WO2009043223A1 - Complexes chiraux du ruthénium et leur utilisation comme médicament contre les tumeurs - Google Patents
Complexes chiraux du ruthénium et leur utilisation comme médicament contre les tumeurs Download PDFInfo
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- WO2009043223A1 WO2009043223A1 PCT/CN2008/001347 CN2008001347W WO2009043223A1 WO 2009043223 A1 WO2009043223 A1 WO 2009043223A1 CN 2008001347 W CN2008001347 W CN 2008001347W WO 2009043223 A1 WO2009043223 A1 WO 2009043223A1
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- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 9
- 150000003303 ruthenium Chemical class 0.000 title abstract description 12
- 239000012327 Ruthenium complex Substances 0.000 claims description 8
- PNAAEIYEUKNTMO-UHFFFAOYSA-N S-Seven Chemical compound C=1C=CC=CC=1P(=S)(OCC)OC1=CC=C(Cl)C=C1Cl PNAAEIYEUKNTMO-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 abstract 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- HXYXTCJDWHHCBW-UHFFFAOYSA-N acetonitrile;toluene Chemical compound CC#N.CC1=CC=CC=C1 HXYXTCJDWHHCBW-UHFFFAOYSA-N 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 12
- 230000007935 neutral effect Effects 0.000 description 9
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 206010009944 Colon cancer Diseases 0.000 description 7
- 208000029742 colonic neoplasm Diseases 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 201000007270 liver cancer Diseases 0.000 description 6
- 208000014018 liver neoplasm Diseases 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 201000005249 lung adenocarcinoma Diseases 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- ADIDVEUHTIRRIM-UHFFFAOYSA-N 2-[2-(trifluoromethyl)phenyl]-1h-imidazole Chemical compound FC(F)(F)C1=CC=CC=C1C1=NC=CN1 ADIDVEUHTIRRIM-UHFFFAOYSA-N 0.000 description 2
- -1 2-substituted phenylimidazole Chemical class 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003517 fume Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- HCCNHYWZYYIOFM-UHFFFAOYSA-N 3h-benzo[e]benzimidazole Chemical compound C1=CC=C2C(N=CN3)=C3C=CC2=C1 HCCNHYWZYYIOFM-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- XTBLDMQMUSHDEN-UHFFFAOYSA-N naphthalene-2,3-diamine Chemical compound C1=CC=C2C=C(N)C(N)=CC2=C1 XTBLDMQMUSHDEN-UHFFFAOYSA-N 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 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
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium 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
Definitions
- the present invention relates to ruthenium complexes and, in particular, to chiral ruthenium complexes and their use as antitumor drugs.
- Malignant tumors are one of the major diseases that endanger human health. Among the deaths caused by various diseases, the mortality rate of cancer is second only to the mortality rate of cardiovascular diseases. In some developed countries, the cause of death is the first. In the 1990s, China is the year. There are more than 2 million new cases. Tumors are treated clinically by chemotherapy, surgery, and radiation therapy.
- Cisplatin has antitumor activity and has rapidly developed into a clinically widely used antitumor drug.
- Cisplatin is clinically used for the treatment of bladder cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, malignant lymphoma and leukemia.
- the drug is poorly water-soluble and can only be administered by injection, with a short remission period, accompanied by severe kidney, gastrointestinal toxicity, ototoxicity and neurotoxicity, and long-term use may cause drug resistance. Therefore, the development of new metal complexes with antitumor activity has attracted people's attention.
- platinum, ruthenium, osmium, iridium, and the like, particularly ruthenium compounds have antitumor activity.
- Another object of the present invention is to provide the use of the above chiral ruthenium complex in the preparation of an antitumor drug.
- the invention designs and synthesizes a series of chiral ruthenium complexes with the following structural features:
- the above chiral ruthenium complex has the general formula: A-[Ru(bpy) 2 L](PF 6 ) 2 ,
- A is ⁇ or ⁇ ;
- L is tFPIP, EPBP, EPBH or PYNI.
- Preferred compounds of the above chiral ruthenium complexes are:
- the above chiral ruthenium complexes have excellent antitumor activity and can be used for the preparation of antitumor drugs.
- the present invention Compared with the prior art, the present invention has the following beneficial effects: the present invention designs and synthesizes a series of chiral ruthenium complexes, and the in vitro cell experimental structure indicates that these ruthenium complexes have obvious inhibition on the liver cancer cell line BEL-7402 and the like. Active, can be used to prepare anti-tumor drugs. detailed description
- 1,10-phenanthroline (4 g, 21.88 mmol) ⁇ KBr (4 g, 33.9 mmol) was placed on an ice bath, and 80 4 and 1 ⁇ 0 3 mixed acid solutions were slowly added dropwise with stirring. The ice bath was removed and heated to reflux for 40 minutes. After the reaction is completed, the bromine is removed, the reaction solution is transferred to a beaker, 6 mol of L NaOH solution is added, and the pH of the solution is carefully adjusted to about 7 (a large amount of golden yellow precipitate is formed in the solution), and extracted with 3 ⁇ 100 mL of chloroform to combine organic After the phase, it was washed 1-2 times with 50 ml of water and dried over anhydrous sodium sulfate overnight.
- the chloroform was evaporated under reduced pressure to give an orange-yellow crude product.
- the crude product was dissolved in ethanol, passed through a 60-100 mesh silica gel column, and a yellow ribbon was collected and recrystallized from ethanol to give yellow needle crystals with a yield of 74.8 %.
- Phenanthroline 5,6-dione (2.6 g, 12 mmol) and 2-trifluorobenzaldehyde (2.5 g, 18 mmol), ammonium acetate (19 g, 25 mmol) and glacial acetic acid (100 ml). 4h, cooling To room temperature, distilled water was added, and the pH was adjusted to neutral with concentrated aqueous ammonia. When a large amount of orange-yellow precipitate was formed, it was extracted with 3 ⁇ 20 mL of chloroform. Spin dry, vacuum dry, to get a crude product. The crude product was dissolved in MeOH (EtOAc m.).
- 5-fluorouracil was used as a positive control.
- Study of sputum complexes on human hepatoma cell line (BEL-7402), colon cancer cell line (HCT-8) and human lung adenocarcinoma cell line (A-549) (cell experiments were performed by the Institute of Materia Medica, China Academy of Medical Sciences) ).
- Tumor cell growth inhibition rate (%) (OD control - OD experiment) / (OD control - OD blank) X 100% Different concentrations of target compound against human hepatoma cell line (BEL-7402), colon cancer cell line (HCT-8) The inhibition rate (%) of growth of cancer cells in human lung adenocarcinoma cell line (A-549) is shown in Table 1.
- liver cancer cells The growth inhibition of BEL-7402 liver cancer cells, HCT-8 colon cancer and ⁇ -549 lung adenocarcinoma cells exceeded that of the positive control drug 5-FU (about 38 ⁇ ).
- the ruthenium complexes on human hepatoma cell line BEL -7402 The inhibition rate of liver cancer cells is stronger than that of HCT-8 colon cancer and ⁇ -549 lung adenocarcinoma, but it is more active against liver cancer cells than colon cancer, especially the left-handed complex, which has more selectivity for liver cancer cells. It is obvious.
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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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
手性钌配合物及其作为抗肿瘤药物的应用 技术领域
本发明涉及钌配合物, 具体的说, 涉及手性钌配合物及其作为抗 肿瘤药物的应用。
背景技术
恶性肿瘤是危害人类健康的主要疾病之一,在各种疾病导致的死 亡中, 癌症的死亡率仅次于心血管疾病的死亡率, 在某些发达国家占 死亡原因的首位, 90年代我国每年新发病例超过 200万人。 临床上普 遍采用化疗、 手术治疗以及放射治疗等手段对肿瘤进行治疗。
1969年 Rosenberg发现顺铂 (cisplatin)具有抗肿瘤活性, 并很快发 展成为临床上广泛使用的抗肿瘤药物。 顺铂临床上用于治疗膀胱癌、 前列腺癌、 肺癌、 头颈部癌、 乳腺癌、 恶性淋巴癌和白血病等。 但该 药物水溶性差, 且仅能注射给药, 缓解期短, 并伴有严重的肾、 胃肠 道毒性、耳毒性及神经毒性, 长期使用会产生耐药性。 因此研制新的 具有抗肿瘤活性的金属配合物引起人们的重视。 近年来已经证实铂、 铑、 锗、 锲等, 特别是钌的化合物具有抗肿瘤活性。
发明内容
本发明的目的在于提供一种手性钌配合物,以克服现有技术存在 的不足。
本发明的另一个目的是提供上述手性钌配合物在制备抗肿瘤药 物中的应用。
本发明设计合成了一系列的手性钌配合物,具有以下结构特点:
1) 以钌作为中心金属离子; 具有刚性八面体空间结构的络离子; 2) 分子中有两个联吡啶基团作为辅助配体; 3) 以 2-取代苯基咪唑 [4,5-/][1,10]菲咯啉作为主配体; 4)具有上述结构特点的金属配合物 的手性异构体, 具有旋光性。
上述手性钌配合物的通式为: A-[Ru(bpy)2L](PF6)2,
其中, A为 Δ或 Λ; L为 tFPIP、 EPBP、 EPBH或 PYNI。
上述手性钌配合物的优选化合物为:
zi-[Ru(bpy)2(tFPIP)](PF6)2, ^-[Ru(bpy)2(tFPIP)](PF6)2,
i-[Ru(bpy)2(IPBP)](PF6)2, i-[Ru(bpy)2(IPBP)](PF6)2,
/-[Ru(bpy)2(IPBH)](PF6)2、 [Ru(bpy)2(IPBH)](PF6)2、
zi-[Ru(bpy)2(PYNI)](PF6)2, -[Ru(bpy)2(PY )](PF6)2。
上述手性钌配合物具有很好的抗肿瘤活性,能用于制备抗肿瘤药 物。
与现有技术相比,本发明具有如下有益效果:本发明设计合成了 一系列的手性钌配合物, 体外细胞实验结构表明,这些钌配合物对肝 癌细胞株 BEL-7402等具有明显的抑制活性, 能用于制备抗肿瘤药物。 具体实施方式
实施例 1 -[Ru(bpy)2(tFPIP)](PF6)2 的合成
i-[Ru(bpy)2(FPIP)](PF6)2 ( l-l)的合成路线见式 ( I ) :
[Ru(bpy)2(^'_二苯甲酰基 -D-酒石酸)]
《
1.1 菲罗啉 5,6-二酮的合成
1,10-邻菲罗啉 (4 g, 21.88 mmol)^ KBr (4 g, 33.9 mmol)置于冰 浴上, 搅拌下缓慢滴加 804和1^03的混酸溶液, 滴加完毕后移去 冰浴, 加热回流 40分钟。 反应结束后, 使溴逸去, 将反应液转移至 烧杯中, 加入 6mol,L NaOH溶液, 小心调节溶液 pH值约为 7(溶液 中有大量金黄色沉淀生成), 用 3xl00mL氯仿萃取, 合并有机相后, 用 50 ml水洗涤 1-2次, 无水硫酸钠干燥过夜。 减压蒸去氯仿, 得橙 黄色粗产品。 用乙醇溶解粗产品, 过 60-100 目硅胶柱, 收集黄色色 带, 乙醇中重结晶, 得黄色针状晶体, 产率 74.8 %。
1.2 2-(2-三氟甲苯基)咪唑 [4,5- ][1,10]菲咯啉 (tFPIP)的合成
菲罗啉 5,6-二酮 (2.6 g, 12 mmol)和 2-三氟基苯甲醛 (2.5 g, 18 mmol), 乙酸铵 (19 g, 25 mmol)和冰乙酸 (100ml), 搅拌回流 4h, 冷却
至室温, 加入蒸馏水, 用浓氨水调 pH值至中性, 有大量橙黄色沉淀 生成时, 用 3X20 mL氯仿萃取。 旋干, 真空干燥, 得粗产品。 粗产 品以甲醇溶解, 过硅胶柱, 甲醇淋洗, 收集黄色洗脱液, 浓缩干燥, 得灰黄色固体, 产率 86.7%。
1.3 ds-[Ru(bpy)2Cl2]-2H20的合成
氯化钌 (RuCl3'nH20) (1.56 g , 6 mmol),联吡啶 (1.87 g, 12 mmol) 和氯化锂 (2.42 g, 57.6 mmol), 溶于 15 ml DMF中, 氩气保护下加热 回流 8小时。冷却至室温, 加入 50 ml丙酮, 摇匀, 置冰箱冷冻过夜。 过滤, 得紫黑色微晶, 以冰水洗至近无色, 干燥, 产率 71.0 % (以联 吡啶计算)。
1.4 cw-[Ru(bpy)2(py)2]Cl2的合成
2.0 g cw-[Ru(bpy)2Cl2] .2H20, 23 ml吡啶和 46 ml水,加热搅拌回 流 4小时。 减压蒸去全部溶剂后, 用 46ml甲醇溶解得到红色固体, 然后加入 300 ml乙醚, 室温放置 1小时, 洗出大量的红色晶体。 抽 滤, 用乙醚洗涤数次, 得到红色晶体, 产率 84.5%。
1.5 zl-[Ru(bpy)2(py)2][0,( -二苯甲酰基- D-酒石酸 ]·12Η20的合成
1.95 g ^-[Ru(bpy)2(py)2Cl2]溶于 30ml水中, 室温搅拌下加入 0.5 M的 Ο,Ο'-二苯甲酰基 -D-酒石酸钠溶液 19.0 ml, 搅拌 10分钟, 将所 得溶液敞口置于通风橱中, 约一个星期后析出大量红色晶体, 产率 79.3%。
1.6 l-[Ru(bpy)2(FPIP)](PF6)2 的合成
zi-[Ru(bpy)2(py)2] [O, O,-dibenzoyl-d- tartrate] · 12H20, tFPIP以及乙二
醇和水的混合溶液加热回流 6小时, 冷至室温后加水稀释, 过滤得到 深红色滤液, 向滤液中加入饱和 N¾PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈 -甲苯溶液淋 洗下主要的红色组分, 减压旋干, 乙腈-甲苯中重结晶, 得到橘红色 固体,产率 79%。 ESl-MS(m/e) 777.2; 389.2。 CD(in Tris-HCl, pH = 7.2, D - 291.0nm。
实施例 2 ^-[Ru(bpy)2(tFPIP)](PF6)2 ( -l)的合成
/l-[Ru(bpy)2(FPIP)](PF0)2(/ )的合成路线见式 ( II ) :
( II )
菲罗啉 5, 6-二酮, 2-(2-三氟甲苯基)咪唑 [4,5:3[1,10]菲咯啉 (tFPIP), c/^[Ru(bpy)2Cl2],c^- [^0¾^2(^2]( 12的合成同实施例 1。 2.1 [Ru(bpy)2(py)2][6>,6>'-二苯甲酰基 -L-酒石酸 ]·12Η20的合成
1.95 g -[Ru(bpy)2(py)2Cl2]溶于 30ml水中, 室温搅拌下加入 0.5 M的 < ,( '-二苯甲酰基 -L-酒石酸钠溶液 19.0 ml。 搅拌 10分钟, 将所 得溶液敞口置于通风橱中,约一星期后析出大量红色晶体,产率 73%。
2.2 i-[Ru(bpy)2(tFPIP)](PF6)2 的合成
yl-[Ru(bpy)2(py)2][< ,( -二苯甲酰基 -L-酒石酸 ]·12Η20 (0.13 g, 0.1 mmol), tFPIP (0.105 g, 0.28 mmol)以及乙二醇和水的混合溶剂加热回 流 6小时, 冷至室温后加水 40ml稀释, 过滤得到深红色滤液, 向滤液 中加入饱和 NH4PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用 水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈-甲苯溶液淋洗下主要的红色组 分, 减压旋干, 乙腈-甲苯中重结晶, 得到橘红色固体, 产率 76%。
ESI- MS(w/e): 777.3; 389.3。 CD(in Tris-HCl, pH = 7.2, U: +291.0讓。 实施例 3 -[Ru(bpy)2(IPBP)](PF6)2 的合成
[Ru(bpy)2(IPBP)](PF6)2 ( i-2)的合成路线见式 (ΠΙ) :
菲罗啉 5, 6-二酮, d Ru(bpy)2Cl2], cw-[Ru(bpy)2(py)2]Cl2, -[Ru(bpy)2(py)2] [Ο, Ο'-二苯甲酰基 -D-酒石酸 ].12¾0的合成同实施 例 1。
3.1 2-(4-甲基小苯并吡喃- 2-酮)咪唑 [4,5- [1,10]菲咯啉)(IPBP)的合成 菲罗啉 -5,6-二酮 0.315 g (1.5 讓 ol), 3-醛基色酮 0.261 g (1.5 mmol), 乙酸铵 2.31 g (30 mmol)和冰乙酸 20 mL的混合物于油浴中 加热回流 2小时。冷却至室温后, 用 80 mL水稀释, 然后滴加浓氨水中 和至近中性, 即析出大量黄色沉淀。抽滤,先后用水, 乙醇洗涤数次, 烘干即得粗产物, 无水乙醇中重结晶, 产率 73%。
3.2 zl- [Ru(¾py)2(IPBP)](PF6)2 Cd-2)的合成
l-[Ru( py)2(py)2] [O,O,-二苯甲酰基 -D-酒石酸 ]' 12H2O(0.26g, 0.2 mmol), EPBP (0.210 g, 0.56 mmol)以及乙二醇和水的混合溶剂加热回 流 6小时, 冷至室温后加水 40ml稀释, 过滤得到深红色滤液, 向滤液 中加入饱和 NH4PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用 水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈-甲苯溶液淋洗下主要的红色组 分, 减压旋干, 乙腈-甲苯中重结晶, 得到红色固体, 产率 70%。 ESI-MS(m/e): 791.3. CD(in Tris-HCl, H = 7.2, U: -291.0nm。
实施例 4 ^-[Ru(bpy)2(]PBP)](PF6)2 的合成
l-[Ru(bpy)2(IPBP)](PF6)2 ( l-2)的合成路线见式 (IV ) :
菲罗啉 5, 6-二酮, c -[Ru(bpy)2Cl2], c -[Ru(bpy)2(py)2]Cl2的合成 同实施例 1 ; ^-[Ru(bpy)2(py)2] [O, O 二苯甲酰基 -D-酒石酸] · 12H20的 合成同实施例 2; IPBP的合成同实施例 3。
( IV ) i-[Ru(bpy)2(py)2][< , < ,-二苯甲酰基 -L-酒石酸 ]· 12Η20 (0.26 g, 0.2 mmol), IPBP (0.210 g, 0.56 mmol)以及乙二醇和水的混合溶剂加热回 流 6小时, 冷至室温后加水 40ml稀释, 过滤得到深红色滤液, 向滤液 中加入饱和 NH4PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用 水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈-甲苯溶液淋洗下主要的红色组 分, 减压旋干, 乙腈-甲苯中重结晶, 得到红色固体, 产率 72%。 ESI-MS(/w/e): 937.0; 791.3; 396.27。 CD(in Tris-HCl, pH = 7.2, U: +291.0腿。
实施例 5 i-[Ru(bpy)2(IPBH)](PF6)2 ( /-3)的合成
)-[Ru(bpy)2(IPBH)](PF6)2 ( l- 3)的合成路线见式 (V ) :
( V )
菲罗啉 5, 6-二酮, c -[Ru(bpy)2Cl2], cis-[Ru(bpy)2(py)2]Cl2, zi-[Ru(bpy)2(py)2] [0,0 '-二苯甲酰基-0-酒石酸]' 12¾0的合成同实施 例 1。
5.1 2-(4/f-l-二氧六环并苯基)咪唑 [4,5- 1,10]菲咯啉 (IPBH)的合成 邻菲咯啉 -5,6-二酮 0.315 g (1.5 mmol), 3-醛基苯并二恶烷 0.246 g (1.5 mmol),乙酸铵 2.31 g (30 mmol)和冰乙酸 20 mL 的混合物于油 浴中加热回流 2小时。冷却至室温后, 用 80 mL水稀释, 然后滴加浓氨 水中和至近中性, 即析出大量棕黄色沉淀。 抽滤, 先后用水, 乙醇洗 涤数次, 烘干即得粗产物, 无水乙醇中重结晶, 产率 67.1%。
5.2 z/-[Ru(bpy)2(IPBH)](PF6)2 ( l-3)的合成
zi-[Ru(bpy)2(py)2] [O, O -dibenzoyl-d-tartrate] - 12H20 (0.13g, 0.1 mmol), IPBH (0.107 g, 0.3 mmol)以及乙二醇和水的混合溶剂加热回 流 6小时, 冷至室温后加水 40ml稀释, 过滤得到深红色滤液, 向滤液
中加入饱和 N¾PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用 水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈-甲苯溶液淋洗下主要的红色组 分, 减压旋干, 乙腈-甲苯中重结晶, 得到橘黄色固体, 产率 74%。 ESI-MS ): 913.0; 767.2; 384.3。 CD(in Tris-HCl, pH = 7.2, ^): -292.0 腿。
实施例 6 -[Ru(bpy)2(IPBH)](PF6)2 的合成
[Ru(bpy)2(IPBH)](PF6)2( l-3)的合成路线见式 (VI) :
(VI) 菲罗啉 5, 6-二酮, -[Ru(bpy)2Cl2], -[Ru(bpy)2(py)2]Cl2的合成 同实施例 1; l- [Ru(bpy)2(py)2][< ,( '-二苯甲酰基- D-酒石酸 ]·12Η20的 合成同实施例 2; ΙΡΒΡ的合成同实施例 5。
yl-[Ru(bpy)2(py)2][( ,0 '-二苯甲酰基 -L-酒石酸 ]·12Η20 (0.13 g, 0.1
mmol), IPBH (0.107 g, 0.3 mmol)以及乙二醇和水的混合溶剂加热回 流 6小时, 冷至室温后加水 40ml稀释, 过滤得到深红色滤液, 向滤液 中加入饱和 N¾PF6溶液, 得到大量橙黄色沉淀, 抽滤, 沉淀分别用 水、 乙醚洗涤数次, 真空干燥, 得到橙红色粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈-甲苯溶液淋洗下主要的红色组 分, 减压旋干, 乙腈-甲苯中重结晶, 得到橘黄色固体, 产率 76%。 ESI-MS(w/e): 912.87; 767.3; 384.3。 CD(in Tris-HCl, pH = 7.2, U: 292.0 nm.
实施例 7 i-[Ru(bpy)2(PY )](PF6)2 ( /-4)的合成
zl-[Ru(bpy)2(PY )](PF6)2(/-4)的合成路线见式 (W) 。
(νπ)
cw-[Ru(bpy)2Cl2] , cw-[Ru(bpy)2(py)2]Cl2,zi-[Ru(bpy)2(py)2] [Ο,Ο'- 二苯甲酰基 -D-酒石酸 ]·12Η20的合成同实施例 1。
7.12-(2'-吡啶)萘并咪唑 (ΡΥΝΙ)的合成
2-氰基-卩比啶 0.312 g (3 mmol), 2, 3-二氨基萘 0.47 g (3 mmol), 多
聚磷酸 6 ml, 加热到 175°C 6小时, 停止反应, 冷至 80°C, 迅速将反 应混合物倒入 50 ml水中, 用 25%氨水中和, 得到棕绿色沉淀, 用乙醇 重结晶, 真空干燥得棕绿色粉末。 产率 76.2%。
7.2 i-[Ru(bpy)2(PYNI)](PF6)2 (zl-4)的合成
l-[Ru(bpy)2(py)2][(,0'-二苯甲酰基 酒石酸 ]· 12Η20 (0.13 g, 0.1 mmol), IPBH (0.0735 g, 0.3 mmol)以及乙二醇和水的混合溶剂 (9:l,v/v,20 ml)于 120 °C回流 6小时, 冷至室温后加水 40 ml稀释, 过滤 得到深红色滤液, 向滤液中加入饱和 NH4PF6溶液, 得到大量橙黄色 沉淀, 抽滤, 沉淀分别用水、 乙醚洗涤数次, 真空干燥, 得到橙红色 粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈: 甲 苯 (10:l,V/v)溶液淋洗下主要的红色组分, 减压旋干, 乙腈-甲苯中重 结晶, 得到棕色固体, 产率 80%。 ESl-MS(m/e) 658.2; 583.9; 329.7。 CD(in Tris-HCl , pH = 7.2U : -294亂
实施例 8 yl-[Ru(bpy)2(PYNI)](PF6)2 ( -4)的合成
-[Ru(bpy)2(PYNI)](PF6)2 W-4)的合成路线见式 ( ) :
c 5-[Ru(bpy)2Cl2], £-w-[Ru(bpy)2(py)2]Cl2的合成同实施例 1; /i-[Ru(bpy)2(py)2][0, O'-二苯甲酰基 酒石酸 ] ·12¾0的合成同实施 例 2; ΡΥΝΙ的合成同实施例 7。
i-[Ru(bpy)2(py)2][Q< ,-二苯甲酰基- L-酒石酸 ]·12Η2Ο (0.13 g, 0.1 mmol), IPBH (0.0735 g, 0.3 mmol)以及乙二醇和水的混合溶剂
(9:l,v/v,2.0 ml)于】 20 °C回流 6小时, 冷至室温后加水 40 ml稀释, 过滤 得到深红色滤液, 向滤液中加入饱和 N¾PF6溶液, 得到大量橙黄色 沉淀, 抽滤, 沉淀分别用水、 乙醚洗涤数次, 真空干燥, 得到橙红色 粗品。 将干燥后得粗品用 5ml乙腈溶解, 过中性氧化铝柱, 乙腈: 甲 苯 (10:l,v/v)溶液淋洗下主要的红色组分, 减压旋干, 乙腈-甲苯中重 结晶, 得到棕色固体, 产率 79%。 ESI-MS(w/e): 658.2; 583.8; 329.8。
CD(in Tris-HCl, pH = 7.2, : +294nm。
实施例 9 钌配合物对肿瘤细胞生长的抑制
以 5-氟尿嘧啶为阳性对照。 研究钌配合物对人肝癌细胞株 (BEL-7402), 结肠癌细胞株 (HCT-8)和人肺腺癌细胞株 (A-549) (细胞 实验均由中国医学科学院药物研究所筛选中心进行)。
一般实验方法:选用对数生长周期的贴壁肿瘤细胞,胰酶消化后,
用 10%小牛血清的 RPMI1640培养液配成 5000个 /ml的细胞悬液,接 种在 96孔培养板中 (每孔接种 100 μ1), 37°C, 5% C02条件下培养 24 h。 待细胞长满单层后, 实验组加样品 10 μ1, 然后加入 RP -1640 培养液 (Flow Laboratories,美国)至每孔终体积为 200 μ103700, 5% CO, 条件下继续培养 72h 后, 将细胞培养板中的营养液弃掉, 每孔加入 ΙΟΟ μΙ新鲜配制的 0.5mg/ml MTT无血清培养液, 37°C, 5% C02条件 下继续培养 4 h。小心弃上清,加入 200 l DMSO溶解 MTT formazon 沉淀, 微型超声振荡器混匀, 酶标仪上测定波长 544 nm处的光密度 值 (OD值), 按下式计算配合物对肿瘤细胞生长的抑制率:
肿瘤细胞生长抑制率 (%) = (OD对照 -OD实验) /(OD对照 -OD空白) X 100% 不同浓度目标化合物对人肝癌细胞株 (BEL-7402),结肠癌细胞株 (HCT-8)和人肺腺癌细胞株 (A-549)肿癌细胞生长的抑制率 (%)见表 1。
表 1 钌配合物对 BEL-7402, HCT-8和 A-549肿瘤细胞株的抑制活性 抑制率%
齐量
配合物
( g/ml) BEL-7402 HCT-8 A-549 肝癌 结肠癌 肺腺癌
ΔΛ 5 85.0 81.6 62.0
50 88.3 86.2 ―
A-1 5 85.2 83.0 56.4
50 88.8 88.9 ―
Δ-2 5 9.6 13.1 18.5
50 86.8 83.4 ―
A-2 5 0.19 2.23 -0.52
50 64.9 53.7 ―
zl-3 5 ― ― ―
50 ― ― ―
Λ-3 5 3.0 2.1 -0.92
50 44.3 39.1 ―
Δ 5 2. 8 1.8 -8.2
50 36.0 38.6 ―
Λ-4 5 4.4 3.6 -2.3
50 22.6 21.4
5-FU 5 81.8 76.3 82.3
50 77.1 86.4 ― 从表 1 数据可以看到, 高浓度 (50μ^πύ)条件下; 钌配合物 (约 50μΜ)对实验肿瘤细胞均表现出明显的生长抑制作用; 特别是 △-1(88.3%; 86.2%); Λ-1(88.8%; 88.9%); Δ- 2(86.8?ό' ; 83.4 ?' ; Λ-2(64.9 53.7%)对人肝癌细胞株 BEL- 7402和结肠癌细胞株 HCT-8生长抑 制率均超过 50 ?0。 在低浓度 5yg/ml 条件下, 钌配合物 A//v-[Ru(bpy)2(FPBP)]?+ (约 5μΜ), 对人肝癌细胞株 BEL-7402肝癌细 胞、 HCT- 8结肠癌和 Α-549肺腺癌细胞生长的抑制均超过了阳性对照 药 5-FU (约 38μΜ)。实验条件下,钌配合物对人肝癌细胞株 BEL-7402 肝癌细胞的抑制率要比 HCT-8结肠癌和 Α-549肺腺癌的强一些, 而 对肝癌细胞的活性比结肠癌更大, 尤其是左旋配合物, 对肝癌细胞的 选择性更为明显。
Claims
1.一种手性钌配合物, 其通式为 A-[Ru(bpy)2L](PF6)2,
其中, A为 Δ或 Λ; L为 tFPEP、 EPBP、 IPBH或 PYNI。
2.如权利要求 1所述的手性钌配合物, 其特征在于为 l-[Ru(bpy)2(tFPIP)](PF6)2, -[Ru(bpy)2(tFPIP)](PF6)2、
z/-[Ru(bpy)2(IPBP)](PF6)2, /l-[Ru(bpy)2(IPBP)](PF6)2,
i-[Ru(bpy)2(IPBH)](PF6)2, -[Ru(bpy)2(IPBH)](PF6)2、
i-[Ru(bpy)2(PYNl)](PF6)2, ^-[Ru(bpy)2(PYNI)](PF6)2 o
3.权利要求 1所述手性钌配合物在制备作为抗肿瘤药物中的应用。
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CN101701024B (zh) * | 2009-10-30 | 2013-07-03 | 暨南大学 | 一种钌配合物及其制备方法和应用 |
CN101735217B (zh) * | 2009-12-15 | 2012-09-26 | 广东药学院 | 咪唑[4,5-f][1,10]菲咯啉及其衍生物在制备抗肿瘤药物中的应用 |
CN101747382B (zh) * | 2009-12-29 | 2012-06-27 | 广东药学院 | 一种以喹诺酮类化合物为配体的钌多吡啶配合物及其制备方法和应用 |
CN101863925B (zh) * | 2010-05-21 | 2012-08-29 | 广东药学院 | 一种芳基钌(ⅱ)配合物及其制备方法和应用 |
WO2014153464A2 (en) * | 2013-03-20 | 2014-09-25 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-d]phenanthroline derivatives and their use in the treatment of cancer |
CN103709202B (zh) * | 2013-12-26 | 2017-09-26 | 广东药科大学 | 钌(ii)配合物及其制备方法及其作为细胞荧光染料的应用 |
JP7304128B2 (ja) | 2014-06-11 | 2023-07-06 | ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム | 白金耐性の克服における使用のためのテキサフィリン-白金(iv)コンジュゲート及び組成物 |
US10183027B2 (en) * | 2016-09-21 | 2019-01-22 | Hong Kong Baptist University | Lanthanide toolbox for multi-modal, non-invasive tumor specific theranostic prodrugs |
CN107793454B (zh) * | 2017-05-19 | 2020-05-05 | 广东药科大学 | 一种芳烃钌配合物及其制备方法与应用 |
CN107400146B (zh) * | 2017-07-27 | 2019-06-25 | 广东药科大学 | 一种抗肿瘤金属铱(ⅲ)配合物及其制备方法和应用 |
KR102016699B1 (ko) * | 2017-12-20 | 2019-09-02 | 서울대학교산학협력단 | 신규 루테늄 착화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
CN109456365B (zh) * | 2018-12-05 | 2020-09-25 | 湖南文理学院 | 一种钌配合物荧光探针、制备方法和用途 |
CN115057889A (zh) * | 2022-05-26 | 2022-09-16 | 广东药科大学 | 一种生物素修饰钌(ii)配合物及其制备方法和应用 |
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US4699978A (en) * | 1985-01-18 | 1987-10-13 | The Trustees Of Columbia University In The City Of New York | Site-specific chiral ruthenium (II) and cobalt (III) antitumor agents |
US5112974A (en) * | 1985-01-18 | 1992-05-12 | The Trustees Of Columbia University In The City Of New York | Mixed ligand complexes and uses thereof as binding agents to DNA |
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LIU, Y.-J. ET AL.: "Synthesis, characterization, and DNA interaction studies of the ruthenium (II) complexes [Ru(bpy)2(ipbp)]2+ and [Ru(ipbp)(phen)2]2+ (ipbp=3-(1H-imidazo[4,5-f][1,10] phenanthrolin-2-yl)-4H- 1-benzopyran-2-one; bpy=2,2'-bipyridine; phen= 1,10-phenanthroline)", HELVETICA CHIMICA ACTA, vol. 87, no. 12, 2004, pages 3119 - 3130 * |
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