CN111848690A - Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof - Google Patents
Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof Download PDFInfo
- Publication number
- CN111848690A CN111848690A CN202010827724.9A CN202010827724A CN111848690A CN 111848690 A CN111848690 A CN 111848690A CN 202010827724 A CN202010827724 A CN 202010827724A CN 111848690 A CN111848690 A CN 111848690A
- Authority
- CN
- China
- Prior art keywords
- platinum complex
- tetravalent platinum
- anticancer
- immune escape
- precipitate
- 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.)
- Pending
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 44
- 230000004054 inflammatory process Effects 0.000 title claims abstract description 21
- 206010061218 Inflammation Diseases 0.000 title claims abstract description 20
- 230000017188 evasion or tolerance of host immune response Effects 0.000 title claims abstract description 17
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002244 precipitate Substances 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 239000012317 TBTU Substances 0.000 claims abstract description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 3
- -1 tetrafluoroborate Chemical compound 0.000 claims abstract description 3
- 238000001291 vacuum drying Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 230000009471 action Effects 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 48
- 150000001875 compounds Chemical class 0.000 description 31
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 21
- 229960004316 cisplatin Drugs 0.000 description 21
- 102000008096 B7-H1 Antigen Human genes 0.000 description 11
- 108010074708 B7-H1 Antigen Proteins 0.000 description 11
- 206010006187 Breast cancer Diseases 0.000 description 11
- 208000026310 Breast neoplasm Diseases 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 10
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 4
- 239000002033 PVDF binder Substances 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 231100000057 systemic toxicity Toxicity 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 238000004294 195Pt NMR spectroscopy Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002038 chemiluminescence detection Methods 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000013115 immunohistochemical detection Methods 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides an anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and a preparation method thereof, and particularly relates to the field of biological medicine, wherein the molecular structure of the anticancer tetravalent platinum complex is as follows:
the synthesis method comprises the following steps: s1, mixing the divalent platinum complex with hydrogen peroxide H2O2Reacting to obtain a tetravalent platinum complex; s2 reaction of tetravalent platinum complex obtained in S1 with
Mixing O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU) and Triethylamine (TEA) in a N, N-Dimethylformamide (DMF) solution, and stirring and mixing uniformly; s3, after the reaction is finished, collecting filtrate, concentrating to 0.5-5 mL, dropwise adding a mixture of ethanol and water, centrifuging and collecting precipitate; and dissolving the precipitate in methanol, washing the precipitate with ether for 3 times, and vacuum drying to obtain the target product. The tetravalent platinum complex has strong toxic activity on tumor cells, inhibits inflammation and immune escape through a plurality of action targets, and shows excellent anti-tumor effect on living bodies.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to an anti-cancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and a preparation method thereof.
Background
Platinum antineoplastic drugs have become the most widely used metal drugs in clinic, and the first generation of platinum antineoplastic drugs represented by Cisplatin (CDDP) has played a leading role in the treatment of various solid tumors such as head and neck cancer, malignant pleural mesothelioma and the like since being approved by FDA for the treatment of testicular cancer and ovarian cancer. However, severe side effects can occur during treatment due to the strong cytotoxicity of cisplatin. In order to overcome the defects and reduce the systemic toxicity of cisplatin, the second-generation platinum antitumor drugs carboplatin (1989), nedaplatin (Japan), the third-generation platinum antitumor drugs oxaliplatin (2002), leplatin (China) and heptaplatin (Korea) were developed. Compared with cisplatin, carboplatin has great improvement on the aspect of relieving renal toxicity, the action mechanism of oxaliplatin is changed due to structural change, cross drug resistance with cisplatin is avoided, and toxic and side effects are reduced, so that the anticancer spectrum of platinum drugs is widened. Statistically, over 50% of the current anti-tumor chemotherapy regimens in clinical tumor treatment are based on or include platinum drugs. However, platinum antineoplastic drugs still face some challenges, such as high systemic toxicity, drug resistance, low selectivity and the like, and although the toxic and side effects of the second and third-generation platinum drugs are reduced, the problems are not solved fundamentally because the platinum antineoplastic drugs are analogues of cisplatin. Therefore, it is necessary to develop a novel platinum anticancer complex to overcome the defects of the conventional platinum drugs.
Inflammation is closely related to angiogenesis, immune tolerance, metastasis, invasion and drug resistance of tumors. The non-steroidal anti-inflammatory drug is an important bridge for connecting cancer and inflammation, and can reduce the risk and the death rate of the cancer; inhibition of cyclooxygenase (COX-2) and blocking of the prostaglandin cascade are the major causes of cancer inhibition. In addition, programmed death ligand 1(PD-L1) plays a key role in tumor evasion immune surveillance, and increased expression of PD-L1 on the surface of cancer cells and resultant T cell suppression contribute to immune escape of cancer cells. It has been found that COX-2 and prostaglandin (PGE2) have effects of promoting tumor inflammation and immunosuppression, and COX-2 can regulate the expression of PD-L1 in various cancers, so that inhibition of COX-2 can also affect PD-L1, thereby possibly promoting the immune response of cancer cells. Meanwhile, the inhibition of inflammation and immune escape provides a new idea for designing anti-tumor drugs and also provides an opportunity for obtaining novel multi-specific platinum drugs.
Disclosure of Invention
The invention aims to provide an anti-cancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and a preparation method thereof, the complex has excellent cytotoxic activity on tumor cells, plays an anti-tumor function through multi-specificity action from the aspects of inhibiting inflammation (inflammatory factors and related biological enzyme activity) and improving immune check point blocking treatment, and shows excellent anti-tumor effect and better anti-inflammatory and immunoregulation functions on a living body.
The invention provides the following technical scheme:
an anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape, which has the following molecular structure:
it is preferable that
The structure of (1) is as follows:
a preparation method of an anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape comprises the following steps:
s1, mixing the divalent platinum complex with hydrogen peroxide H2O2Reacting to obtain a tetravalent platinum complex;
wherein the divalent platinum complex is
S2 reaction of tetravalent platinum complex obtained in S1 with
Mixing O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU) and Triethylamine (TEA) in a N, N-Dimethylformamide (DMF) solution, and stirring and mixing uniformly;
s3, after the reaction is finished, collecting filtrate, concentrating to 0.5-5 mL, dropwise adding a mixture of ethanol and water, centrifuging and collecting precipitate; and dissolving the precipitate in methanol, washing the precipitate with ether for 1-10 times, and vacuum drying to obtain the target product.
Preferably, in the step S2, the mixture is stirred and mixed uniformly under the protection of nitrogen.
Preferably, in the step S3, the solution is concentrated to 1mL by rotary evaporation; the precipitate was washed 3 times with diethyl ether.
The invention has the beneficial effects that:
the tetravalent platinum complex has excellent antitumor activity in vivo and in vitro, treats cancer from two aspects of inhibiting inflammation and blocking immune check points, has a plurality of action targets participating in an antitumor process, and has an action mechanism different from that of the traditional platinum drugs. The derivatives also comprise stereoisomers or pharmaceutically acceptable salts thereof, and preparations prepared by taking the derivatives as active ingredients or main active ingredients and auxiliary pharmaceutically acceptable auxiliary materials.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 shows the preparation of the compound of example 1 of the present invention1H-NMR spectrum (DMSO-d)6，400MHz)；
FIG. 2 shows the preparation of the compound of example 1 of the present invention13C-NMR spectrum (DMSO-d)6，101MHz)；
FIG. 3 shows the preparation of the compound of example 1 of the present invention195Pt-NMR Spectrum (DMSO-d)6，86MHz)；
FIG. 4 is a graph showing the relative amounts of the compounds prepared in example 1 of the present invention and the inflammatory factors IL-6 and IL-1. beta. in mouse macrophage RAW264.7 after stimulation with LPS;
FIG. 5 shows prostaglandin E of breast cancer cells MCF-7 by the compound prepared in example 1 of the present invention2Inhibitory effects of secretion;
FIG. 6 shows the inhibitory effect of the compound prepared in example 1 of the present invention on cyclooxygenase COX-2 in breast cancer cells MCF-7;
FIG. 7 shows the inhibitory effect of the compound prepared in example 1 on PD-L1 in breast cancer cells MDA-MB-231;
FIG. 8 is a graph showing the inhibition of Balb/C nude mice carrying MDA-MB-231 transplanted breast cancer by the compound prepared in example 1 and cisplatin according to the present invention;
FIG. 9 is a graph showing the effect of the compound prepared in example 1 of the present invention and cisplatin on the volume of mouse MDA-MB-231 transplanted breast cancer;
FIG. 10 is a graph showing the effect of the compound prepared in example 1 of the present invention and cisplatin on body weight during MDA-MB-231 transplantation breast cancer tumor-bearing mice treatment;
FIG. 11 is an image of an immunohistochemical section of the compound prepared in example 1 of the present invention and cisplatin on inflammatory and immune-related proteins in mouse MDA-MB-231 transplanted breast cancer tissues;
FIG. 12 is a schematic diagram of the mechanism of action of the compound prepared in example 1 of the present invention.
Detailed Description
Example 1
Synthesis of tetravalent platinum complexes
S1, dropwise adding hydrogen peroxide (30 wt%, 20mL) into a cisplatin (CDDP, 400mg,1.33mmol) aqueous solution (12mL), refluxing and stirring at 60 ℃ for 4h, after the reaction is finished, cooling the bright yellow solution at room temperature overnight to obtain pale yellow crystals, filtering, washing with ice water, and drying in vacuum to obtain a tetravalent Oxoplatin yellow powdery product;
s2, mixing oxyplatin (100mg, 0.30mmol) with
(NPX, 207.23mg, 0.90mmol), TEA (125. mu.L, 0.90mmol) and TBTU (288.99mg, 0.90mmol) were mixed in DMF (15mL) and stirred for 48h, protected from light.
S3, after the reaction is finished, adding a mixture of ethanol and water into the mixture, and precipitating a yellow crude product. The precipitate was dissolved in methanol, washed several times with ether and dried in vacuo to give a pale yellow powder with a yield of about 65%.
EXAMPLE 2 cytotoxic Activity assay of Compounds
The compound prepared in the embodiment 1 of the invention is subjected to cytotoxic activity test, breast cancer cells (MFC-7, MDA-MB-231, MDA-MB-435), ovarian cancer cells (Caov-3) and cervical cancer cells (HeLa) are respectively used as models, the compound synthesized in the embodiment 1 and cisplatin are used as the substances to be detected, after the substances to be detected act on the cells, the survival condition of the cells is observed, and the survival rate of the cells is tested by a thiazole blue (MTT) method, and the specific operation steps are as follows:
s1, collecting the cells in the logarithmic phase, adjusting the concentration of the cell suspension, and adding the cells into a 96-well plate, wherein the number of the cells in each well is about 5000;
s2, placing the experimental cells at 37 ℃ and 5% CO2Culturing for 18h in the cell culture box;
s3, preparing compounds or cisplatin solutions with different concentration gradients by using a complete culture medium containing 10% FBS respectively, adding the compounds or cisplatin solutions into the 96-well plate, setting 3 parallel multiple wells for each concentration, and incubating the cells for 48 hours by using the medicine;
s4, adding MTT solution (5mg/mL, 20 mu L) into each well, continuously incubating for 4h, absorbing the culture medium, adding DMSO (150 mu L) into each well, and shaking the shaking table at a low speed for 10 min;
s5, detecting the absorbance value (O.D.) of each hole at 570nm by using a microplate reader;
s6, setting the zero setting wells (medium, MTT, DMSO) and the control group (cell, medium, DMSO, MTT) at the same time, and calculating the cell survival rate according to the following formula:
survival (%) - (o.d.(sample)-O.D.(blank))/(O.D.(control)-O.D.(blank))]×100％
Wherein, O.D.(sample)Is the absorbance value of the sample group cells; and (D) O.D.(blank)The absorbance value of the withered holes is obtained; and (D) O.D.(control)The absorbance value of the control group cells;
s7, making cell survival rate-concentration curve, calculating half Inhibitory Concentration (IC) of compound50) The results are shown in Table 1.
Table 1 shows the compounds prepared in example 1 of the present invention and the IC of cisplatin on various cells50Value (μ M,48h)
| Name of drug | MCF-7 | MDA-MB-435 | MDA-MB-231 | Caov-3 | HeLa |
| Complex | 0.17±0.04 | 0.34±0.09 | 0.16±0.01 | 0.45±0.06 | 0.22±0.01 |
| CDDP | 4.00±1.00 | 8.34±0.09 | 29.98±1.10 | 24.00±2.50 | 4.50±0.50 |
EXAMPLE 3 detection of anti-inflammatory Capacity of Compounds
The compound prepared in the embodiment 1 of the invention is subjected to anti-inflammatory capability detection, a mouse macrophage RAW264.7 and a human breast cancer cell MCF-7 are selected as models, the compound synthesized in the embodiment 1 and cisplatin are used as objects to be detected, after the objects to be detected act on cells, an ELISA kit is used for detecting the relative content of inflammatory factors IL-6 and IL-1 beta in the supernatant of the RAW264.7 cells, and an immunoblotting test is used for detecting the change of COX-2 protein in the MCF-7 cells and the relative content of PGE2 in the cell supernatant, and the specific operation steps are as follows:
s1, collecting the logarithmic phase cells, adjusting the concentration of the cell suspension to 2X 10 per well5The density of individual cells was seeded in 6-well plates;
s2, placing the experimental cells at 37 ℃ and 5% CO2Culturing for 18h in the cell culture box;
s3, stimulating RAW264.7 cells with lipopolysaccharide (LPS, 100ng/mL) for 6 h; compound or cisplatin (0.4. mu.M) was then added to the cell culture medium and incubation continued for 18 h. The contents of inflammatory factors IL-6 and IL-1 beta in the supernatant were measured according to the protocol provided by the ELISA kit, and the results are shown in FIG. 4;
s4, for the MCF-7 cells, after the cells grow adherent to the walls for 24 hours, adding 2mL of complete culture medium containing the compound or the cisplatin into each hole again, and continuing to culture for 36 hours respectively;
s5, collecting cell supernatant after finishing the culture, carrying out ELISA test, and detecting the content of PGE2, wherein the result is shown in figure 5;
s6, digesting and collecting adherent cells by pancreatin, and centrifuging to obtain cell sediment;
s7, using the prepared RIPA cell lysate to lyse the cells, collecting the supernatant in a clean EP tube, determining the protein concentration in the tube, and adjusting the protein concentration of the sample to be the same according to the protein concentration. The expression quantity of the target protein in the collected protein is determined by immunoblotting test, namely, a sample protein is subjected to an electrophoresis experiment by using 10% SDS-PAGE gel according to the concentration of 40 mu g per hole, the electrophoresis is stopped after the target protein is properly separated, the protein is transferred onto a polyvinylidene fluoride (PVDF) membrane, the membrane is rotated for 1.5h under the conditions of 100V and 200mA, the protein membrane is placed in 5% skimmed milk powder which is prepared in advance for sealing for 0.5h after the membrane is transferred, then primary antibody solution is prepared according to the dilution ratio of COX-2 antibody and is incubated with the PVDF membrane containing the detected protein at 4 ℃ for overnight, after the incubation is finished, the primary antibody is washed by using PBST (PBS + Tween-20), and then secondary antibody is continuously incubated by using goat anti-rabbit HRP marked by peroxidase. After 1h, the secondary antibody was washed away, the PVDF membrane was further washed three times with PBST, and the result of exposure and photographing by using a chemiluminescence detection system was shown in FIG. 6.
EXAMPLE 4 testing of the immunomodulatory Capacity of Compounds
The compound prepared in the embodiment 1 of the invention is subjected to immunoregulatory capacity detection, a human breast cancer cell MDA-MB-231 is selected as a model, the compound synthesized in the embodiment 1 and cisplatin are used as a substance to be detected, and after the substance to be detected acts on cells, the change of PD-L1 protein in the cells is detected by an immunofluorescence assay, and the specific operation steps are as follows:
s1, collecting the logarithmic phase cells, adjusting the concentration of the cell suspension, and paving the cells in a 20mm confocal small dish;
s2, placing the experimental cellsAt 37 ℃ with 5% CO2Culturing for 18h in the cell culture box;
s3, adding 500 mu L of complete culture medium containing the compound or the cisplatin into each hole again, and continuing to culture for 36h respectively;
s4, the medium was removed and washed three times with pre-cooled PBS. Fixing the cells with 4% paraformaldehyde for 20min (4 deg.C), allowing PBS solution containing 1 ‰ Triton X-100 to permeate for 20min, and sealing with 5% skimmed milk powder solution at 4 deg.C for 30 min;
s5, the cells were washed three times with PBS and incubated overnight at 4 ℃ with diluted PD-L1 primary antibody solution. Followed by three washes with PBS for 5min each; incubating with a secondary antibody FITC-conjugated anti-rabbitIgG (Invitrogen) for 1h at room temperature;
s6, continuously washing the cells for three times by using PBS, wherein each time lasts for 5 min; the cells were then incubated with Hoechst3342 for 10min, washed 3 times with PBS, and finally observed for expression of PD-L1 protein on the cells by fluorescence microscopy, as shown in FIG. 7.
In vivo tumor inhibition assay for the Compounds of example 5
Subcutaneously planting human breast cancer cell MDA-MB-231(5 multiplied by 10) into Balb/c nude mice6cells/mouse), after the tumor formation, randomly grouping the mice, and each group comprises 5 mice;
the mice were administered tail vein with cisplatin and compound at a dose of 1.5mg Pt/kg every three days while tumor volume was measured and mouse weight was weighed, and the results are shown in fig. 8, 9 and 10.
EXAMPLE 6 immunohistochemical detection of Compounds
Tumor tissues of the mice in example 5 were respectively excised, fixed in 4% paraformaldehyde, washed, dehydrated, waxed, embedded, and subjected to immunohistochemical experiments after antigen retrieval, and the inflammatory and immune-related proteins COX-2 and PD-L1 were respectively detected in the tumor tissues treated with the compound or cisplatin, and the results are shown in fig. 11.
The tetravalent platinum complex has the characteristics of dynamic inertia, low reaction activity, small toxic and side effects and the like. Currently, 4 tetravalent platinum complexes have entered clinical trials, and the most representative tetravalent platinum prodrug, Satraplatin, has entered phase III clinical trials. In the process of generating and developing tumors, angiogenesis, immune tolerance, metastasis, invasiveness, drug resistance and the like are accompanied by inflammatory processes; in the inflammatory microenvironment of tumor cells, a number of proinflammatory cytokines are also involved in the immune escape of tumors, where cyclooxygenase, a key enzyme involved in the inflammatory response, regulates the expression of PD-L1 in many types of cancers. The tetravalent platinum complex can inhibit the growth of tumor cells from two aspects of inflammation inhibition and immune escape, and plays an anti-tumor effect by intervening the biological functions of a plurality of potential targets, and the action mechanism of the tetravalent platinum complex is shown in figure 12. The derivative also comprises a stereoisomer or pharmaceutically acceptable salt thereof, and other dosage forms prepared by taking the derivative as an active ingredient or a main active ingredient and adding pharmaceutically acceptable auxiliary materials.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. An anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape is characterized in that the molecular structure is as follows:
2. an anti-cancer tetravalent platinum complex according to claim 1, capable of inhibiting inflammation and immune escape, characterized in that:
the structure of (1) is as follows:
3. a preparation method of an anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape is characterized by comprising the following steps: s1, mixing the divalent platinum complex with hydrogen peroxide H2O2Reacting to obtain a tetravalent platinum complex;
wherein the divalent platinum complex is
S2 reaction of tetravalent platinum complex obtained in S1 with
Mixing O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate (TBTU) and Triethylamine (TEA) in a N, N-Dimethylformamide (DMF) solution, and stirring and mixing uniformly;
s3, after the reaction is finished, collecting filtrate, concentrating to 0.5-5 mL, dropwise adding a mixture of ethanol and water, centrifuging and collecting precipitate; and dissolving the precipitate in methanol, washing the precipitate with ether for 1-10 times, and vacuum drying to obtain the target product.
4. The method of claim 3, wherein the preparation of the tetravalent platinum complex for anticancer capable of suppressing inflammation and immune escape comprises: in step S2, stirring and mixing under nitrogen protection.
5. The method of claim 3, wherein the preparation of the tetravalent platinum complex for anticancer capable of suppressing inflammation and immune escape comprises: in the step S3, concentrating to 1mL by rotary evaporation; the precipitate was washed 3 times with diethyl ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010827724.9A CN111848690A (en) | 2020-08-17 | 2020-08-17 | Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010827724.9A CN111848690A (en) | 2020-08-17 | 2020-08-17 | Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111848690A true CN111848690A (en) | 2020-10-30 |
Family
ID=72968767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010827724.9A Pending CN111848690A (en) | 2020-08-17 | 2020-08-17 | Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111848690A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336801A (en) * | 2021-06-08 | 2021-09-03 | 中国人民解放军空军军医大学 | Tetravalent platinum complex containing BET inhibitor and application |
| CN113416216A (en) * | 2021-08-23 | 2021-09-21 | 江苏南创化学与生命健康研究院有限公司 | High-activity Pt complex and preparation method and application thereof |
-
2020
- 2020-08-17 CN CN202010827724.9A patent/CN111848690A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 金素星: "靶向能量代谢和炎症因子的铂类抗癌前药设计及性能研究", 《中国博士学位论文全文数据库-医药卫生科技辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336801A (en) * | 2021-06-08 | 2021-09-03 | 中国人民解放军空军军医大学 | Tetravalent platinum complex containing BET inhibitor and application |
| CN113336801B (en) * | 2021-06-08 | 2023-08-22 | 中国人民解放军空军军医大学 | Tetravalent platinum complexes containing BET inhibitors and use thereof |
| CN113416216A (en) * | 2021-08-23 | 2021-09-21 | 江苏南创化学与生命健康研究院有限公司 | High-activity Pt complex and preparation method and application thereof |
| CN113416216B (en) * | 2021-08-23 | 2021-10-29 | 江苏南创化学与生命健康研究院有限公司 | High-activity Pt complex and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111205331B (en) | Anti-tumor tetravalent platinum complex with anti-drug resistance function and preparation method thereof | |
| CN111039990B (en) | Low-toxicity iridium complex and synthesis method and application thereof | |
| CN110950914B (en) | Iridium complex and synthesis method and application thereof | |
| CN111848690A (en) | Anticancer tetravalent platinum complex capable of inhibiting inflammation and immune escape and preparation method thereof | |
| CN107629089A (en) | Tacrine platinum (II) complex of high activity and its synthetic method and application | |
| CN113024584A (en) | 8-hydroxyquinoline complex for treating lung cancer and preparation method thereof | |
| CN107602367B (en) | 4 '-hydroxy-3' -methoxychalcone derivative, preparation method thereof and application thereof in tumor resistance | |
| CN112010839A (en) | Crystalline forms of a targeted silk/threonine kinase inhibitor | |
| CN111377975B (en) | Novel mitochondrion-targeted iridium complex and preparation method and application thereof | |
| CN110305166B (en) | Ruthenium (II) complex with curcumin derivative as ligand and preparation method and application thereof | |
| CN110041375A (en) | Compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure | |
| CN109675053A (en) | Targeting preparation of Podophyllotoxin and its derivatives and preparation method thereof | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN114605475B (en) | Oral Pt (IV) anticancer prodrugs containing 3-bromopyruvate ligand axially | |
| CN111072725A (en) | Compound with naproxen tetravalent platinum structure, preparation method and application thereof in preparation of antitumor drugs | |
| CN102827116A (en) | Alpha-aryl-gamma-methylene butene lactone compounds, and synthesis method and application thereof | |
| CN108017608B (en) | Flavone derivatives, preparation method and application thereof | |
| CN110078770B (en) | Compound with quinolinone tetravalent platinum structure, preparation method and application thereof in preparation of antitumor drugs | |
| CN113735781A (en) | Copper complex and preparation method and application thereof | |
| CN109867708B (en) | Preparation method and application of glycyrrhetinic acid series derivatives (TNGA-X) with anti-tumor effect | |
| CN111393318A (en) | Synthesis of novel sildenafil acid amide derivative and application of novel sildenafil acid amide derivative in antitumor drugs | |
| CN114891044B (en) | Tetravalent platinum complex with anti-tumor activity and preparation method and application thereof | |
| CN103833766B (en) | Shore, Agra dimethylamine fumarate and the purposes in prepared by medicine thereof | |
| CN115340577B (en) | Synthesis method of platinum (II) complex and application of platinum (II) complex in antitumor drugs | |
| CN113683645B (en) | Binuclear Pt (II) complex with anti-tumor activity and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201030 |
|
| RJ01 | Rejection of invention patent application after publication |