CN116874519A - Andrographolide modified compound H4 and preparation method and application thereof - Google Patents
Andrographolide modified compound H4 and preparation method and application thereof Download PDFInfo
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- CN116874519A CN116874519A CN202311141800.0A CN202311141800A CN116874519A CN 116874519 A CN116874519 A CN 116874519A CN 202311141800 A CN202311141800 A CN 202311141800A CN 116874519 A CN116874519 A CN 116874519A
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- andrographolide
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- cancer
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 143
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 136
- 150000001875 compounds Chemical class 0.000 title claims abstract description 133
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 37
- 238000002407 reforming Methods 0.000 claims description 30
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 29
- 206010017758 gastric cancer Diseases 0.000 claims description 29
- 201000011549 stomach cancer Diseases 0.000 claims description 29
- 206010038389 Renal cancer Diseases 0.000 claims description 28
- 201000001441 melanoma Diseases 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- 238000010828 elution Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 11
- -1 andrographolide derivative compound Chemical class 0.000 claims description 11
- 201000010982 kidney cancer Diseases 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 6
- 239000006071 cream Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000006210 lotion Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000375 suspending agent Substances 0.000 claims description 3
- 235000013311 vegetables Nutrition 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 18
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 238000011160 research Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 81
- 230000005764 inhibitory process Effects 0.000 description 27
- 230000035755 proliferation Effects 0.000 description 22
- 208000006265 Renal cell carcinoma Diseases 0.000 description 17
- 201000010174 renal carcinoma Diseases 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 244000118350 Andrographis paniculata Species 0.000 description 10
- 238000001514 detection method Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 6
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 6
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- 238000012986 modification Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 208000020588 necrotizing soft tissue infection Diseases 0.000 description 3
- 239000003883 ointment base Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000007747 plating Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000003127 anti-melanomic effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 241000207965 Acanthaceae Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 244000089409 Erythrina poeppigiana Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 235000009776 Rathbunia alamosensis Nutrition 0.000 description 1
- 229910004161 SiNa Inorganic materials 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000035899 viability Effects 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemistry, in particular to an andrographolide modified compound H4, a preparation method and application thereof. The andrographolide modified compound H4 provided by the invention has the effect of treating cancers, and the research of the invention shows that compared with andrographolide, the andrographolide modified compound H4 has more remarkable effect of inhibiting tumors, and can be used for preparing medicaments for treating cancers.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to an andrographolide modified compound H4, a preparation method and application thereof.
Background
The traditional Chinese medicine herba Andrographitis is dry aerial parts of herba Andrographitis of Acanthaceae, and has effects of clearing heat, removing toxic substances, cooling blood and detumescence, and inducing heart, lung, large intestine and bladder meridian. Andrographolide is white prismatic crystal, and is the main active ingredient of medicinal plant Andrographis paniculata Nees. Because andrographolide is a diterpenoid lactone compound, the andrographolide has the defects of poor water solubility, poor in vivo stability and the like, so that the in vivo bioavailability is low, the clinical use is limited to a certain extent, and based on the nature defect of andrographolide and the relatively active structural characteristics of the andrographolide, researchers in recent years do a large number of structural modification and activity screening work so as to find more effective candidate compounds.
The research finds that the anti-tumor effect of andrographolide is closely related to the apoptosis of tumor cells mediated by the andrographolide, and the andrographolide can promote the apoptosis of various cancer cells such as liver cancer, prostate cancer and the like, and the tumor inhibition effect of the andrographis paniculata reconstruction compound is to be discussed.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to provide an andrographolide modified compound H4, a preparation method and application thereof.
For this purpose, the invention provides the following technical scheme:
an andrographolide-modified compound H4 has the following structural formula:
。
the preparation method of the andrographolide modified compound H4 comprises the following steps:
s1, in a weak alkaline reaction system, andrographolide and tert-butyl dimethyl chlorosilane are mixed to generate nucleophilic substitution reaction, so as to obtain an andrographolide modified compound E1;
s2, mixing an andrographolide reforming compound E1 with acetic anhydride, heating to 120-180 ℃, and carrying out nucleophilic substitution reaction on acyl carbon to modify hydroxyl groups at positions 3 and 14 of the andrographolide reforming compound E1 into acetyl groups to obtain an andrographolide reforming compound H4; the synthetic route is as follows:
。
optionally, primary hydroxyl at 19 th position of andrographolide is protected by tert-butyldimethylsilyl (TBS), and secondary hydroxyl at 3 rd and 14 th positions are protected by acetyl to obtain andrographolide modified compound H4.
。
Optionally, in the step S1, the molar ratio of andrographolide to tert-butyldimethyl chlorosilane is 0.2:1-0.3:6; and/or
In the step S1, stirring and reacting for 1-4 hours at room temperature under the nucleophilic substitution reaction condition; and/or
In step S1, the method further comprises the steps of quenching, extracting, washing, drying, filtering, concentrating under reduced pressure and/or purifying the obtained andrographolide derivative compound E1.
Optionally, in the step S2, the mass-volume ratio of the andrographolide-modified compound E1 to acetic anhydride is less than or equal to 93:4, and the proportional relationship is mg/ml; and/or
In the step S2, the nucleophilic substitution reaction time is 1-4 hours; and/or
In the step S2, the method further comprises the steps of extracting, washing, drying, filtering, concentrating under reduced pressure and/or purifying the obtained andrographolide derivative compound H4.
Optionally, in step S1, the purification step is to separate the crude product of andrographolide derivative compound E1 by silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate according to the volume ratio of (40-60): (0.5-2) → (1-20) → (0.1-2) for gradient elution, and preferably 50:1→10:1, gradient elution is carried out; and/or
In the step S2, the purification step is to separate the andrographolide reconstruction compound H4 crude product by silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate according to the volume ratio of (40-80): (0.5-2) → (1-20): (0.1-2) for gradient elution, and the preferable ratio is 50:1→10:1 gradient elution.
The andrographolide modified compound H4 is prepared by the preparation method of the andrographolide modified compound H4.
The andrographolide modified compound H4 or the derivative thereof has application in preparing medicaments for treating cancers.
Alternatively, the cells of the cancer include gastric cancer, renal cancer or melanoma.
Optionally, the cells of the gastric cancer are selected from gastric cancer MKN45 cells; and/or
The cells of kidney cancer are selected from kidney cancer 786O cells; and/or
The melanoma cells are selected from melanoma A375 cells.
Alternatively, the derivative of andrographolide reforming compound H4 includes its cis-trans isomer, its diastereoisomer, its geometric isomer, its racemate, its solvate, its pharmaceutically acceptable salt or its prodrug.
A pharmaceutical composition for the treatment of cancer comprising a therapeutically effective amount of said andrographolide modifying compound H4 or a derivative thereof.
Optionally, a pharmaceutically acceptable carrier is also included, including water, oil, vegetables, minerals, a cream base, a lotion base, or an ointment base.
Optionally, the cream, lotion or ointment base comprises a suspending agent, a viscosity increasing agent and/or a transdermal enhancer.
Definition and description
Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are present in the present invention, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The andrographolide reforming compound H4 of the present invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
The andrographolide-modified compound H4 of the present invention may have an asymmetric carbon atom (optical center) or a double bond. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
Pharmaceutically acceptable carriers for andrographolide-modifying compound H4 refer to any formulation or carrier medium representative of carriers including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like capable of delivering an effective amount of the active substances of the present invention, without interfering with the biological activity of the active substances and without toxic or side effects to the host or patient. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like.
The technical scheme of the invention has the following advantages:
1. the andrographolide modified compound H4 provided by the invention has the effect of treating cancers, and the research of the invention shows that compared with andrographolide, the andrographolide modified compound H4 has more remarkable effect of inhibiting tumors, and can be used for preparing medicaments for treating cancers.
2. The invention provides a preparation method of an andrographolide modified compound H4, which comprises the following steps: s1, under a weak alkaline environment, andrographolide and tert-butyl dimethyl chlorosilane are mixed to generate nucleophilic substitution reaction, so as to obtain an andrographolide modified compound E1; s2, mixing an andrographolide reforming compound E1 with excessive acetic anhydride, heating to 120-180 ℃, and carrying out nucleophilic substitution reaction on acyl carbon to modify hydroxyl groups at positions 3 and 14 of the andrographolide reforming compound E1 into propionyl groups to obtain an andrographolide reforming compound H4; the preparation method is simple and quick, the types of the reaction substrates required to be added are fewer, the subsequent purification steps are facilitated, and the propionic anhydride can be used as a reactant or a reactant, so that the preparation method has no toxic or side effect.
3. The application of the andrographolide reforming compound H4 or the derivative thereof in preparing medicaments for treating cancers including gastric cancer, renal cancer or melanoma is verified by the invention, and compared with the anti-tumor effect of the non-reforming andrographolide, the andrographolide reforming compound H4 or the derivative thereof has more remarkable inhibition effect on gastric cancer, renal cancer or melanoma.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a HRMS of andrographolide derivative H4 obtained in example 1;
FIG. 2 shows the result of example 1 in the production of andrographolide reforming Compound H4 1 H NMR chart;
FIG. 3 shows the result of example 1 in the production of andrographolide reforming Compound H4 13 C NMR chart;
FIG. 4 is an HPLC chart of andrographolide modified compound H4 obtained in example 1;
FIG. 5 shows the proliferation inhibition of gastric cancer MKN45 cells by andrographolide modifying compound H4 at various concentrations for 24 hours;
FIG. 6 shows the proliferation inhibition of gastric cancer MKN45 cells by andrographolide modifying compound H4 at different concentrations at 48 hours;
FIG. 7 shows the proliferation inhibition of gastric cancer MKN45 cells by andrographolide modifying compound H4 at various concentrations for 72 hours;
FIG. 8 shows the effect of andrographolide modifying compound H4 on gastric cancer MKN45 cells;
FIG. 9 shows the compound concentrations at which gastric cancer MKN45 cells reached half inhibition 24 hours after administration of andrographolide reforming compound H4;
FIG. 10 shows the half-inhibitory compound concentrations of gastric cancer MKN45 cells 48 hours after administration of andrographolide reforming compound H4;
FIG. 11 shows the compound concentrations at which gastric cancer MKN45 cells reached half inhibition when andrographolide reforming compound H4 was administered for 72 hours;
FIG. 12 shows the proliferation inhibition of 786O cells of renal carcinoma by andrographolide reforming compound H4 at various concentrations for 24 hours;
FIG. 13 shows the proliferation inhibition of 786O cells of renal carcinoma by andrographolide reforming compound H4 at various concentrations at 48 hours;
FIG. 14 shows the proliferation inhibition of 786O cells of renal carcinoma by andrographolide reforming compound H4 at various concentrations for 72 hours;
FIG. 15 shows the effect of andrographolide-modifying compound H4 on renal carcinoma 786O cells;
FIG. 16 shows the half-inhibitory compound concentrations of andrographolide-modified compound H4 administered 24 hours to renal carcinoma 786O cells;
FIG. 17 shows the half-inhibitory compound concentrations of andrographolide-modified compound H4 administered 48 hours for renal carcinoma 786O cells;
FIG. 18 shows the half-inhibitory compound concentrations of andrographolide-modified compound H4 administered for 72 hours to renal carcinoma 786O cells;
FIG. 19 shows the proliferation inhibition of melanoma A375 cells by andrographolide structuring compound H4 at various concentrations over 24 hours;
FIG. 20 shows the proliferation inhibition of melanoma A375 cells by andrographolide modifying compound H4 at various concentrations at 48 hours;
FIG. 21 shows the proliferation inhibition of melanoma A375 cells by andrographolide structuring compound H4 at various concentrations over 72 hours of administration;
FIG. 22 shows the effect of andrographolide modifying compound H4 on melanoma A375 cells;
FIG. 23 shows the compound concentrations at which half inhibition of melanoma A375 cells was achieved 24 hours after administration of andrographolide reforming compound H4;
FIG. 24 shows the compound concentrations at which half inhibition of melanoma A375 cells was achieved 48 hours after administration of andrographolide reforming compound H4;
FIG. 25 shows the compound concentrations at which melanoma A375 cells reached half inhibition 72 hours after administration of andrographolide reforming compound H4;
FIG. 26 shows the proliferation inhibition of gastric cancer MKN45 cells at various concentrations of AG at 24 hours of administration;
FIG. 27 shows the proliferation inhibition of gastric cancer MKN45 cells at various concentrations of AG at 48 hours of administration;
FIG. 28 shows the proliferation inhibition of gastric cancer MKN45 cells at various concentrations of AG for 72 hours;
FIG. 29 is a graph showing half-inhibitory compound concentrations of gastric cancer MKN45 cells at 24 hours AG administration;
FIG. 30 is a graph showing half-inhibitory compound concentrations in gastric cancer MKN45 cells at 48 hours AG administration;
FIG. 31 is a graph showing half-inhibitory compound concentrations of gastric cancer MKN45 cells at 72 hours AG administration;
FIG. 32 shows the proliferation inhibition of renal carcinoma 786O cells by AG at various concentrations over 24 hours of administration;
FIG. 33 shows the proliferation inhibition of 786O cells of renal carcinoma by AG at various concentrations for 48 hours;
FIG. 34 shows the proliferation inhibition of 786O cells of renal carcinoma by AG at various concentrations over 72 hours of administration;
FIG. 35 is a graph showing the half-inhibitory concentration of compounds in renal carcinoma 786O cells 24 hours after AG administration;
FIG. 36 shows the compound concentrations to half inhibition of renal carcinoma 786O cells 48 hours after AG administration;
FIG. 37 is a graph showing the half-inhibitory concentration of compounds in renal carcinoma 786O cells at 72 hours of AG administration;
FIG. 38 shows the proliferation inhibition of melanoma A375 cells by AG at various concentrations over 24 hours of administration;
FIG. 39 shows the proliferation inhibition of melanoma A375 cells by AG at various concentrations over 48 hours of administration;
FIG. 40 shows the proliferation inhibition of melanoma A375 cells by AG at various concentrations over 72 hours of administration;
FIG. 41 is a graph showing the half-maximal inhibitory compound concentration of melanoma A375 cells at 24 hours of AG administration;
FIG. 42 is a graph showing the half-maximal inhibitory compound concentration of melanoma A375 cells at 48 hours of AG administration;
FIG. 43 is a graph showing the half-maximal inhibitory compound concentration of melanoma A375 cells at 72 hours of AG administration;
the base of log on the abscissa in the figures above for half-inhibited compound concentrations is 10.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1
The present embodiment provides an andrographolide derivative compound H4, wherein the name is: (3S, 4E) -4- {2- [ (1R, 4aS,5R,6R,8 aS) -6- (acetoxy) -5- { [ (tert-butyldimethylchlorosilane) methoxy } -5,8 a-dimethyl-2-ethylene-decahydronaphthalen-1-yl ] ethylene } -5-oxooxoxolan-3-acetic acid ethyl ester having the following structural formula:
。
the synthetic route is as follows:
。
the preparation method comprises the following steps:
(1) Andrographolide (100.0 mg,0.285 mmol) and pyridine (2 mL) were added to the flask, followed by tert-butyldimethylsilyl (TBDMSCl) (500.0 mg, 3.32 mmol) and magnetic stirring at room temperature (25 ℃) for reaction 3h. Into the reaction mixtureEtOAc (30 mL) was added to dilute, then water (40 mL) was added to quench the reaction, and extracted with ethyl acetate (EtOAc, 80 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 Drying, filtering, and separating the crude product of the organic filtrate by vacuum concentration by silica gel column chromatography (PE: EA=50:1→10:1, v/v) gradient elution to obtain 107 mg white solid (compound E1), yield: 81%.
(2) Into a reaction flask were added compound E1 (93.0 mg,0.2 mmol) and acetic anhydride (Ac) 2 O) (4 mL), heated to 145 ℃, and reacted further at 145 ℃ for 1h. After cooling to room temperature, etOAc (100 mL) was added to the reaction mixture to dilute it, followed by saturated NaHCO 3 The solution (100 mL) was quenched, washed with water and extracted with EtOAc (100 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 Drying, filtering, and separating the crude product of the organic filtrate by vacuum concentration by silica gel column chromatography (PE: EA=50:1→10:1, v/v) gradient elution to obtain 81 mg white solid (andrographolide reconstruction compound H4), yield: 74%.
Carrying out mass spectrum and nuclear magnetic resonance detection on the andrographolide modified compound H4 obtained in the above way:
Hi-Res MS (ESI):m/z[M+Na] + ：C 30 H 48 O 7 SiNa 571.3055 (calculated. 571.3062). As shown in fig. 1.
1 H NMR (400 MHz, CDCl 3 ) δ 7.01 (t,J= 6.6 Hz, 1H), 5.91 (d,J= 6.4 Hz, 1H), 4.87 (s, 1H), 4.62-4.50 (m, 2H), 4.48 (s, 1H), 4.24 (d,J= 12.8 Hz, 1H), 3.81 (d,J= 10.4 Hz, 1H), 3.58 (d,J=10.4 Hz, 1H), 2.50-2.33 (m, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.90-1.78 (m, 3H), 1.76-1.65 (m, 3H), 1.34-1.21 (m, 3H), 0.93 (s, 3H), 0.87 (s, 9H), 0.80 (s, 3H), 0.02 (s, 6H). As shown in fig. 2.
13 C NMR (101 MHz, CDCl 3 ) δ 170.90, 170.65, 169.22, 150.82, 147.40, 123.90, 108.48, 80.21, 71.72, 67.95, 63.81, 56.18, 55.63, 42.54, 39.14, 38.36, 37.47, 25.99, 25.41, 24.49, 23.40, 21.41, 20.86, 18.35, 14.47, -5.52, -5.59. As shown in fig. 3.
HPLC test is carried out on the andrographolide as a starting material, and the chromatographic conditions are as follows: the mobile phase is methanol-water (95:5, v/v); the elution procedure is isocratic elution; the chromatographic column is RPC18 column; the detection wavelength is 230 nm; the column temperature was room temperature (27 ℃); the results of the detection are shown in Table 1 below, and the purity of andrographolide is 98.8%.
TABLE 1
Carrying out HPLC detection on the obtained andrographolide modified compound E1, wherein the chromatographic conditions are as follows: the mobile phase is methanol-water (90:10, v/v); the elution procedure is isocratic elution; the chromatographic column is RPC18 column; the detection wavelength is 230 nm; the column temperature was room temperature (27 ℃); the results of the detection are shown in the following table, and the purity of the andrographolide derivative compound E1 is 98.1%.
TABLE 2
Carrying out HPLC detection on the obtained andrographolide modified compound H4, wherein the chromatographic conditions are as follows: the mobile phase is methanol-water (90:10, v/v); the elution procedure is isocratic elution; the chromatographic column is RPC18 column; the detection wavelength is 230 nm; the column temperature was room temperature (27 ℃); the results of the tests are shown in the following table and in FIG. 4, the purity of Andrographis paniculata Nees modified compound H4 is 98.8%.
TABLE 3 Table 3
Example 2
The preparation method of the andrographolide modified compound H4 comprises the following steps:
(1) Andrographolide (0.2 mmol) and pyridine (2 mL) were added to the flask, and tert-butyldimethylsilyl (TBDMSCl) (1 mmol) was added thereto at room temperature (20deg.C)) The reaction was stirred magnetically for 1h. EtOAc (30 mL) was added to the reaction mixture to dilute it, then water (40 mL) was added to quench the reaction, and extracted with ethyl acetate (EtOAc, 80 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 Drying, filtering, and separating the crude product of the organic filtrate by vacuum concentration by silica gel column chromatography (PE: EA=40:0.5→1:0.1, v/v) gradient elution to obtain white solid (compound E1).
(2) Adding compound E1 and acetic anhydride (Ac) to a reaction flask 2 O) (mass-to-volume ratio of compound E1 and propionic anhydride is 93:5, proportional relationship is mg/ml), heated to 120 ℃, and reacted for 3 hours at 120 ℃. After cooling to room temperature, etOAc (100 mL) was added to the reaction mixture to dilute it, followed by saturated NaHCO 3 The solution (100 mL) was quenched, washed with water and extracted with EtOAc (100 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 Drying, filtering, and separating the crude product of the organic filtrate after reduced pressure concentration by silica gel column chromatography (PE: EA=40:0.5→1:0.1, v/v) gradient elution to obtain white solid (andrographolide reconstruction compound H4).
Example 3
The preparation method of the andrographolide modified compound H4 comprises the following steps:
(1) Andrographolide (0.3 mmol) and pyridine (4 mL) were added to the flask, and tert-butyldimethylsilyl (TBDMSCl) (6 mmol) was added thereto, followed by magnetic stirring at room temperature (20deg.C) for 24 hours. EtOAc (30 mL) was added to the reaction mixture to dilute it, then water (40 mL) was added to quench the reaction, and extracted with ethyl acetate (EtOAc, 80 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 The crude product was dried, filtered, and the organic filtrate was concentrated under reduced pressure and separated by a silica gel column chromatography (PE: ea=60:2→20:2, v/v) gradient elution to give a white solid (compound E1).
(2) Adding compound E1 and acetic anhydride (Ac) to a reaction flask 2 O) (mass volume of Compound E1 and propionic anhydrideThe ratio was 93:4, the ratio was mg/ml), heated to 180℃and the reaction was continued at 180℃for 4h. After cooling to room temperature, etOAc (100 mL) was added to the reaction mixture to dilute it, followed by saturated NaHCO 3 The solution (100 mL) was quenched, washed with water and extracted with EtOAc (100 mL ×3). The combined organic phases were washed successively with brine (100 mL), anhydrous Na 2 SO 4 Drying, filtering, and separating the crude product of the organic filtrate by vacuum concentration by silica gel column chromatography (PE: EA=80:2→20:2, v/v) gradient elution to obtain white solid (andrographolide reconstruction compound H4).
EXAMPLE 4 action of Andrographolide modification Compound H4 in inhibiting human gastric cancer
1. Experimental materials
Cell origin and culture: human gastric cancer cell line MKN45 was purchased from the cell resource center of the college of synergetics, which is the national infrastructure of cell line resources, headquarters of NSTI, and the cells were cultured at 37℃in a medium of 1640 containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin, 5% CO 2 In an incubator.
Test sample: andrographolide modified compound H4 prepared in example 1, commercially available Andrographolide (AG) and a commercially available anti-gastric cancer positive drug cyclophosphamide.
2. Experimental method
And the influence of the andrographis paniculata compound H4 on the gastric cancer cell viability is detected by adopting a CCK8 experimental method. The specific operation is as follows: MKN45 cells were seeded at a density of 5000 cells/well in 96-well plates for culture; the cells were grouped as follows: andrographolide-modified Compound H4 different final concentration gradient drug administration groups (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 75. Mu.M, 100. Mu.M); AG different final concentration gradient dosing groups (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M); cyclophosphamide group as an anti-gastric cancer positive drug (final concentration 3.583 mM); the control group is 1640 culture medium group without adding medicine; a blank group without cells and without medicine is additionally arranged.
Drug intervention after 24 hours of cell plating, and after 24, 48 and 72 hours of drug administration, CCK8 reagent (purchased from Japanese homozygote) was added to detect tumor cell survival rate, and IC was calculated 50 。
The results are shown in FIGS. 5-11 and 26-31, and the herba Andrographitis modified compound H4 can significantly inhibit gastric cancer MKN45 cell proliferation, and exert antitumor effect, and its IC 50 (24h) 18.46. Mu.M, IC 50 (48h) 12.22. Mu.M, IC 50 (72h) IC of 13.48. Mu.M, AG 50 (24h) 47.16. Mu.M, IC 50 (48h) 15.52. Mu.M, IC 50 (72h) 12.52. Mu.M, it can be seen that Andrographis paniculata Nees Compound H4 was administered 24, 48H after IC 50 Compared with AG, the effect of the andrographis paniculata modified compound H4 on inhibiting the proliferation of gastric cancer MKN45 cells is obvious, and meanwhile, the effect of the andrographis paniculata modified compound H4 on inhibiting the proliferation of gastric cancer MKN45 cells is quick.
EXAMPLE 5 action of Andrographis paniculata modification Compound H4 in inhibiting human renal carcinoma
1. Experimental materials
Cell origin and culture: human renal carcinoma cell line 786O was purchased from the institute of Association and medicine cell resource center (which is the national infrastructure for cell line resources, headquarters of NSTI) and cells were cultured at 37℃in 5% CO using 1640 medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin 2 In an incubator.
Test sample: andrographolide modified compound H4 prepared in example 1, commercially available Andrographolide (AG) and a commercially available renal cancer positive drug fluorouracil.
2. Experimental method
The experimental method comprises the following steps: the effect of andrographis paniculata compound H4 on the viability of kidney cancer cells was examined by CCK8 assay. The specific operation is as follows: 786O cells were seeded at a density of 5000 cells/well in 96-well plates for culture; the cells were grouped as follows: andrographolide-modified Compound H4 different concentration gradient administration groups (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 75. Mu.M, 100. Mu.M); AG different concentration gradient dosing groups (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M); fluorouracil group (38.4. Mu.M, 192. Mu.M) as positive drug for renal cancer; the control group is 1640 culture medium group without adding medicine; a blank group without cells and without medicine is additionally arranged.
Dosing intervention 24 hours after cell plating,after 24, 48 and 72 hours, respectively, after administration, the survival rate of tumor cells was measured by adding CCK8 reagent (purchased from Japanese homozygote), and IC was calculated 50 。
The results are shown in FIG. 12-FIG. 18 and FIG. 32-FIG. 37, and andrographolide derivative H4 can significantly inhibit proliferation of 786-O cells of renal carcinoma, and exert antitumor effect, and its IC 50 (24h) 6.406. Mu.M, IC 50 (48h) 3.462. Mu.M, IC 50 (72h) IC of 3.349. Mu.M, AG 50 (24h) 22.37. Mu.M, IC 50 (48h) 11.11. Mu.M, IC 50 (72h) From the above, it can be seen that andrographolide has been modified to have an IC of H4 of 6.397. Mu.M 50 (24h)、IC 50 (48h)、IC 50 (72h) All are significantly lower than AG, indicating that andrographolide-modified compound H4 is more pronounced than AG in inhibiting renal carcinoma 786-O cell proliferation, and also indicating a faster effect.
EXAMPLE 6 Andrographolide modification Compound H4 inhibition of human melanoma
1. Experimental materials
Cell origin and culture: human melanoma A375 was purchased from the institute of medicine and Association cell resource center (which is the national infrastructure for cell line resources, headquarters of NSTI) and the cells were cultured in high-sugar DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. Mu.g/ml streptomycin at 37℃and 5% CO 2 In an incubator.
Test sample: andrographolide modified compound H4 prepared in example 1, commercially available Andrographolide (AG) and commercially available anti-melanoma positive drug paclitaxel.
2. Experimental method
The effect of compound H4 on melanoma cell viability was examined using CCK8 assay. The specific operation is as follows: a375 cells were seeded at a density of 5000 cells/well in 96-well plates for culture; the cells were grouped as follows: compound H4 different final concentration gradient dosing groups (1 μm,5 μm,10 μm,25 μm,50 μm,75 μm,100 μm); AG different final concentration gradient dosing groups (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M, 200. Mu.M); the anti-melanoma positive drug paclitaxel group (final concentration 5. Mu.M, final concentration 10. Mu.M); the control group is 1640 culture medium group without adding medicine; a blank group without cells and without medicine is additionally arranged.
Drug intervention after 24 hours of cell plating, and after 24, 48 and 72 hours of drug administration, CCK8 reagent (purchased from Japanese homozygote) was added to detect tumor cell survival rate, and IC was calculated 50 。
The results are shown in FIGS. 19-25 and 38-43, and the Andrographis paniculata Nees modified compound H4 can significantly inhibit proliferation of melanoma A375 cells, and exert antitumor effect, and its IC 50 (24h) 5.021. Mu.M, IC 50 (48h) 6.368. Mu.M, IC 50 (72h) IC of 3.044. Mu.M, AG 50 (24h) 18.6. Mu.M, IC 50 (48h) 14.11. Mu.M, IC 50 (72h) From this, it can be seen that andrographolide has been modified to compound H4 IC at 12.06. Mu.M 50 (24h)、IC 50 (48h)、IC 50 (72h) All are significantly lower than AG, indicating that andrographolide-modified compound H4 is more pronounced than AG in inhibiting melanoma A375 cell proliferation, and also indicating that it is more potent.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (10)
1. An andrographolide-modified compound H4 is characterized by having the following structural formula:
。
2. a method for preparing the andrographolide derivative compound H4 according to claim 1, comprising the following steps:
s1, in a weak alkaline reaction system, andrographolide and tert-butyl dimethyl chlorosilane are mixed to generate nucleophilic substitution reaction, so as to obtain an andrographolide modified compound E1;
s2, mixing an andrographolide reforming compound E1 with acetic anhydride, heating to 120-180 ℃, performing nucleophilic substitution reaction on acyl carbon, and modifying hydroxyl groups at positions 3 and 14 of the andrographolide reforming compound E1 into acetyl groups to obtain an andrographolide reforming compound H4; the synthetic route is as follows:
。
3. the method for preparing andrographolide reforming compound H4 according to claim 2, wherein in step S1, the molar ratio of andrographolide to t-butyldimethylchlorosilane is 0.2:1-0.3:6; and/or
In the step S1, stirring and reacting for 1-24 hours at room temperature under the nucleophilic substitution reaction condition; and/or
In the step S1, the weakly alkaline reaction system is pyridine; and/or
In the step S1, the method further comprises the steps of quenching, extracting, washing, drying, filtering, concentrating under reduced pressure and/or purifying the obtained andrographolide modified compound E1; and/or
In the step S2, the mass volume ratio of the andrographolide modified compound E1 to acetic anhydride is less than or equal to 93:4, and the proportional relationship is mg/ml; and/or
In the step S2, the nucleophilic substitution reaction time is 1-4 hours; and/or
In the step S2, the method further comprises the steps of extracting, washing, drying, filtering, concentrating under reduced pressure and/or purifying the obtained andrographolide derivative compound H4.
4. The method for preparing andrographolide reforming compound H4 according to claim 3,
in the step S1, the purification step is to separate the crude andrographolide reconstruction compound E1 by silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate according to the volume ratio of (40-60): (0.5-2) → (1-20): (0.1-2) for gradient elution; and/or
In the step S2, the purification step is to separate the andrographolide reconstruction compound H4 crude product by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate according to the volume ratio of (40-80)/(0.5-2) → (1-20)/(0.1-2) and carry out gradient elution.
5. An application of the andrographolide derivative H4 or the derivative thereof as defined in claim 1 or the andrographolide derivative H4 prepared by the preparation method of the andrographolide derivative H4 as defined in any one of claims 2 to 4 in preparing medicines for treating cancers.
6. The use of andrographolide modifying compound H4 or a derivative thereof according to claim 5, for the preparation of a medicament for the treatment of cancer, wherein the cancer comprises gastric cancer, renal cancer or melanoma.
7. The use of andrographolide modifying compound H4 or a derivative thereof according to claim 6 for preparing a medicament for treating cancer, wherein the cells of gastric cancer are selected from gastric cancer MKN45 cells; and/or
The cells of kidney cancer are selected from kidney cancer 786O cells; and/or
The melanoma cells are selected from melanoma A375 cells.
8. Use of an andrographolide modifying compound H4 or a derivative thereof according to any one of claims 5 to 7 for the preparation of a medicament for the treatment of cancer, wherein the derivative of andrographolide modifying compound H4 comprises its cis-trans isomer, its diastereoisomer, its geometric isomer, its racemate, its solvate, a pharmaceutically acceptable salt or a prodrug thereof.
9. A pharmaceutical composition for the treatment of cancer, characterized by comprising a therapeutically effective amount of andrographolide reforming compound H4 or a derivative thereof according to claim 1 or andrographolide reforming compound H4 or a derivative thereof prepared by the method for preparing andrographolide reforming compound H4 according to any one of claims 2 to 4.
10. The pharmaceutical composition for treating cancer according to claim 9, further comprising a pharmaceutically acceptable carrier comprising water, oil, vegetables, minerals, a cream base, or a lotion base;
the cream or lotion base includes a suspending agent, a viscosity increasing agent, and/or a transdermal enhancer.
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| RADA BUNTHAWONG ET AL.: "Synthesis and cytotoxic activity of new 7-acetoxy-12-amino-14-deoxy andrographolide analogues", 《BIOORG. MED.CHEM.LETT.》, vol. 33, pages 127741 * |
| SAI GIRIDHAR SARMA KANDANUR ET AL.: "Synthesis and biological evaluation of new C-12(α/β)-(N-) sulfamoylphenylamino- 14-deoxy-andrographolide derivatives as potent anticancer agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 27, pages 2854 * |
| 欧阳德亮等: "穿心莲内酯对胃癌AGS 细胞增殖侵袭的影响", 《中南医学科学杂志》, vol. 42, no. 3, pages 246 - 250 * |
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