CN114409712A - Cannabidiol-containing Pt (IV) complex and preparation method and application thereof - Google Patents
Cannabidiol-containing Pt (IV) complex and preparation method and application thereof Download PDFInfo
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- CN114409712A CN114409712A CN202210200809.3A CN202210200809A CN114409712A CN 114409712 A CN114409712 A CN 114409712A CN 202210200809 A CN202210200809 A CN 202210200809A CN 114409712 A CN114409712 A CN 114409712A
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- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 61
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 61
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 title claims abstract description 61
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000010668 complexation reaction Methods 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000002243 precursor Substances 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 10
- -1 halide ions Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 6
- 229960002317 succinimide Drugs 0.000 claims description 6
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012317 TBTU Substances 0.000 claims 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 description 4
- 238000000746 purification Methods 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 60
- 210000004027 cell Anatomy 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 11
- 229960004316 cisplatin Drugs 0.000 abstract description 11
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 229910052697 platinum Inorganic materials 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 7
- 230000002588 toxic effect Effects 0.000 abstract description 7
- 206010006187 Breast cancer Diseases 0.000 abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 4
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 4
- 239000003446 ligand Substances 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 4
- 206010009944 Colon cancer Diseases 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 3
- 230000003013 cytotoxicity Effects 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- 230000033116 oxidation-reduction process Effects 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 2
- 229910021529 ammonia Inorganic materials 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 8
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
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- 206010047700 Vomiting Diseases 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 201000007547 Dravet syndrome Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000036572 Myoclonic epilepsy Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 190014017285 satraplatin Chemical compound 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 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 2
- 230000008685 targeting Effects 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGYFLNZBLKNHOR-UHFFFAOYSA-N ClN(Cl)Cl.[K] Chemical compound ClN(Cl)Cl.[K] VGYFLNZBLKNHOR-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 231100000268 induced nephrotoxicity Toxicity 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
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- 230000009401 metastasis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 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 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
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- 229940014800 succinic anhydride Drugs 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
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- 230000035897 transcription Effects 0.000 description 1
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- 230000008673 vomiting 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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)
- Health & Medical Sciences (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)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a cannabidiol-containing Pt (IV) complex with a structural formula shown as a formula Ia, a formula Ib, a formula IIa or a formula IIb: formula Ia
Formula Ib
Formula IIa
Formula IIb
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a cannabidiol-containing Pt (IV) complex, and a preparation method and an anti-tumor application thereof.
Background
Since the professor Barnett Rosenberg discovered incidentally that cisplatin could inhibit cell division in 1969, a large number of platinum compounds were designed for the study of antitumor activity, and are called cisplatin-like drugs because they have a similar structure to cisplatin. To date, 7 platinum complexes have been approved for the treatment of cancer, however, in clinical applications, the drugs are found to cause serious toxic and side effects such as nephrotoxicity, ototoxicity, nausea and vomiting, and to cause drug resistance to cancer cells after long-term use. This series of disadvantages is attributed to the reaction of the Pt (II) complex with the biological nucleophile before reaching the tumor cells, and to overcome these disadvantages, the use of Pt (IV) complexes as prodrugs has been extensively studied as an advantageous strategy. The Pt (IV) complex enters cells through transmembrane transport, reacts with intracellular reducing agents such as glutathione, ascorbic acid and the like, is reduced into a Pt (II) medicament with cytotoxicity and releases two axial ligands which can endow the prodrug with good pharmacological properties, such as lipophilicity increase, reduction potential change, cancer cell targeting, drug resistance overcoming, toxic and side effects reducing and the like. The generated Pt (II) complex is usually cis-platinum or a derivative thereof, has the same action mechanism as cis-platinum, is combined with DNA, inhibits the replication and transcription of the DNA, and induces apoptosis. The Pt (IV) complex is obtained by oxidizing and adding a square planar Pt (II) complex, is less prone to being substituted than the Pt (II) complex, and has the potential of oral administration, higher bioavailability and lower toxic and side effects.
Cannabidiol (CBD) is a triterpenoid phenolic compound with 21 carbons, which is a non-psychoactive ingredient in cannabis. In 6 months 2018, the FDA approved the first CBD drug Epidiolex for the treatment of Lenox-Gastaut syndrome (LGS) and Dravet Syndrome (DS) related epilepsy. CBD is safe and shows pharmacological actions in various pathological models, including inflammation, vomiting, pain relief, epilepsy, cancer, arthritis, schizophrenia, multiple sclerosis and the like. Numerous studies have demonstrated that CBD exhibits good chemopreventive effects in a variety of cancer types, such as breast, lung, colon, prostate and brain cancers. Aiming at different tumor cells, the CBD respectively shows the effects of inhibiting the proliferation, angiogenesis, invasion, metastasis, chemical resistance and the like, simultaneously induces apoptosis and autophagy, and has selectivity on normal cells. The excellent pharmacological activity of the CBD in combination with chemotherapeutic drugs in recent years shows good research and development potential, and the good antioxidant, anti-inflammatory and immunoregulation functions of the CBD are proved to be capable of resisting the cisplatin-induced nephrotoxicity and improving the renal function; by enhancing antioxidant activity and inhibiting secretion of pro-inflammatory cytokines, CBD can act as a neuroprotective agent, thereby alleviating the neurotoxic side effects of oxaliplatin.
At present, no report that the cannabidiol and the platinum drugs synergistically enhance the antitumor activity is found.
Disclosure of Invention
The invention provides a cannabidiol-containing Pt (IV) complex, which has a structural formula shown as a formula Ia, a formula Ib, a formula IIa and a formula IIb:
formula Ia
Formula Ib
Formula IIa
Formula IIb
Wherein Z is selected from NH3,
R1Selected from the group consisting of halide ions,
R2Is selected from
L1Is composed of
L2Selected from OH-、Cl-、
The preparation method of the cannabidiol-containing Pt (IV) complex comprises the following steps:
dissolving a Pt (IV) precursor respectively containing one hydroxyl and one chlorine in the axial direction in DMSO, adding a condensing agent TBTU and triethylamine under the stirring condition at 50-60 ℃, then adding carboxylic acid-derivatized cannabidiol (CBD-C) to react for 6-8 h in a dark place, extracting for 3-4 times by using dichloromethane and purified water, collecting an organic phase, carrying out reduced pressure distillation, carrying out column chromatography purification, concentrating and drying to obtain a Pt (IV) complex containing one chlorine and mono-substituted cannabidiol; the molar ratio of the Pt (IV) precursor containing one hydroxyl and one chlorine to the carboxylic acid-derived cannabidiol is 1: 1-2;
taking Ia and IIa as examples, the synthetic route is as follows:
wherein the Pt (IV) precursor containing one hydroxyl group and one chlorine is selected from
Z、R1、R2、L1、L2As above, the Pt (IV) precursor is prepared by conventional methods.
Or dissolving carboxylic acid-derived cannabidiol (CBD-C) in DMF, adding N-hydroxysuccinimide and carbodiimide hydrochloride, stirring at 50 ℃ for reaction for 3-4 h, and then carrying out reduced pressure distillation, column chromatography, concentration and drying to obtain a cannabidiol succinimide ester derivative (CBD-CN), wherein the molar weight ratio of the carboxylic acid-derived cannabidiol to the N-hydroxysuccinimide is 1: 1-3, and the molar ratio of the carboxylic acid-derived cannabidiol to the carbodiimide hydrochloride is 1: 1-3; dissolving a cannabidiol succinimide ester derivative and a Pt (IV) precursor containing two axial hydroxyl groups in DMSO (dimethyl sulfoxide), stirring at 50-60 ℃ for a light-shielding reaction for 6-8 h, extracting for 3-4 times by using ethyl acetate and purified water, collecting an organic phase, carrying out reduced pressure distillation, carrying out column chromatography purification, concentrating and drying to obtain a Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol; dissolving a Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol in DMSO, adding anhydride, stirring for 3-4 hours at 40-50 ℃ in the dark, extracting for 3-4 times by using ethyl acetate and purified water, collecting an organic phase, carrying out reduced pressure distillation, purifying a crude product by column chromatography, concentrating and drying to obtain L2Is OH-Or Cl-Other cannabidiol-containing Pt (IV) complexes; the molar ratio of the Pt (IV) precursor containing two axial hydroxyl groups to the cannabidiol succinimide ester derivative is 1: 1-3, and the molar ratio of the Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol to the acid anhydride is 1: 1-2;
taking Ia and IIa as examples, the synthetic route is as follows:
wherein the Pt (IV) precursor containing two axial hydroxyl groups is selected from
Z、R1、R2、L1、L2As above, the Pt (IV) precursor is prepared by conventional methods.
The invention also aims to provide the application of the cannabidiol-containing Pt (IV) complex in preparing medicines for treating colon cancer, lung cancer, breast cancer, liver cancer and the like.
The invention has the advantages that:
on the basis of the design of a classical platinum anti-tumor medicament, the cannabidiol-containing Pt (IV) complex enhances the anti-tumor activity and overcomes the drug resistance of tumor cells by introducing cannabidiol active molecules at axial positions, and the cannabidiol molecules have various pharmacological properties (such as anti-inflammation, vomiting-arresting and pain-relieving) and can also improve the toxic and side effects generated in the use of the platinum complex. The introduction of axial groups at the other end can improve the oxidation-reduction potential, the reduction rate, the lipophilicity and the cytotoxicity of the Pt (IV) complex, chloride ions can reduce the negative value of the oxidation-reduction potential of the Pt (IV) complex and increase the reduction power, hydroxyl groups can ensure that the novel Pt (IV) complex is preferentially combined with reducing agents (such as glutathione and ascorbic acid) in a human body after entering the human body and is reduced into a Pt (II) complex to achieve the effect of treating tumors, and different types of axial carboxylates can adjust the lipophilicity, the water solubility and the stability of the complex. The complex is a candidate drug with the advantages of low toxicity, high efficiency, good lipophilicity and selectivity and no cross drug resistance with cisplatin, and in the example, part of the complex initially shows in-vitro inhibition effect superior to cisplatin and satraplatin in various tumor cells, so the complex is expected to become a novel Pt (IV) complex for overcoming the drug resistance and the toxic and side effect of platinum drugs in the future.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited to the above-mentioned contents, and the compounds prepared in the examples were determined by nmr hydrogen spectroscopy and high resolution mass spectrometry to determine the structures of the compounds; the examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The materials or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained by purchasing, and the used methods are all conventional methods if no special instructions exist;
potassium trichloro-amine platinate, potassium iodide, cyclohexylamine, potassium chloride, potassium oxalate, succinic anhydride, N-hydroxysuccinimide, carbodiimide hydrochloride and the like used in the present example are all commercially available products.
In the preparation of this example S1-S4, the synthetic routes of the cannabidiol derivative and the Pt (IV) complex precursor are as follows:
1. platinum (IV) precursors Z1, Z2, Z3 and Z4 are references 201910418221.3, and are prepared by a method in a novel Pt (IV) complex with tumor targeting;
Z1:
Z2:
Z3:
Z4:
2. the carboxylic acid-derivatized cannabidiol (CBD-C) is prepared by a method of preparing a cannabidiol cyclodextrin conjugate, as described in reference 202011045913.7;
3. cannabidiol succinimidyl ester derivatives (CBD-CN) were synthesized as follows: 4.14g (10mmol) of CBD-C is dissolved in 50mL of DMF solvent, 1.73g (15mmol) of N-hydroxysuccinimide and 2.87g (15mmol) of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) are respectively added, the mixture is stirred and reacted for 4 hours at 50 ℃, and after reduced pressure distillation and silica gel column chromatography (dichloromethane: methanol volume ratio 40:1 elution) are carried out, eluent is collected and dried, 4.88g of CBD-CN is prepared, the yield: 95.4 percent.
1H NMR(600MHz,Chloroform-d)δ6.56(s,1H),6.41(d,J＝1.7Hz,1H),6.02(s,1H),5.52(s,1H),4.60(t,J＝1.8Hz,1H),4.43(s,1H),3.46(s,1H),3.14–2.90(m,4H),2.87–2.81(m,4H),2.50–2.42(m,2H),2.27–2.01(m,2H),1.84–1.67(m,5H),1.59(s,3H),1.58–1.53(m,2H),1.32–1.26(m,4H),0.87(t,J＝7.0Hz,3H)。HR-MS(m/z):[C29H37NO7+H]+＝512.2648.
Example 1: synthesis of cannabidiol-containing Pt (iv) complex S1: (C)31H50Cl2N2O6Pt，Mol.Wt.:812.73)
Weighing 4.15g (10mmol) of Pt (IV) precursor Z1 in 20mL DMSO, adding 5.11g (10mmol) of ligand CBD-CN, stirring at 60 ℃ in the dark for 8h, extracting for 3 times by using ethyl acetate and purified water after the reaction is finished, collecting an organic phase, and distilling at 45 ℃ under reduced pressure to obtain a crude product; purifying and separating the crude product by silica gel column chromatography (dichloromethane: methanol volume ratio is 30:1 elution), collecting eluent and drying to prepare 4.86g of Pt (IV) complex S1 containing monohydroxy and monosubstituted cannabidiol axially, wherein the yield is as follows: and (5) 59.9%.
1H NMR(600MHz,Chloroform-d)δ6.54(s,1H),6.43(d,J＝6.7Hz,1H),6.20(s,3H),6.02(s,1H),5.51(s,1H),4.58(s,1H),4.40(s,1H),3.49(d,J＝21.1Hz,1H),2.97(d,J＝22.5Hz,1H),2.85–2.68(m,4H),2.49(t,J＝7.8Hz,2H),2.27–2.16(m,2H),2.11–1.98(m,2H),1.81–1.67(m,7H),1.61–1.54(m,5H),1.27(tq,J＝14.0,7.7,6.9Hz,10H),0.86(t,J＝6.9Hz,3H)。HR-MS(m/z)：[M+H]+＝813.2755(100％)，812.2764(75.05％)，814.2754(66.96％)，815.2753(62.54％)，811.2739(55.25％)，816.2761(24.58％)，817.2752(17.35％)。
Example 2: synthesis of cannabidiol-containing Pt (iv) complex S2: (C)31H49Cl3N2O5Pt，Mol.Wt.:831.18)
Weighing 4.33g (10mmol) of Pt (IV) precursor Z2 in 20mL DMSO, sequentially adding 4.82g (15mmol) of TBTU, 1.01g (10mmol) of triethylamine and 4.14g (10mmol) of CBD-C at 50 ℃ under the stirring condition, stirring at 50 ℃ in the dark for 6h, after the reaction is finished, extracting with dichloromethane and purified water for 3 times, collecting an organic phase, distilling at 35 ℃ under reduced pressure to obtain a crude product, purifying and separating the crude product by silica gel column chromatography (dichloromethane: methanol volume ratio 30:1 elution), collecting eluent and drying to obtain 1.79g of Pt (IV) complex S2 containing chlorine and monosubstituted cannabidiol in the axial direction, wherein the yield is as follows: 21.6 percent.
1H NMR(600MHz,Chloroform-d)δ6.55(d,J＝6.4Hz,1H),6.47(d,J＝10.5Hz,1H),6.04(d,J＝19.2Hz,1H),5.53–5.46(m,1H),4.58(d,J＝10.6Hz,1H),4.40(d,J＝16.1Hz,1H),3.53–3.41(m,1H),3.11–3.02(m,1H),2.87–2.69(m,4H),2.48(t,J＝7.8Hz,2H),2.25–2.00(m,4H),1.77(s,7H),1.61–1.54(m,5H),1.32–1.21(m,10H),0.86(t,J＝6.9Hz,3H)。HR-MS(m/z)：[M+H]+＝831.2408(100％)，833.2405(80.11％)，832.2409(77.17％)，830.2420(63.80％)，829.2395(47.18％)，834.2407(38.90％)，835.2397(31.58％)，836.2413(10.66％)。
Example 3: synthesis of cannabidiol-containing pt (iv) complex S3: (C)33H50N2O10Pt，Mol.Wt.:829.85)
Weighing 4.33g (10mmol) of Pt (IV) precursor Z3 in 20mL DMSO, adding 5.11g (10mmol) of ligand CBD-CN, reacting for 7h at 55 ℃ in a dark place, after the reaction is finished, extracting for 3 times by using ethyl acetate and purified water, collecting an organic phase, carrying out reduced pressure distillation at 45 ℃ to obtain a crude product, purifying and separating the crude product by silica gel column chromatography (dichloromethane: methanol volume ratio 20:1 elution), collecting eluent and drying to obtain 3.30g of Pt (IV) complex S3 containing monohydroxy and monosubstituted cannabidiol in the axial direction, wherein the yield is as follows: 39.8 percent.
1H NMR(600MHz,Chloroform-d)δ6.53(s,1H),6.43–6.32(m,1H),6.00(s,1H),5.50(s,1H),4.57(s,1H),4.40(s,1H),3.12–2.88(m,1H),2.87–2.29(m,6H),2.19(s,1H),2.05(d,J＝24.4Hz,1H),1.83(s,2H),1.75(s,4H),1.62–1.50(m,5H),1.42(s,1H),1.31–1.22(m,8H),0.86(d,J＝12.5Hz,3H)。HR-MS(m/z)：[M+Na]+＝852.3012(100％)，853.3020(88.45％)，851.2987(71.44％)，854.3038(27.90％)，855.3040(21.71％)。
Example 4: synthesis of cannabidiol-containing pt (iv) complex S4: (C)33H49ClN2O9Pt，Mol.Wt.:848.29)
Weighing 4.51g (10mmol) of Pt (IV) precursor Z4 in 20mLDMSO, sequentially adding 4.82g (15mmol) of TBTU, 1.01g (10mmol) of triethylamine and 4.14g (10mmol) of CBD-C at 60 ℃ under the condition of stirring, reacting for 6h at 60 ℃ in a dark place, extracting for 4 times by using dichloromethane and purified water after the reaction is finished, collecting an organic phase, distilling at 35 ℃ under reduced pressure to obtain a crude product, purifying and separating the crude product by silica gel column chromatography (dichloromethane: methanol volume ratio 20:1 elution), collecting eluent and drying to obtain 2.27g of Pt (IV) complex S4 containing chlorine and monosubstituted cannabidiol in the axial direction, wherein the yield is as follows: 26.8 percent.
1H NMR(600MHz,Chloroform-d)δ6.56(s,1H),6.41(d,J＝1.7Hz,1H),6.07–5.98(m,1H),5.53(s,1H),4.64–4.57(m,1H),4.44(d,J＝13.6Hz,1H),3.46(s,1H),3.06(dq,J＝15.0,8.4,7.0Hz,1H),2.96–2.83(m,4H),2.49(dd,J＝9.4,5.6Hz,2H),2.25(s,1H),2.11–1.94(m,1H),1.86–1.64(m,6H),1.57(t,J＝12.0Hz,9H),1.32–1.24(m,6H),0.88–0.86(m,3H)。HR-MS(m/z)：[M+H]+＝847.4751(100％)，848.4782(64.92％)，849.4809(24.59％)，850.4831(7.40％)。
The in vitro inhibition effect of the 4 cannabidiol-containing platinum (IV) complexes on human liver cancer cells (HepG-2), human lung adenocarcinoma cells (A549), human breast cancer cells (MCF-7), colon cancer cells (SW480), human ovarian cancer cells (A2780) and other tumor strains is tested by adopting an MTT method, and cisplatin and satraplatin are respectively used as positive controls. The tumor cell strain culture and test method comprises the following steps:
the tumor cells were inoculated in DMEM medium containing 10% (v/v) fetal bovine serum, 100. mu.g/mL penicillin and 100. mu.g/mL streptomycin, respectively, at saturated humidity, 37 ℃ and 5% CO2Culturing in the environment of (1); pt (iv) complex was dissolved in DMSO beforehand, control cisplatin was dissolved in PBS, and diluted with culture medium to the required concentration of different gradients when tested (DMSO final concentration cannot exceed 0.1%); inoculating 2000-6000 cells per hole of 5 human tumor cell lines in a logarithmic growth phase into a 96-hole plate, wherein the hole volume per hole is 100 mu L; adding the medicines with different concentrations, and placing in 5% CO2Incubating in an incubator at 37 ℃ for 48 hours, adding MTT 20 mu L/hole 4 hours before the incubation is finished, discarding the supernatant after 4 hours, adding DMSO150 mu L/hole, vibrating for 5min, and then measuring the OD value by using an enzyme-labeling instrument, wherein the wavelength is set to 492 nm; calculating the survival rate of the tested tumor cells, simultaneously mapping and solving the IC50Values, evaluation of the antitumor activity of the complexes, results are shown in table 1;
TABLE 1 IC containing cannabidiol platinum (IV) complex prepared according to the invention50Value of
It can be seen from the table that the S1-S4 compound has better in vitro anti-tumor activity than the traditional cisplatin medicines, the introduction of cannabidiol active molecules has anti-tumor synergistic effect, and the toxic and side effects of the traditional cisplatin medicines are greatly reduced, so that the compound has excellent application prospect in the aspect of anti-tumor.
Claims (6)
1. A cannabidiol-containing Pt (iv) complex of the formula ia, ib, iia or iib:
formula Ia
Formula Ib
Formula IIa
Formula IIb
Wherein Z is selected from NH3、
R1Selected from the group consisting of halide ions,
R2Is selected from
L1Is composed of
L2Selected from OH-、Cl-、
2. A process for the preparation of a Pt (iv) complex containing cannabidiol as claimed in claim 1 characterised by the steps of:
dissolving Pt (IV) precursors respectively containing one hydroxyl and one chlorine in the axial direction in DMSO, adding a condensing agent TBTU and triethylamine under the stirring condition at 50-60 ℃, then adding carboxylic acid-derivatized cannabidiol to react for 6-8 h in a dark place, extracting for 3-4 times by using dichloromethane and purified water, collecting an organic phase, carrying out reduced pressure distillation, carrying out column chromatography purification, concentrating and drying to obtain a Pt (IV) complex containing one chlorine and single-substituted cannabidiol;
wherein the Pt (IV) precursor containing one hydroxyl group and one chlorine is selected from
Or dissolving the carboxylic acid-derived cannabidiol in DMF, adding N-hydroxysuccinimide and carbodiimide hydrochloride, stirring at 50 ℃ for reaction for 3-4 h, and performing reduced pressure distillation, column chromatography, concentration and drying to obtain the cannabidiol succinimide ester derivative; dissolving a cannabidiol succinimide ester derivative and a Pt (IV) precursor containing two axial hydroxyl groups in DMSO (dimethyl sulfoxide), stirring at 50-60 ℃ for a light-shielding reaction for 6-8 h, extracting for 3-4 times by using ethyl acetate and purified water, collecting an organic phase, carrying out reduced pressure distillation, carrying out column chromatography purification, concentrating and drying to obtain a Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol; dissolving a Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol in DMSO, adding anhydride, stirring for 3-4 hours at 40-50 ℃ in the dark, extracting for 3-4 times by using ethyl acetate and purified water, collecting an organic phase, carrying out reduced pressure distillation, purifying a crude product by column chromatography, concentrating and drying to obtain L2Is OH-Or Cl-Other cannabidiol-containing Pt (IV) complexes;
wherein the Pt (IV) precursor containing two axial hydroxyl groups is selected from
3. The method of claim 2, wherein: the molar weight ratio of the carboxylic acid-derived cannabidiol to the N-hydroxysuccinimide is 1: 1-3, and the molar ratio of the carboxylic acid-derived cannabidiol to the carbodiimide hydrochloride is 1: 1-3.
4. The method of claim 2, wherein: the molar ratio of the Pt (IV) precursor containing one hydroxyl and one chlorine to the carboxylic acid-derived cannabidiol is 1: 1-2.
5. The method of claim 2, wherein: the molar ratio of the Pt (IV) precursor containing two axial hydroxyl groups to the cannabidiol succinimide ester derivative is 1: 1-3, and the molar ratio of the Pt (IV) complex containing one hydroxyl group and mono-substituted cannabidiol to the acid anhydride is 1: 1-2.
6. The use of the cannabidiol-containing Pt (iv) complex of claim 1 in the preparation of an anti-tumour medicament.
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