunate and camptothecine, not as good as clinical medicine topotecan hydrochloride, the solvability of this and compound has certain relation.
By Mouse Weight is monitored (as shown in Figure 2), we can find out that camptothecine is to the having the greatest impact of Mouse Weight, and mouse mean body weight, by the 17.8g starting to camptothecine, drops to 11.9g after 8 days, and toxicity is very large; And to Artesunate group Mouse Weight and the basic identical 17g of control group, toxicity can be ignored substantially; Mouse Weight to conjugate group dropped to 15.8g after 8 days, illustrated that conjugate toxicity is between Artesunate and camptothecine, far below camptothecine.
Claims (9)
1. the camptothecine shown in a formula (I) and Artesunate conjugate:
2. the preparation method of a camptothecine as claimed in claim 1 and Artesunate conjugate, it is characterized in that described preparation method is: Artesunate shown in camptothecine shown in formula (II) and formula (III) is dissolved in organic solvent a, under the effect of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and DMAP, in 15～50 DEG C of stirring reactions, TLC tracking monitor to reaction is no longer carried out, reaction solution aftertreatment, obtains the camptothecine shown in formula (I) and Artesunate conjugate;
3. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, is characterized in that described organic solvent a is chloroform or methylene dichloride.
4. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, is characterized in that the volumetric usage of described organic solvent a is counted 1～10mL/mmol with the molar weight of camptothecine.
5. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, is characterized in that described camptothecine is 1:1～10 with the ratio of the amount of substance that feeds intake of Artesunate; The ratio of the amount of substance that feeds intake of described camptothecine and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:1～5.
6. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, is characterized in that the quality consumption of described DMAP is counted 1～20mg/mmol with the molar weight of camptothecine.
7. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, is characterized in that described post-treating method is:
After reaction finishes, in reaction solution, add organic solvent b, suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, and gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target compound, concentrate drying, obtains the camptothecine shown in formula (I) and Artesunate conjugate; Described organic solvent b is chloroform or methylene dichloride, and its volumetric usage is 2 times of organic solvent a volume.
8. the preparation method of camptothecine as claimed in claim 2 and Artesunate conjugate, it is characterized in that described preparation method is: under room temperature, Artesunate is dissolved in organic solvent a, after dissolving completely, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, stir 30 minutes, add again DMAP, continue to stir 30 minutes, finally add camptothecine, stirring reaction 3 hours at 25 DEG C, after reaction finishes, in reaction solution, add organic solvent b, suction filtration, filtrate is successively with saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing, use again anhydrous magnesium sulfate drying, suction filtration, filtrate decompression is concentrated into dry, gained enriched material carries out silica gel column chromatography, eluent is methylene dichloride and the methyl alcohol mixed liquor of volume ratio 100:1, collect the elutriant containing target compound, concentrate drying, obtain the camptothecine shown in formula (I) and Artesunate conjugate, wherein, described organic solvent a is chloroform, and the volumetric usage of described organic solvent a is counted 3～5mL/mmol with the molar weight of camptothecine, described camptothecine is 1:3 with the ratio of the amount of substance that feeds intake of Artesunate, the ratio of the amount of substance that feeds intake of described camptothecine and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:3, the quality consumption of described DMAP is counted 5～10mg/mmol with the molar weight of camptothecine, in last handling process, described organic solvent b is chloroform or methylene dichloride, and its volumetric usage is 2 times of organic solvent a volume.
9. camptothecine as claimed in claim 1 and Artesunate conjugate, in the application of preparing in antitumor drug, is characterized in that described tumour is cerebral tumor, oral carcinoma, laryngocarcinoma, the esophageal carcinoma, lung cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, colorectal carcinoma, mammary cancer, ovarian cancer, carcinoma of the pancreas, bladder cancer, skin carcinoma, leukemia, sarcoma, the rectum cancer, glioma or human immunodeficiency virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410181237.4A CN104163823B (en) | 2014-04-30 | 2014-04-30 | camptothecin and artesunate conjugate as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410181237.4A CN104163823B (en) | 2014-04-30 | 2014-04-30 | camptothecin and artesunate conjugate as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104163823A true CN104163823A (en) | 2014-11-26 |
| CN104163823B CN104163823B (en) | 2016-03-09 |
Family
ID=51907824
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410181237.4A Active CN104163823B (en) | 2014-04-30 | 2014-04-30 | camptothecin and artesunate conjugate as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104163823B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315294A (en) * | 2014-06-26 | 2016-02-10 | 王杭祥 | 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof |
| CN108484623A (en) * | 2018-05-17 | 2018-09-04 | 浙江工业大学 | camptothecin derivative and preparation method and application thereof |
| CN109575051A (en) * | 2019-01-23 | 2019-04-05 | 遵义医学院 | A kind of natural medicinal ingredients modified derivative and its antitumor application thereof |
| CN109675050A (en) * | 2018-12-27 | 2019-04-26 | 浙江工业大学 | conjugate of analogue taking camptothecin as parent nucleus and non-steroidal anti-inflammatory drug, preparation and application thereof |
| CN110423259A (en) * | 2019-08-13 | 2019-11-08 | 广东工业大学 | A kind of camptothecine glycoconjugate and its preparation method and application |
| CN113788848A (en) * | 2021-10-18 | 2021-12-14 | 福州大学 | Phthalocyanine-artemisinin conjugate used as acoustic power/optical power sensitizer and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1214686A (en) * | 1996-01-30 | 1999-04-21 | 斯特林癌症研究基金会 | Derivatives of camptothecin for use in treating cancer |
| CN1553802A (en) * | 2001-01-18 | 2004-12-08 | ����������̫ƽ��ҽѧ���� | Camptothecin derivatives |
| CN1850828A (en) * | 2006-05-26 | 2006-10-25 | 华东理工大学 | Podophyllotoxin derivatives and their preparing method |
| CN102649795A (en) * | 2011-06-23 | 2012-08-29 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
-
2014
- 2014-04-30 CN CN201410181237.4A patent/CN104163823B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1214686A (en) * | 1996-01-30 | 1999-04-21 | 斯特林癌症研究基金会 | Derivatives of camptothecin for use in treating cancer |
| CN1553802A (en) * | 2001-01-18 | 2004-12-08 | ����������̫ƽ��ҽѧ���� | Camptothecin derivatives |
| CN1850828A (en) * | 2006-05-26 | 2006-10-25 | 华东理工大学 | Podophyllotoxin derivatives and their preparing method |
| CN102649795A (en) * | 2011-06-23 | 2012-08-29 | 东北林业大学 | 10-methoxyl camptothecin derivative, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| IKUHIKO NAKASE ET AL.: ""Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》, vol. 354, 6 September 2007 (2007-09-06), pages 28 - 33, XP022550487, DOI: doi:10.1016/j.ijpharm.2007.09.003 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315294A (en) * | 2014-06-26 | 2016-02-10 | 王杭祥 | 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof |
| CN108484623A (en) * | 2018-05-17 | 2018-09-04 | 浙江工业大学 | camptothecin derivative and preparation method and application thereof |
| CN109675050A (en) * | 2018-12-27 | 2019-04-26 | 浙江工业大学 | conjugate of analogue taking camptothecin as parent nucleus and non-steroidal anti-inflammatory drug, preparation and application thereof |
| CN109575051A (en) * | 2019-01-23 | 2019-04-05 | 遵义医学院 | A kind of natural medicinal ingredients modified derivative and its antitumor application thereof |
| CN109575051B (en) * | 2019-01-23 | 2021-07-27 | 遵义医科大学 | Natural medicine component modified derivative and anti-tumor application thereof |
| CN110423259A (en) * | 2019-08-13 | 2019-11-08 | 广东工业大学 | A kind of camptothecine glycoconjugate and its preparation method and application |
| CN110423259B (en) * | 2019-08-13 | 2021-01-26 | 广东工业大学 | Camptothecin glycoconjugate and preparation method and application thereof |
| CN113788848A (en) * | 2021-10-18 | 2021-12-14 | 福州大学 | Phthalocyanine-artemisinin conjugate used as acoustic power/optical power sensitizer and preparation method and application thereof |
| CN113788848B (en) * | 2021-10-18 | 2022-07-22 | 福州大学 | Phthalocyanine-artemisinin conjugate used as sonodynamic/photodynamic sensitizer and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104163823B (en) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104163823B (en) | camptothecin and artesunate conjugate as well as preparation method and application thereof | |
| CN108358973B (en) | Naphthalimide tetravalent platinum compound, preparation method and application thereof in preparation of antitumor drugs | |
| CN102617610B (en) | Preparation method of porphyrin photosensitizer and anticarcinogen diad | |
| CN102675323A (en) | Pyrrole-(2, 1-f) (1, 2 and 4) triazine derivative (I) and antitumor effect thereof | |
| CN116917288A (en) | 7, 9-dihydro purine derivative and pharmaceutical application thereof | |
| CN104478890B (en) | A kind of all-trans-retinoic acid-camptothecin cancer therapy drug conjugate and its preparation method and application | |
| CN113416199B (en) | Lycorine beta-aryl acrylate derivative and preparation method and application thereof | |
| CN111662250A (en) | Quaternized modified taxane derivative, pharmaceutical composition, synthetic route and application thereof | |
| CN107216283B (en) | A kind of beta-elemene derivatives and its preparation method and application containing dihydropyridine structure | |
| CN108836937A (en) | Cisplatin nano pharmaceutical preparation, preparation method and application | |
| CN108084177A (en) | A kind of jamaicin 9- pyrazole derivatives and its preparation and application | |
| CN107141284B (en) | Coptisine analog derivative, preparation method, pharmaceutical composition and anticancer usage | |
| RU2561118C2 (en) | Camptothecin derivatives, possessing antitumour activity | |
| CN104530081A (en) | Nitrogenous heterocyclic derivative of rapamycin and application | |
| EP3369740B1 (en) | New cytidine derivative dimers and applications thereof | |
| CN104292211A (en) | Desloratadine nitric oxide donor, and preparation method and application thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN108164476B (en) | Isophthalonitrile compound, application thereof and medicine containing compound | |
| CN104230913A (en) | Piperazine-substituted quinazoline compound and use thereof | |
| CN112279863A (en) | Conjugate of Hsp90 inhibitor and camptothecin derivative as well as preparation method and application thereof | |
| CN108727245B (en) | Salicylic acid compound and preparation method and application thereof | |
| CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
| WO2022258035A1 (en) | Choline carbonate prodrug, preparation method therefor and use thereof | |
| CN104961794B (en) | Tanshinone IIA derivative, and preparation and application of tanshinone IIA derivative | |
| CN109748917B (en) | Ellipticine derivatives, pharmaceutical compositions thereof, process for their preparation and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |