CN111187303A - Novel platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof - Google Patents
Novel platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof Download PDFInfo
- Publication number
- CN111187303A CN111187303A CN202010053582.5A CN202010053582A CN111187303A CN 111187303 A CN111187303 A CN 111187303A CN 202010053582 A CN202010053582 A CN 202010053582A CN 111187303 A CN111187303 A CN 111187303A
- Authority
- CN
- China
- Prior art keywords
- platinum
- complex
- ligand
- chelerythrine
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 32
- KURWKDDWCJELSV-UHFFFAOYSA-N cryptolepine Chemical compound N1=C2C=CC=C[C]2C(N2C)=C1C=C1[C]2C=CC=C1 KURWKDDWCJELSV-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 20
- 229960005503 cryptolepine Drugs 0.000 title abstract description 7
- 238000010189 synthetic method Methods 0.000 title description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 80
- 239000003446 ligand Substances 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 12
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 lutidine amine Chemical class 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 9
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002798 polar solvent Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- UBWVEGSADBOAEC-BASWHVEKSA-N Picrinine Natural products COC(=O)C1C2CC3C4Nc5ccccc5C14CCN3C/C/2=C/C UBWVEGSADBOAEC-BASWHVEKSA-N 0.000 claims abstract description 4
- BDXYPHKGNUGUFG-WAYFEFRKSA-N deacetyl-deformopicraline Natural products COC(=O)[C@@H]1[C@H]2C[C@@H]3N(CC2=CC)[C@@H]4C[C@]15c6ccccc6N[C@]35O4 BDXYPHKGNUGUFG-WAYFEFRKSA-N 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- BDXYPHKGNUGUFG-VETGLWQVSA-N picrinine Chemical compound C12=CC=CC=C2N[C@]2(O3)[C@@H]4C[C@@H]5[C@@H](C(=O)OC)[C@]12C[C@H]3N4C\C5=C\C BDXYPHKGNUGUFG-VETGLWQVSA-N 0.000 claims abstract description 4
- 239000000843 powder Substances 0.000 claims abstract description 4
- 238000001308 synthesis method Methods 0.000 claims abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- LLEJIEBFSOEYIV-UHFFFAOYSA-N chelerythrine Chemical compound C1=C2OCOC2=CC2=CC=C3C4=CC=C(OC)C(OC)=C4C=[N+](C)C3=C21 LLEJIEBFSOEYIV-UHFFFAOYSA-N 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 16
- 206010006187 Breast cancer Diseases 0.000 claims description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- RATMHCJTVBHJSU-UHFFFAOYSA-N Dihydrochelerythrine Natural products C1=C2OCOC2=CC2=C(N(C)C(O)C=3C4=CC=C(C=3OC)OC)C4=CC=C21 RATMHCJTVBHJSU-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
- KDADQDWVKZJTDQ-UHFFFAOYSA-L methylsulfinylmethane;platinum(2+);dichloride Chemical compound [Cl-].[Cl-].[Pt+2].CS(C)=O.CS(C)=O KDADQDWVKZJTDQ-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- GHKISGDRQRSCII-ZOCIIQOWSA-N chelidonine Chemical compound C1=C2[C@H]3N(C)CC4=C(OCO5)C5=CC=C4[C@H]3[C@@H](O)CC2=CC2=C1OCO2 GHKISGDRQRSCII-ZOCIIQOWSA-N 0.000 claims 2
- GHKISGDRQRSCII-UHFFFAOYSA-N chelidonine Natural products C1=C2C3N(C)CC4=C(OCO5)C5=CC=C4C3C(O)CC2=CC2=C1OCO2 GHKISGDRQRSCII-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 7
- 238000001727 in vivo Methods 0.000 abstract description 4
- 230000005917 in vivo anti-tumor Effects 0.000 abstract description 4
- 230000008685 targeting Effects 0.000 abstract description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical class CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 12
- 229960004316 cisplatin Drugs 0.000 description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 229910052697 platinum Inorganic materials 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 244000309466 calf Species 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 210000005260 human cell Anatomy 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 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 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- WEEFNMFMNMASJY-UHFFFAOYSA-M 1,2-dimethoxy-12-methyl-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium;chloride Chemical compound [Cl-].C1=C2OCOC2=CC2=CC=C3C4=CC=C(OC)C(OC)=C4C=[N+](C)C3=C21 WEEFNMFMNMASJY-UHFFFAOYSA-M 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MXTLAHSTUOXGQF-UHFFFAOYSA-O Jatrorrhizine Chemical class COC1=CC=C2C=C3C(C=C(C(=C4)O)OC)=C4CC[N+]3=CC2=C1OC MXTLAHSTUOXGQF-UHFFFAOYSA-O 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- 229910019032 PtCl2 Inorganic materials 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical class C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 125000004429 atom Chemical group 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
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000000006 cell growth inhibition assay Methods 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 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
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- RXVGBQCEAQZMLW-UHFFFAOYSA-N alpha-solanine Natural products CC1CCC2C(C)C3C(CC4C5CC=C6CC(CCC6(C)C5CCC34C)OC7OC(CO)C(O)C(OC8OC(CO)C(O)C(O)C8O)C7OC9OC(CO)C(O)C(O)C9O)N2C1 RXVGBQCEAQZMLW-UHFFFAOYSA-N 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YKLWRYOORWTCQQ-HKUMRIAESA-N phyllanthine Chemical class C1[C@@]23OC(=O)C=C2C=C[C@H]1N1CC[C@@H](OC)C[C@@H]13 YKLWRYOORWTCQQ-HKUMRIAESA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930002966 sinomenine Natural products 0.000 description 1
- ZGVSETXHNHBTRK-OTYSSXIJSA-N solanine Chemical compound O([C@H]1[C@@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@@H]5N6C[C@@H](C)CC[C@@H]6[C@H]([C@@H]5[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZGVSETXHNHBTRK-OTYSSXIJSA-N 0.000 description 1
- 229940031352 solanine Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 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 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
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel platinum (II) complex with high antitumor activity for cryptolepine, which has a chemical formula of [ Pt (Tm) R ] Cl, wherein a ligand Tm is a compound synthesized by cryptolepine derivatives and dimethyl pyridylamine derivatives, m is a natural number which is not zero, and R is halogen. The synthesis method of the complex comprises the steps of reacting a cryptolepine derivative with a lutidine amine derivative in the presence of a solvent and strong base to generate a yellow solid powder ligand Tm; and carrying out coordination reaction on the Tm ligand and a platinum (II) compound in an amount equal to the Tm ligand in the presence of a polar solvent to obtain a yellow target product, namely the platinum (II) complex of the picrinine. The platinum (II) coordination compound of the cryptolepine shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
Description
Technical Field
The invention relates to a complex, in particular to a novel platinum (II) complex with high antitumor activity for cryptolepine. Meanwhile, the invention also relates to a synthetic method and application of the complex.
Background
Cisplatin antineoplastic drugs are widely used in clinical treatment because of their unique antineoplastic mechanism, significant antineoplastic effect and broad antineoplastic spectrum (white N J, Walker S, Craig G E, et al. the state of platinum anticancer drugs in the clinical treatment and in the clinical trials [ J ] Dalton transformations, 2010,39(35): 8113-). Currently, more than 50% of chemotherapy treatment regimens involve the use of platinum drugs, of which FDA-approved Cisplatin (CDDP), carboplatin (carboplatin) and oxaliplatin (oxaliplatin) are the mainstay drugs in clinical chemotherapy regimens for malignant tumors, which cause tumor cell apoptosis mainly through interaction with tumor DNA (liufengfan, threo. And the platinum drugs on the market lack selectivity and have low bioavailability, and adverse reactions in the treatment process are serious, and the drug resistance and cross drug resistance of tumor cells are easily caused, so that the further expansion application of the platinum drugs is limited. In order to overcome the clinical defects of the classical cisplatin drugs, scholars at home and abroad synthesize a large amount of novel platinum complexes on the basis of the structures of the platinum antitumor drugs on the market so as to obtain the antitumor platinum drugs with higher biological activity, lower toxicity and drug resistance or cross drug resistance.
The Sinomenine alkaloid has wide physiological activities of antibiosis, antivirus, antitrypanosoma, anti-inflammation and the like, and no metal complex reported by taking the Sinomenine and the derivative as ligands exists.
Disclosure of Invention
The invention aims to provide a novel platinum (II) complex with high antitumor activity for cryptolepine.
Specifically, the novel platinum (II) complex with high antitumor activity is represented by the chemical formula [ Pt (Tm) R ] Cl (Tm-Pt for short), and the chemical structural formula is shown as the following formula:
the ligand Tm is a compound synthesized by a phyllanthine derivative and a lutidine amine derivative, m is a natural number which is not zero, n is a natural number which is not zero, and R is halogen.
The second purpose of the invention is to provide a method for synthesizing a novel platinum (II) complex with high antitumor activity.
Specifically, the synthesis method of the novel platinum (II) coordination compound with high antitumor activity comprises the following steps:
(1) reacting a cryptolepine derivative (SM) with a lutidine amine derivative in the presence of a solvent and strong base to generate a yellow solid powder ligand Tm, wherein m is a natural number different from zero;
(2) the ligand Tm and platinum (II) compounds with the same amount of substances are subjected to coordination reaction in the presence of a polar solvent to obtain a yellow target product, namely a platinum (II) chelerythrine complex Tm-Pt.
The synthetic route of the invention is as follows:
the structural formula of the lutidine amine derivative is as follows:
n is a natural number different from zero.
In the step (1), the molar ratio of the cryptolepine derivative (SM) to the lutidine amine derivative is 1: 1-1.5.
In the step (1), the cryptolepine derivative (SM) and the lutidine derivative react for 1-10 hours at 20-30 ℃.
In step (2), platinum (II) compounds include, but are not limited to, dichloro-bis (dimethyl sulfoxide) platinum (II) solid (Pt (DMSO))2Cl2)。
In the step (2), the coordination reaction temperature is 30-100 ℃, and the reaction time is 10-80 h.
In the step (2), the polar solvent is any one of methanol, ethanol, water, dimethyl sulfoxide and acetone or a mixed solution of two solvents, wherein the two solvents in the mixed solution are in any ratio. As an embodiment of the present invention, the polar solvent is a mixed solution of methanol and water or acetone, or a mixed solution of ethanol and water or acetone, or a mixed solution of dimethyl sulfoxide and methanol or ethanol.
The invention also aims to provide application of the platinum (II) complex of the cryptolepine. In particular to application of the platinum (II) complex of the picrinine in preparing antitumor drugs. More specifically, an application of the platinum (II) complex of the solanine in the preparation of a drug for targeted therapy of breast cancer is provided.
The invention has the beneficial effects that:
compared with the prior art, the invention provides a novel jatrorrhizine derivative active ligand Tm, and a platinum complex [ Pt (Tm) R ] is synthesized by taking the novel jatrorrhizine derivative active ligand Tm as a ligand]Cl (Tm-Pt). The inventor researches the activity and toxicity experiments of the complex Tm-Pt on human cervical cancer cells HeLa, human breast cancer cells (MCF-7 and MDA-MB-231), human ovarian cancer drug-resistant strains SK-OV-3/DDP cells and human normal liver HL-7702 cells. MTT experimental results show that the complex Tm-Pt has high anti-tumor activity on human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, and the in vitro anti-tumor activity of the complex is far greater than that of the ligand Tm and a clinical classical metal-based anti-cancer drug cis-platinum; in addition, the Tm-Pt complex has little toxicity (IC) to HL-7702 of normal cells50More than 100 mu M), shows good target inhibition of human breast cancer proliferation. The complex Tm-Pt shows excellent in vivo and in vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
Drawings
FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of T3 obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of T3 obtained in example 1 of the present invention;
FIG. 3 is an electrospray mass spectrum of a complex T3-Pt prepared in example 1 of the present invention;
FIG. 4 is a NMR chart of T3-Pt obtained in example 1 of the present invention;
FIG. 5 is a NMR carbon spectrum of T3-Pt prepared in example 1 of the present invention;
FIG. 6 is a hydrogen nuclear magnetic resonance spectrum of T4 obtained in example 4 of the present invention;
FIG. 7 is a nuclear magnetic resonance carbon spectrum of T4 obtained in example 4 of the present invention;
FIG. 8 is an electrospray mass spectrum of a complex T4-Pt prepared in example 4 of the present invention;
FIG. 9 is a NMR spectrum of T4-Pt obtained in example 4 of the present invention;
FIG. 10 shows the NMR spectrum of T4-Pt prepared in example 4 of the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples.
The raw material of the cryptolepine derivative SM involved in the synthesis method of the present invention is prepared by referring to the existing literature (Gu, L. -Q.; et al.J.Med.chem.,2005,48: 7315-7321.). In addition, platinum (II) bis (dimethyl sulfoxide) dichloride can be prepared by reference to the existing literature (Al-Allaf, T.A.K.; et Al. Transit. Met. chem.,1998,23:403-406.), abbreviated in the present application as cis-PtCl2(DMSO)2Or PtCl2(DMSO)2。
Example 1
(1) Synthesis and characterization of ligand T3:
in a 25.0mL round bottom flask, 1.0mol of compound SM, 1.05mol of the lutidine amine derivative and 2.00mol of NaH were weighed and dissolved in a solution containing 5.0mL of Dimethylacetamide (DMA), and after 10.0 hours of reaction at 25.0 ℃, T3 ligand was obtained as a yellow solid powder with a yield of 53.0%.
The resulting T3 was characterized:
(1) the NMR spectrum is shown in FIG. 1.
1H NMR(400MHz,CHCl3-d)δ8.49(d,J＝4.9Hz,2H),8.35(dd,J＝8.0,17.5Hz,2H),8.20(d,J＝8.6Hz,1H),7.70(t,J＝7.7Hz,1H),7.65-7.54(m,4H),7.53-7.41(m,4H),7.12-7.06(m,2H),5.29(s,1H),4.93(t,J＝6.4Hz,2H),3.81(s,4H),2.61(t,J＝6.9Hz,2H),1.91(quin,J＝6.9Hz,2H),1.73-1.54(m,4H).
(2) NMR spectrum of carbon, as shown in FIG. 2.
13C NMR(101MHz,CHCl3-d)δ159.99,158.66,147.38,144.12,136.31,134.51,130.58,128.64,128.42,124.76,123.48,123.19,122.86,122.33(d,J＝15.4Hz,1C),121.86,121.39,111.99,72.78,60.57,54.30,29.93,26.91,23.70.
(3) The results of elemental analysis are shown in Table 1.
Table 1 elemental analysis results of Compounds T3 and T3-Pt in the examples
Thus, the yellow target product obtained was identified as compound T3, having the formula:
(2) synthesis and characterization of the complex T3-Pt:
1.0mmol of ligand T3 and 1.0mmol of bis (dimethyl sulfoxide) dichloroplatinum (II) solid (cis-Pt) (DMSO)2Cl2) Dissolving the product in 30mL of mixed solution of methanol and acetone (the volume ratio is 20:1), carrying out coordination reaction for 36h at 40 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product T3-Pt. The yield was 91.3%.
The obtained T3-Pt was identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 3.
ESI-MS m/z:731.9[M-Cl]+Wherein M is the molecular weight of compound T3-Pt.
(2) NMR spectrum as shown in FIG. 4.
1H NMR(500MHz,DMSO-d6)δ8.76(dd,J＝5.8,1.6Hz,2H),8.29–8.22(m,3H),8.20(dd,J＝8.9,1.2Hz,1H),8.14–8.10(m,1H),7.79(d,J＝7.9Hz,2H),7.78–7.72(m,3H),7.65–7.60(m,2H),7.57(ddd,J＝8.2,6.7,1.2Hz,1H),7.53(ddd,J＝7.9,6.5,1.5Hz,1H),5.41(d,J＝15.9Hz,2H),4.89(d,J＝15.8Hz,2H),4.79(t,J＝6.1Hz,2H),3.15–3.07(m,2H),1.77(dq,J＝12.2,6.3Hz,2H),1.65(dq,J＝13.8,7.1Hz,2H),1.51(q,J＝7.8Hz,2H).
(3) NMR spectrum of carbon, as shown in FIG. 5.
13C NMR(126MHz,DMSO-d6)δ166.34,158.54,149.44,148.79,147.20,143.63,141.73,134.33,131.75,129.11,128.93,125.76,125.61,124.41,123.91,122.87,122.51,122.30,121.12,112.87,72.78,68.29,64.57,40.92,40.51,40.34,40.18,40.01,39.84,39.68,39.51,29.47,27.13,22.94.
(4) The results of elemental analysis are shown in Table 1.
Therefore, the obtained yellow target product can be determined to be a complex T3-Pt, and the structural formula of the complex is as follows:
example 2
1.0mmol of ligand T3 and 1.0mmol of bis (dimethyl sulfoxide) platinum (II) dichloride solid (Pt (DMSO))2Cl2) Dissolving the obtained product in 15mL of mixed solution of ethanol and dimethyl sulfoxide (the volume ratio is 2:1), carrying out coordination reaction for 5h at 80 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product T3-Pt. The yield was 75.2%.
Example 3
1.0mmol of ligand T3 and 1.0mmol of bis (dimethyl sulfoxide) platinum (II) dichloride solid (Pt (DMSO))2Cl2) Dissolving the obtained product in 80mL of mixed solution of ethanol and acetone (volume ratio is 50:3), carrying out coordination reaction for 72h at 30 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 45 ℃ to obtain a yellow target product T3-Pt. The yield was 88.3%.
Experimental example 1
Experiment on proliferation inhibition activity of novel platinum (II) chelerythrine complex T3-Pt on various human tumor cell lines
1. Cell lines and cell cultures
The experiment selects 5 human cell strains such as human cervical carcinoma HeLa cells, human ovarian cancer cisplatin drug-resistant SK-OV-3/DDP cells, human breast cancer cells (MCF-7 and MDA-MB-231) and human normal liver HL-7702 cells.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10 wt% calf blood, and 100U/mL streptomycin, and placed at 37 deg.C with 5% CO by volume2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the ligand T3 and the complex T3-Pt is more than or equal to 95 percent, the DMSO stock solutions of the ligand T3 and the complex T3-Pt are diluted into a final solution of 20 mu mol/L (the final concentration of DMSO is less than or equal to 1 percent) by using a physiological buffer solution, and the inhibition degree of each compound on the growth of normal cells or selected tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking normal cells or tumor cells in a logarithmic growth phase, digesting the cells or tumor cells by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the density of cells to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, culture solution, MTT, a drug dissolving medium with the same concentration, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of each compound on the growth of the selected cells, and calculating the IC of each tested ligand T3 and the complex T3-Pt on each selected cell strain by a Bliss method50The value is obtained. The results are shown in table 2 below.
TABLE 2 IC of ligand T3 and complex T3-Pt on various cell lines50Value (μ M)
Slave IC50According to the result of activity screening, the proliferation inhibition activity of the complex T3-Pt on 4 tested human tumor cell lines (human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells and human breast cancer cells (MCF-7 and MDA-MB-231)) is obviously higher than that of metal salt cis-Pt (DMSO)2Cl2Ligand T3 and cisplatin, which exhibit the synergistic effect of ligand T3 and platinum central atom. MTT results show that the complex T3-Pt has high anti-tumor activity on human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, and IC of the complex50The value range is 0.05-2.35 mu M, and the in vitro anti-tumor activity of the compound is far greater than that of T3 ligand and a clinical classical metal-based anti-cancer drug cisplatin; in addition, the toxicity of the complex T3-Pt to the normal cell HL-7702 is very small (IC)50More than 100 mu M), shows good target inhibition of human breast cancer proliferation. In a word, the complex T3-Pt shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
Example 4
(1) Synthesis and characterization of ligand T4:
in a 50.0mL round bottom flask, 1.0mol of compound SM, 1.20mol of the lutidine amine derivative and 2.20mol of NaH were weighed out and dissolved in a solution containing 5.0mL of Dimethylacetamide (DMA), and after 1.7 hours of reaction at 25.0 ℃, T4 ligand was obtained as a yellow solid in 61.0% yield.
The resulting T4 was characterized:
(1) the NMR spectrum is shown in FIG. 6.
1H NMR(400MHz,CHCl3-d)δ8.48(br d,J＝4.4Hz,2H),8.35(t,J＝9.2Hz,2H),8.18(d,J＝8.6Hz,1H),7.68(dt,J＝1.3,7.7Hz,1H),7.64-7.57(m,3H),7.55-7.46(m,3H),7.46-7.38(m,1H),7.10(dd,J＝5.5,6.6Hz,2H),4.94(t,J＝6.5Hz,2H),3.78(s,4H),3.47(s,1H),2.57-2.44(m,2H),2.02-1.87(m,2H),1.65-1.44(m,4H),1.42-1.32(m,2H),1.32-1.19(m,6H).
(2) NMR spectrum of carbon, as shown in FIG. 7.
13C NMR(101MHz,CHCl3-d)δ160.12,158.63,149.15-148.75(m,1C),147.29,144.22,136.37,134.48,130.59,128.48(d,J＝5.9Hz,1C),124.75,123.48,123.11,122.84,122.37(d,J＝18.3Hz,1C),121.85,121.38,111.97,72.95,60.48,54.53,50.57,30.09,29.63-29.17(m,1C),27.19(d,J＝24.9Hz,1C),25.91.
(3) The results of elemental analysis are shown in Table 3.
Elemental analysis results of Compounds T4 and T4-Pt in Table 3
Thus, the yellow target product obtained was identified as compound T4, having the formula:
(2) synthesis and characterization of the complex T4-Pt:
1.0mmol of ligand T4 and 1.0mmol of bis (dimethyl sulfoxide) platinum (II) dichloride solid (Pt (DMSO))2Cl2) Dissolved in 50mL of a mixed solution of methanol and water (volume ratio: 100:1), and then the mixture was stirred at 50 ℃And performing coordination reaction for 20 hours, filtering, and drying the product in a vacuum drying oven at 40 ℃ by using 5.0mL of diethyl ether for 3 times to obtain a yellow target product T4-Pt. The yield was: 90.9 percent.
The obtained T4-Pt was identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 8.
ESI-MS m/z:788.0[M-Cl]+Wherein M is the molecular weight of compound T4-Pt.
(2) NMR spectrum as shown in FIG. 9.
1H NMR(500MHz,DMSO-d6)δ8.79(dt,J＝6.0,1.8Hz,2H),8.32–8.24(m,4H),8.17–8.11(m,1H),7.83(d,J＝7.9Hz,2H),7.77–7.73(m,2H),7.68–7.65(m,2H),7.55(dddd,J＝30.5,8.0,6.9,1.2Hz,2H),5.39(d,J＝15.7Hz,2H),4.95–4.81(m,4H),3.03–2.98(m,2H),1.84(dq,J＝13.6,6.7Hz,2H),1.46(q,J＝10.9,7.2Hz,4H),1.25(t,J＝7.2Hz,2H),1.16–1.07(m,6H).
(3) NMR spectrum of the sample, as shown in FIG. 10.
13C NMR(126MHz,DMSO-d6)δ166.36,158.56,149.47,148.80,147.24,143.78,141.78,134.38,131.72,129.10,128.95,125.81,125.57,124.39,123.93,122.90,122.49,122.28,121.20,112.86,73.06,68.33,64.68,40.94,40.53,40.36,40.20,40.03,39.86,39.69,39.53,29.81,29.09,29.06,28.90,27.44,26.24,25.69.
(4) The results of elemental analysis are shown in Table 3.
Therefore, the obtained yellow target product can be determined to be a complex T4-Pt, and the structural formula of the complex is as follows:
example 5
1.0mmol of ligand T4 and 1.0mmol of bis (dimethyl sulfoxide) platinum (II) dichloride solid (Pt (DMSO))2Cl2) Dissolving in 100mL of mixed solution of ethanol and acetone (volume ratio of 100:9), performing coordination reaction at 30 deg.C for 80h, filtering, adding 5.0mL of diethyl ether for 3 times, and drying in vacuum drying oven at 40 deg.C to obtain yellowThe target product, T4-Pt, was colored. The yield was: 50.2 percent.
Example 6
1.0mmol of ligand T4 and 1.0mmol of bis (dimethyl sulfoxide) platinum (II) dichloride solid (Pt (DMSO))2Cl2) Dissolving the product in 10mL of mixed solution of methanol and acetone (the volume ratio is 50:3), carrying out coordination reaction for 10h at 100 ℃, filtering, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 40 ℃ to obtain a yellow target product T4-Pt. The yield was: 80.0 percent.
Experimental example 2
Experiment on proliferation inhibition activity of novel platinum (II) coordination compound T4-Pt with high antitumor activity on various human tumor cell strains
1. Cell lines and cell cultures
The experiment selects 5 human cell strains such as human cervical carcinoma HeLa cells, human ovarian cancer cisplatin drug-resistant SK-OV-3/DDP cells, human breast cancer cells (MCF-7 and MDA-MB-231) and human normal liver HL-7702 cells.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10 wt% calf blood, and 100U/mL streptomycin, and placed at 37 deg.C with 5% CO by volume2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the ligand T4 and the complex T4-Pt is more than or equal to 95 percent, the DMSO stock solutions of the ligand T4 and the complex T4-Pt are diluted into a final solution of 20 mu mol/L (the final concentration of DMSO is less than or equal to 1 percent) by using a physiological buffer solution, and the inhibition degree of each compound on the growth of normal cells or selected tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking normal cells or tumor cells in a logarithmic growth phase, digesting the cells or tumor cells by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the density of cells to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating at 37 deg.C for 24 hr until cell monolayer is spread on the bottom of each well, and adding medicine with certain concentration gradient into each well10 mu L, and each concentration gradient is provided with 4 compound holes;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, culture solution, MTT, a drug dissolving medium with the same concentration, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of each compound on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by a Bliss method50The value is obtained. The results are shown in table 4 below.
TABLE 4 IC of ligand T4 and complex T4-Pt on various cell lines50Value (μ M)
Slave IC50According to the result of activity screening, the proliferation inhibition activity of the complex T4-Pt on 4 tested human tumor cell lines (human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells and human breast cancer cells (MCF-7 and MDA-MB-231)) is obviously higher than that of metal salt cis-Pt (DMSO)2Cl2Ligand T4 and cisplatin, which exhibit the synergistic effect of ligand T4 and platinum central atom. The result of an activity screening experiment shows that the complex T4-Pt has high anti-tumor activity on human breast cancer cells HeLa, MCF-7, MDA-MB-231 and SK-OV-3/DDP, and the IC of the complex is50Value rangeThe total content is 0.01-1.89 mu M, and the in vitro anti-tumor activity of the compound is far greater than that of T4 ligand and a clinical classical metal-based anti-cancer drug cisplatin; in addition, the toxicity of the complex T4-Pt to the normal cell HL-7702 is very small (IC)50More than 100 mu M), shows good target inhibition of human breast cancer proliferation. In a word, the complex T4-Pt shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing various anti-tumor medicaments.
Claims (10)
1. A novel platinum (II) complex of picrinine with high anti-tumor activity is characterized in that the chemical formula is [ Pt (Tm) R ] Cl, and the chemical structural formula is shown as the following formula:
wherein m is a non-zero natural number, n is a non-zero natural number, and R is halogen.
2. A synthesis method of a novel platinum (II) complex with high antitumor activity is characterized by comprising the following steps:
(1) reacting the cryptolepine derivative with a lutidine amine derivative in the presence of a solvent and strong base to generate a yellow solid powder ligand Tm, wherein m is a natural number different from zero;
(2) ligand Tm and platinum (II) compounds with equal substance amount are subjected to coordination reaction in the presence of a polar solvent to obtain a yellow target product, namely a platinum (II) chelerythrine complex Tm-Pt, which has a chemical formula of [ Pt (Tm) R ] Cl and has a chemical structural formula shown as the following formula:
n is a natural number different from zero, and R is halogen.
3. The method for synthesizing the platinum (II) chelerythrine complex according to claim 2, wherein in step (1), the molar ratio of the chelerythrine derivative to the lutidine derivative is 1: 1-1.5.
4. The method for synthesizing platinum (II) chelerythrine complex according to claim 2 or 3, wherein in step (1), the chelerythrine derivative is reacted with the lutidine-amine derivative at 20-30 ℃ for 1-10 hours.
5. The method for synthesizing platinum (II) complexes of picrinine according to claim 2 or 3, wherein in the step (2), the coordination reaction temperature is 30-100 ℃ and the reaction time is 10-80 h.
6. The method for synthesizing platinum (II) chelidonine complex as claimed in claim 2 or 3, wherein in the step (2), the platinum (II) compound includes but is not limited to bis (dimethyl sulfoxide) dichloroplatinum (II).
7. The method for synthesizing platinum (II) chelerythrine complex according to claim 2 or 3, wherein in step (2), said polar solvent is any one solvent or two-by-two mixed solution of methanol, ethanol, water, dimethyl sulfoxide and acetone, wherein the ratio of the two solvents in the mixed solution is arbitrary.
8. The method for synthesizing platinum (II) chelerythrine complex according to claim 7, wherein in said step (2), said polar solvent is a mixed solution of methanol and water or acetone, or a mixed solution of ethanol and water or acetone, or a mixed solution of dimethyl sulfoxide and methanol or ethanol.
9. The use of the platinum (II) chelerythrine complex according to claim 1 for the preparation of an antitumor medicament.
10. Use of the platinum (II) chelerythrine complex according to claim 1 for the preparation of a medicament for the targeted treatment of breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010053582.5A CN111187303B (en) | 2020-01-17 | 2020-01-17 | Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010053582.5A CN111187303B (en) | 2020-01-17 | 2020-01-17 | Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111187303A true CN111187303A (en) | 2020-05-22 |
| CN111187303B CN111187303B (en) | 2022-10-04 |
Family
ID=70706451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010053582.5A Active CN111187303B (en) | 2020-01-17 | 2020-01-17 | Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111187303B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539294A (en) * | 2022-03-21 | 2022-05-27 | 玉林师范学院 | Targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex, and synthesis method and application thereof |
| CN114573598A (en) * | 2022-03-21 | 2022-06-03 | 玉林师范学院 | White leaf vine zinc (II) complex with high activity in vivo and in vitro and synthesis method and application thereof |
| CN115160347A (en) * | 2022-08-11 | 2022-10-11 | 玉林师范学院 | High-activity glycosyl solanum lyratum zinc (II) complex and application |
| CN115385940A (en) * | 2022-08-11 | 2022-11-25 | 玉林师范学院 | White leaf vine zinc (II) complex and application thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020151540A1 (en) * | 2000-05-05 | 2002-10-17 | Medinox, Inc. | Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor |
| US20080038390A1 (en) * | 2004-04-22 | 2008-02-14 | Francois Frappier | Alkaloid compounds and their use as anti-malarial drugs |
| CN101250187A (en) * | 2008-03-28 | 2008-08-27 | 中山大学 | Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs |
| CN101787023A (en) * | 2010-02-10 | 2010-07-28 | 浙江工业大学 | Dimer salt of quinoline alkaloid, preparation method and application thereof |
| CN101845016A (en) * | 2009-03-25 | 2010-09-29 | 中国科学院大连化学物理研究所 | Method for synthesizing derivatives of chiral tetrahydroquinoline by catalyzing asymmetric hydrosilylation with iridium |
| CN104513240A (en) * | 2015-01-14 | 2015-04-15 | 中国药科大学 | Preparation method and use of iso-cryptolepine derivatives |
| CN110054651A (en) * | 2019-06-10 | 2019-07-26 | 玉林师范学院 | A kind of targeting human bladder cancer's jateorrhizine platinum (II) complex and its synthetic method and application |
| CN110054652A (en) * | 2019-06-10 | 2019-07-26 | 玉林师范学院 | A kind of high activity jateorrhizine platinum (II) complex and its synthetic method and application |
-
2020
- 2020-01-17 CN CN202010053582.5A patent/CN111187303B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020151540A1 (en) * | 2000-05-05 | 2002-10-17 | Medinox, Inc. | Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor |
| US20080038390A1 (en) * | 2004-04-22 | 2008-02-14 | Francois Frappier | Alkaloid compounds and their use as anti-malarial drugs |
| CN101250187A (en) * | 2008-03-28 | 2008-08-27 | 中山大学 | Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs |
| CN101845016A (en) * | 2009-03-25 | 2010-09-29 | 中国科学院大连化学物理研究所 | Method for synthesizing derivatives of chiral tetrahydroquinoline by catalyzing asymmetric hydrosilylation with iridium |
| CN101787023A (en) * | 2010-02-10 | 2010-07-28 | 浙江工业大学 | Dimer salt of quinoline alkaloid, preparation method and application thereof |
| CN104513240A (en) * | 2015-01-14 | 2015-04-15 | 中国药科大学 | Preparation method and use of iso-cryptolepine derivatives |
| CN110054651A (en) * | 2019-06-10 | 2019-07-26 | 玉林师范学院 | A kind of targeting human bladder cancer's jateorrhizine platinum (II) complex and its synthetic method and application |
| CN110054652A (en) * | 2019-06-10 | 2019-07-26 | 玉林师范学院 | A kind of high activity jateorrhizine platinum (II) complex and its synthetic method and application |
Non-Patent Citations (6)
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539294A (en) * | 2022-03-21 | 2022-05-27 | 玉林师范学院 | Targeted human lung adenocarcinoma cis-platinum-resistant cell solanum lyratum-phenanthroline zinc (II) complex, and synthesis method and application thereof |
| CN114573598A (en) * | 2022-03-21 | 2022-06-03 | 玉林师范学院 | White leaf vine zinc (II) complex with high activity in vivo and in vitro and synthesis method and application thereof |
| CN114539294B (en) * | 2022-03-21 | 2023-10-20 | 玉林师范学院 | Cisplatin-resistant cell white rattan-phenanthrene Luo Linxin (II) complex for targeting human lung adenocarcinoma, synthesis method and application thereof |
| CN115160347A (en) * | 2022-08-11 | 2022-10-11 | 玉林师范学院 | High-activity glycosyl solanum lyratum zinc (II) complex and application |
| CN115385940A (en) * | 2022-08-11 | 2022-11-25 | 玉林师范学院 | White leaf vine zinc (II) complex and application thereof |
| CN115385940B (en) * | 2022-08-11 | 2023-09-12 | 玉林师范学院 | Zinc (II) complex of sinomenine and application thereof |
| CN115160347B (en) * | 2022-08-11 | 2023-09-12 | 玉林师范学院 | Glycosyl white vine zinc (II) complex and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111187303B (en) | 2022-10-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111187303B (en) | Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof | |
| CN107746418B (en) | Synthesis and application of 9-chloro-1, 2,3, 4-tetrahydroacridine-platinum (II) complex targeting liver cancer | |
| CN110950914B (en) | Iridium complex and synthesis method and application thereof | |
| CN108774270B (en) | Sorafenib antitumor platinum (II) complex targeting drug-resistant cells of human lung cancer and preparation method and application thereof | |
| CN108774269B (en) | Novel targeted benzimidazole derivative antitumor platinum (II) and ruthenium (II) complex and preparation method and application thereof | |
| CN111039990B (en) | Low-toxicity iridium complex and synthesis method and application thereof | |
| WO2013086804A1 (en) | 4-pyridyl porphyrin bridged crisscross quad-nuclear platinum complex, and preparation method and anti-tumor activity thereof | |
| CN110054652B (en) | Jatrorrhizine platinum (II) complex and synthesis method and application thereof | |
| CN111205311A (en) | Novel high-antitumor-activity white leaf vine zinc (II) complex and synthesis method and application thereof | |
| CN111253418A (en) | Novel white leaf vine zinc (II) complex and synthesis method and application thereof | |
| CN111153916A (en) | White leaf vine zinc (II) complex and synthesis method and application thereof | |
| CN110330534B (en) | Novel 2-phenylpyridine-platinum (IV) precursor anticancer complex and synthesis method and application thereof | |
| CN113683644B (en) | Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof | |
| CN109908364B (en) | Synthetic method and application of gold (III) metal complex with human serum albumin as carrier | |
| CN108558952B (en) | 2-phenylpyridine binuclear palladium (II) complex and preparation method and application thereof | |
| CN113527370A (en) | Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof | |
| CN114539294B (en) | Cisplatin-resistant cell white rattan-phenanthrene Luo Linxin (II) complex for targeting human lung adenocarcinoma, synthesis method and application thereof | |
| CN114573598B (en) | White She Tengxin (II) complex with high in-vivo and in-vitro activity and synthesis method and application thereof | |
| CN107827934B (en) | Tetravalent platinum complex with anticancer activity, preparation method and application | |
| CN110172075B (en) | Novel coumarin-quinoline-platinum (II) complex and synthesis method and application thereof | |
| CN108997436B (en) | Rueglini antitumor platinum (II) complex and preparation method and application thereof | |
| CN110054651B (en) | Targeted human bladder cancer jatrorrhizine platinum (II) complex and synthesis method and application thereof | |
| CN109265488B (en) | Iridium anticancer complex containing phosphinimine bidentate chelating ligand and preparation method and application thereof | |
| CN115385940B (en) | Zinc (II) complex of sinomenine and application thereof | |
| CN110105402B (en) | Berberine antitumor platinum (II) complex and synthesis 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20200522 Assignee: Guangxi Xinghui Technology Co.,Ltd. Assignor: Yulin Normal University Contract record no.: X2022450000344 Denomination of invention: Platinum (II) Complexes of Leucine with High Antitumor Activity and Their Synthesis and Application Granted publication date: 20221004 License type: Common License Record date: 20221219 |
|
| EE01 | Entry into force of recordation of patent licensing contract |