CN105732723B - A kind of ruthenium (II) multi-pyridine ligand and its preparation and application - Google Patents
A kind of ruthenium (II) multi-pyridine ligand and its preparation and application Download PDFInfo
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- CN105732723B CN105732723B CN201610157250.5A CN201610157250A CN105732723B CN 105732723 B CN105732723 B CN 105732723B CN 201610157250 A CN201610157250 A CN 201610157250A CN 105732723 B CN105732723 B CN 105732723B
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- 239000003446 ligand Substances 0.000 title claims abstract description 64
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 39
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims description 20
- 210000003411 telomere Anatomy 0.000 claims abstract description 39
- 108091035539 telomere Proteins 0.000 claims abstract description 39
- 102000055501 telomere Human genes 0.000 claims abstract description 39
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 11
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims abstract description 8
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 6
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 238000010992 reflux Methods 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 20
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 239000007789 gas Substances 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 229910052786 argon Inorganic materials 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 239000004254 Ammonium phosphate Substances 0.000 claims description 7
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 7
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 7
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 7
- 229910000474 mercury oxide Inorganic materials 0.000 claims description 7
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000011011 black crystal Substances 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 2
- 229910019891 RuCl3 Inorganic materials 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- VXJIMUZIBHBWBV-UHFFFAOYSA-M lithium;chloride;hydrate Chemical compound [Li+].O.[Cl-] VXJIMUZIBHBWBV-UHFFFAOYSA-M 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 108010017842 Telomerase Proteins 0.000 abstract description 8
- 108700020978 Proto-Oncogene Proteins 0.000 abstract description 6
- 102000052575 Proto-Oncogene Human genes 0.000 abstract description 6
- 230000004913 activation Effects 0.000 abstract description 5
- 230000006641 stabilisation Effects 0.000 abstract description 5
- 238000011105 stabilization Methods 0.000 abstract description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 229910000765 intermetallic Inorganic materials 0.000 abstract 1
- 150000005041 phenanthrolines Chemical class 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- 108020004414 DNA Proteins 0.000 description 21
- 239000007853 buffer solution Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 229910001414 potassium ion Inorganic materials 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229910001415 sodium ion Inorganic materials 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241000736199 Paeonia Species 0.000 description 4
- 235000006484 Paeonia officinalis Nutrition 0.000 description 4
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 150000004987 o-phenylenediamines Chemical class 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000000137 annealing Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 150000003303 ruthenium Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ILXAOQAXSHVHTM-UHFFFAOYSA-M sodium;2-amino-2-(hydroxymethyl)propane-1,3-diol;chloride Chemical compound [Na+].[Cl-].OCC(N)(CO)CO ILXAOQAXSHVHTM-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 2
- 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 1
- 230000004568 DNA-binding Effects 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000012327 Ruthenium complex Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- XQGPKZUNMMFTAL-UHFFFAOYSA-L dipotassium;hydrogen phosphate;trihydrate Chemical class O.O.O.[K+].[K+].OP([O-])([O-])=O XQGPKZUNMMFTAL-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to ruthenium (II) multi-pyridine ligands, the complex is with 2 (1,10 ferrosin, 5 base) benzimidazole) it is main ligand, complex is with 2,2 ' bipyridyls or 1,10 ' phenanthrolines are co-ligand, and the chemical formula of the complex is [Ru (bpy)2pbi]2+Or [Ru (phen)2pbi]2+；The complex is made by following steps：(1) pbi is prepared；(2) ruthenium metallic compound of the synthesis with co-ligand group；(3) target ruthenium (II) multi-pyridine ligand is synthesized；(4) the isolated product of silica gel column chromatography is used；The complex is used to prepare the drug for the stability that tetra- serobilas of telomere G are combined, improved with tetra- serobilas of telomere G.Compared with prior art, the present invention prepares ruthenium (II) multi-pyridine ligand has identification, combination and stabilization to tetra- serobilas of telomere G, inhibits telomerase activation, regulates and controls expression of proto-oncogenes, theoretical foundation is provided for the screening of anticancer drug.
Description
Technical field
The present invention relates to metal complexs, and in particular to a kind of ruthenium (II) multi-pyridine ligand and its preparation and application.
Background technology
Nucleic acid is the material base of biological heredity.We are not only facilitated for the research of nucleic acid and explores the origin of life,
And it is also particularly important when solving gene-associated diseases.Other than traditional double-spiral structure, there is also many for nucleic acid
Non-classical configuration, wherein most noticeable surely belong to tetra- serobilas of G- (G4) structure, it is that people pass through chemical interference to be primarily due to it
To adjust the Effective target site of biological function.G4 is a kind of nucleic acid structure of four chains, is by passing through Huo Shi between G bases
(Hoogsteen) the G- tetrads that pairing is formed are accumulated, this assembling phenomenon is extremely general in the nucleic acid sequence rich in G
Time.Since rich G sequence is in many functional gene regions (telomere of such as eukaryocyte, the promoter of certain important proto-oncogenes)
Middle rich content, therefore G4 is considered as the critical medication target spot for inhibiting telomerase activation and regulating and controlling expression of proto-oncogenes.Research
It has been shown that, the human body telomeric dna (Tel22, also known as 22AG) containing 22 bases can be under different alkali metal ion existence conditions
Form four serobilas of various configuration.In Na+In ion buffer solution, 22AG uses antiparallel G4 conformations, and in K+Ion buffer solution
In, it but shows and parallel/antiparallel mixes type conformation.
Ruthenium outermost layer has 4d75s1Structure, common valence state is Ru (I), Ru (II) and Ru (III), and is easily formed six
The complex of coordination.Transition metal ruthenium (II) multi-pyridine ligand has unique DNA binding abilities, good electrochemistry, light
Chemistry, Photophysics and abundant fluorescent property, and there is hypotoxicity, easy the characteristics of absorbing and easily draining.Specially such as China
102464676 A of sharp CN disclose a kind of ruthenium (II) multi-pyridine ligand, and ruthenium (II) multi-pyridine ligand is with two pyridines
[3,2-a, 2 ', 3 '-c] and azophenlyene -11,12- imidazoles are main ligand, using bipyridyl or phenanthroline as the ruthenium of assistant ligand
(II) multi-pyridine ligand, ruthenium (II) multi-pyridine ligand are used for tetra- serobila DNA molecular photoswitches of G-.But the compound is only used
In the searching of G4, for being combined with G-4 tetrads, for inhibiting telomerase activation and regulation and control expression of proto-oncogenes, there is no fine
Effect.
Invention content
It is insighted to telomeric dna that it is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of
Ruthenium (II) multi-pyridine ligand of other ability, binding ability and stabilizing power and its preparation and application.
The purpose of the present invention can be achieved through the following technical solutions：A kind of ruthenium (II) multi-pyridine ligand, the cooperation
Object is with 2- (1,10- ferrosin -5- bases)-benzimidazole) it is main ligand, complex is with 2,2 '-bipyridyls or 1,10 '-adjacent luxuriant and rich with fragrance hello
Quinoline is co-ligand, and the chemical formula of the complex is [Ru (bpy)2pbi]2+Or [Ru (phen)2pbi]2+, the complex
Structural formula is：
Wherein, 2 bpy, 2 '-bipyridyls, 1,10 '-phenanthrolines of phen, pbi are 2- (1,10- ferrosin -5- bases) -
Benzimidazole).
Wherein Ru is divalent in the complex, therefore the complex is ruthenium (II) multi-pyridine ligand.
The synthesis step for the ligand that the present invention uses is simple, and yield is high so that production cost substantially reduces, in addition, master matches
For body using the benzimidazole of synthesis, which is exactly many pharmaceutical intermediates, toxicity smaller for other opposite ligands, medical latent
In property higher.
A kind of preparation method of ruthenium as described above (II) multi-pyridine ligand, which includes following steps：
(1) synthesis of pbi：By 1:1:2 molar ratio weighs o-phenylenediamine, 5- aldehyde radicals Phen and sodium hydrogensulfite,
DMF is added to dissolve to obtain solution, is heated at reflux until starting to precipitate in solution, it is heavy to obtain yellow for addition water into solution
Form sediment, yellow mercury oxide is filtered, washing, it is dry after up to pbi, for use；
(2) 1 is pressed:1:2 molar ratio weighs RuCl3·3H2O, a chloride hydrate lithium and co-ligand are added DMF and dissolve to obtain
Solution is heated at reflux to obtain solidliquid mixture under the protection of protection gas, and acetone is added after being cooled to room temperature, and stirring keeps solid equal
Even dispersion preserves 15~30h at -25~-4 DEG C, and suction filtration obtains purple black crystal, for use；
(3) purple black crystal obtained by pbi obtained by step (1) and step (2) is dissolved in the mixed solution of ethylene glycol and water,
It protects under the protection of gas in being heated at reflux, then cools to room temperature, water dilution is added, suction filtration obtains filtrate, in gained filtrate
Hexafluoro is added and closes ammonium phosphate or sodium perchlorate, stirs to get precipitation, stands, filter, washing, vacuum drying obtains crude product；
(4) crude product obtained by step (3) is detached with silica gel chromatography, it is ruthenium to obtain powdery product after dry
(II) multi-pyridine ligand.By ruthenium (II) multi-pyridine ligand made from above-mentioned reaction condition, yield is high.
The synthesis step of the present invention is simple and practicable, only needs a step that can synthesize main ligand, and without purification, yield is high.Compared with
Preceding ligand synthesizes simple and practicable reduction production cost.
Step (1) volume that water is added into solution is 5~10 times of liquor capacity, and step flows back described in (1)
The temperature of heating is 120~180 DEG C, and the time being heated at reflux is 5~12h.
Step (2) described co-ligand includes bipyridyl or phenanthroline.
Step (2) amount that acetone is added is 4~6 times of the solidliquid mixture, and step is heated at reflux described in (2)
Temperature be 130~150 DEG C, the time being heated at reflux be 5~10h.
Step (2), step (3) the protection gas are selected from argon gas, nitrogen or helium.
Step (3) ethylene glycol and H2The in the mixed solvent ethylene glycol and H of O2The molar ratio of O is 7：1, the hexafluoro of addition
It is 1g to close the ratio between the quality of ammonium phosphate or sodium perchlorate and the mole of ethylene glycol：(15~20) mol, the washing are to use successively
Water and ether wash at least 3 times, and it is 110~130 DEG C that temperature is heated at reflux described in step (3), be heated at reflux the time be 5~
8h。
Step (4) described eluant, eluent with used in silica gel chromatography is acetonitrile and toluene, and the ratio of acetonitrile and toluene is second
Nitrile：Toluene=3:1.
A kind of application of ruthenium as described above (II) multi-pyridine ligand, the complex be used to prepare for telomere G- tetra-
Serobila in conjunction with, improve tetra- serobilas of telomere G- stability drug.
The action principle of the complex is as follows：It states ruthenium (II) multi-pyridine ligand and uses pi-pi accumulation with tetra- serobilas of telomere G-
The mode of action interaction, in normal body cell, telomere can shorten with the division of cell, when its length reaches
Cell will become feeble and die when critical point.And in most of tumour cell and cancer cell, telomere is lengthened by Telomerase, is made up
Its loss in normal cell, makes cancer cell infinitely divide and is able to immortality.Studies have shown that the G4 that telomerase is formed can
Effectively inhibit the activity of Telomerase so that G4 becomes the important target spot of anticancer drug.So can stablize the molecules of G4 structures at
For potential anticancer drug.
Tetra- serobilas of telomere G- are tetra- serobilas of telomere G- of people, and tetra- serobilas of telomere G- include 22 bases.
The application of obtained ruthenium (II) complex can be by UV spectrum titration, obtained spectroscopic data peak value display
Reduce and with red shift, illustrates that with tetra- serobila DNA of telomere G- combination occurs for ruthenium (II) complex.
Ruthenium (II) complex puies forward tetra- serobila melting temperatures of telomere G- by the DNA melting temperatures determination experiment of PCR instrument
Height illustrates that complex can stablize tetra- stranded structures of G-.
Designed ruthenium (II) complex synthesized is had detected to G- using means such as double light path uv-vis spectra and PCR instruments
Four serobila binding abilities and stabilizing power.
The measurement of complex and the uv-vis spectra of DNA effects uses double beam system, instrument Perkin
40 type ultraviolet-uisible spectrophotometers of Elmer lambda Bio, cuvette are 10mm x10mm quartz colorimetric utensils, scanning range
230-600nm.It is stronger to show that ruthenium (II) complex and tetra- serobilas of telomere G- have by the red shift occurred in ultraviolet spectra and blue shift
Binding ability
It carries out applying FRET technologies in PCR instrument (BIORAD icycler (iQ5)), tests ruthenium (II) complex to glimmering
Signal DNA F22T (the melting temperature T of sequence (FAM- [(G3T2A) 3AG3]-TAMRA)mThe change of value.To reflect not
The difference that tetra- serobila DNA Thermodynamically stables of G- are acted on complex.
Compared with prior art, beneficial effects of the present invention are embodied in：
(1) present invention passes through the apparent red shift of ultraviolet chromatogram and hypochromic effect and the raised description of test of PCR temperature
G4 and DNA has apparent interaction, and can stablize the structure of G4, due to the more difficult destruction of the rigid structure of G4, so pushing away
The mode of action for surveying the two is the pattern of outside stacking binding；
(2) synthesis step of ligand is simple, and yield is high, the originally many pharmaceutical intermediates of benzimidazole of synthesis, institute
With toxicity for other opposite ligands may smaller, medical potentiality higher.
Description of the drawings
Fig. 1 is 1 gained complex of embodiment and ultra-violet absorption spectrum of tetra- serobilas of telomere G- in potassium ion buffer solution
Figure；
Fig. 2 is 1 gained complex of embodiment and ultra-violet absorption spectrum of tetra- serobilas of telomere G- in sodium ion buffer solution
Figure；
Fig. 3 is that the melting temperature experiment in potassium ion buffer solution is bent with tetra- serobilas of telomere G- for 1 gained complex of embodiment
Line chart；
Fig. 4 is 2 gained complex of embodiment and ultra-violet absorption spectrum of tetra- serobilas of telomere G- in potassium ion buffer solution
Figure；
Fig. 5 is 2 gained complex of embodiment and ultra-violet absorption spectrum of tetra- serobilas of telomere G- in sodium ion buffer solution
Figure；
Fig. 6 is that the melting temperature experiment in sodium ion buffer solution is bent with tetra- serobilas of telomere G- for 2 gained complex of embodiment
Line chart.
Specific implementation mode
It elaborates below to the embodiment of the present invention, the present embodiment is carried out lower based on the technical solution of the present invention
Implement, gives detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
A kind of ruthenium (II) multi-pyridine ligand, the complex is with 2- (1,10- ferrosin -5- bases)-benzimidazole) based on match
Body, for complex with 2,2 '-bipyridyls for co-ligand, the chemical formula of the complex is [Ru (bpy)2pbi]2+, the cooperation
The structural formula of object is：
It is denoted as a1。
The complex is through the following steps that be made：
1. synthetic ligands pbi (pbi=2- (1,10-Phenanthrolin-5-yl)-benzo [d] imidazole) is obtained
Yellow powder：0.001mol o-phenylenediamines are added into single neck flask, 0.001mol 5- aldehyde radicals Phens and 0.002mol are sub-
Niter cake, and 3mL DMF dissolvings are added, 6 hours are heated to reflux at 150 DEG C, obtain brown solution, and have a small amount of precipitation production
It is raw.Into reaction solution plus 30mL water has a large amount of yellow mercury oxides to generate, and filters, filter cake is washed with water for several times, be dried in vacuo.Obtain Huang
Color powder 0.255g, yield 86%.
2. 6mmol ruthenium trichlorides (RuCl is added in three-neck flask3·3H2O), mono- chloride hydrate lithiums of 6mmol, and
12mmol bipyridyls are dissolved in 10ml DMF, are heated to reflux under protection of argon gas in 140 DEG C 8 hours.It is cooled to room temperature, adds
50mL acetone, stirred with glass bar it is evenly dispersed to bottom solid, set refrigerator freezing stay overnight.Filter to obtain atropurpureus solid.By institute
There is the ethyl alcohol that 150mL is added in solid to be heated to reflux 0.5 hour, be cooled to room temperature, suction filtration obtains atropurpureus crystallite, is washed till with ice water
It is close colourless, it is dry, obtain cis- [Ru (bpy)2Cl2]·2H2O.It is calculated with bipyridyl, yield about 65%.
3. accurately weighing 0.4mmol cis- [Ru (bpy)2Cl2]·2H2The product of O, 0.229g (0.6mmol) step 1,
It is dissolved in 35mL ethylene glycol and 5mL H2The mixed solvent of O flows back 6 hours in 120 DEG C under protection of argon gas.Reaction starts solution
In atropurpureus, gradually become red as reaction tends to perfect solution color.It is cooled to room temperature after reaction, adds 50mL water
Dilution filters and removes unreacted ligand, obtains claret clear filtrate.2g hexafluoros are added into filtrate and close ammonium phosphate, stirring obtains
Peony precipitates, and after standing a night, filters, washs filter cake for several times with water and ether respectively, is dried in vacuo.Crude product is crossed 200
~300 mesh neutral alumina columns are detached, with acetonitrile/toluene (3:1, v/v) it elutes, collects intermediate red zone eluent, use
Preservative film sealing, which is placed on draught cupboard, makes solvent volatilize, and can obtain product about 0.2~0.3g, yield about 50%.
To gained complex carried out hydrogen spectrum (1H NMR) and electrospray ionization mass spectrum (ES-MS) characterization, it is as a result as follows：
1H-NMR(DMSO-d6, 400Hz):13.46 (1H, s), 10.08 (1H, d), 8.88 (6H, m), 8.23 (4H, dd),
8.13 (2H, t), 8.01 (1H, dd), 7.96 (1H, dd), 7.85 (3H, t), 7.65 (5H, m), 7.34 (4H, dd, TOF-MS
for a1:m/z 709.1(M-2PF6- H), 355.07 (M-2PF6/2)。
Gained ruthenium (II) multi-pyridine ligand is used to be combined with tetra- serobilas of telomere G-, tetra- chains of telomere G- can be improved
The stability of body regulates and controls expression of proto-oncogenes to inhibit telomerase activation.Tetra- serobilas of telomere G- are tetra- chains of telomere G- of people
Body, tetra- serobilas of telomere G- include 22 bases.
Ruthenium (II) multi-pyridine ligand with tetra- serobilas of telomere G- for including the following steps：
(1) Tris-HCl buffer solutions：
Buffer solution A：10mM Tris, 100mM KCl, pH=7.0；
Buffer solution B：10mM Tris, 100mM NaCl, pH=7.0；
General preparation method：0.303g Tris salt accurately is weighed, 1.865g KCl or 1.460g NaCl are sterilized with 60mL
Triple distillation water is completely dissolved, and pH value is slowly adjusted with dilute hydrochloric acid to 7.0, is transferred to 250ml volumetric flasks, fixed with triple distillation water
Hold, it is spare after mixing.
(2) phosphate buffer：
Buffer solution C：10mM KH2PO4-K2HPO4, 100mM KCl, pH=7.0.
Preparation method：0.174g dipotassium hydrogen phosphate trihydrates and 0.746g KCl are taken with electronic balance scale, with specification specification
The KCl of a concentration of 100mM, the K of 10mM are configured to for the volumetric flask and triple distillation water of 100mL2HPO4Solution；Weigh 0.136g
Potassium dihydrogen phosphate and 0.746gKCl are configured to the KCl of a concentration of 100mM, the KH of 10mM with above-mentioned same preparation method2PO4
Solution.Above-mentioned liquor capacity 61.5mL dipotassium hydrogen phosphate solutions and 38.5mL potassium dihydrogen phosphates is taken to be mutually mixed, you can
To the potassium phosphate buffer solution of the 10mM of the KCl containing a concentration of 100mM.
(3) preparation of complex solution：
Accurately weighing 2~3mg complexs, (depending on complex molecule amount, prepared ruthenium complex is expected concentration herein
It is 200 μM, volume 10mL, is 15mL Corning centrifuge tubes with container, so the theoretical value that needs weigh is：Molecule
Amount/1000*2mg), 50-100 μ L DMSO dissolvings are first used, then 10mL is settled to get 200 μM of complex deposit with pure water
Liquid.
(4) measurement of the preparation of DNA solution and concentration：
Tetra- serobila DNA (22AG) of G-
Preparation method：The 22AG DNA for taking about 10OD are dissolved with the buffer solution A and B of corresponding volume, are added with water-bath after sealing
Heat is to 90 DEG C and is kept for 5 minutes, is put into 4 DEG C of refrigerators and refrigerates 24 hours or more after being slowly cooled to room temperature, spare.
The application of obtained ruthenium (II) complex can be by UV spectrum titration, and steps are as follows：
Take the complex storing solution (200uM) of 70uL, 2000uL buffer solution Tris-KCl pH 7.0 or Tris-NaCl pH
7.0, in 10mm × 10mm quartz colorimetric utensils, shake mixing, are placed in ultraviolet light absorption photometer sample cell.Reference cell, which is put, to be contained
The buffer solution display scanning recording curve of 2000uL Tris-KCl pH 7.0 or Tris-NaCl pH 7.0.Later respectively to sample
The 22AG DNA solutions (100uM Tris salt buffers) for adding 10uL in product pond and reference cell add mixing, scanning record gained
Curve.The titration of repetitive operation at least four times and no longer change, illustrate that titration reaches saturation.Preserve data, Origin mappings, knot
Fruit is as depicted in figs. 1 and 2.
Spectroscopic data peak value display has apparent hypochromic effect and red shift, illustrates that complex and tetra- serobila DNA effects of G- are strong
It is strong.But be between being inserted into two G- tetrads of tetra- serobilas of G- for the ligand of these four ruthenium complexes it is extremely difficult,
This is because four serobilas be a rigidity and stablize structure, if to destroy its structural intergrity need to consume it is relatively high
Energy.Therefore speculate that complex is to be acted on tetra- serobilas of G- by being stacked into tetra- serobila distal portions of G-, that is, be called outer
Portion's accumulation mode.
Ruthenium (II) complex is measured by the DNA melting temperatures of PCR instrument, and concrete operation step is as follows：
Using FRET technologies, complex obtained by the present embodiment is tested to fluorescent label DNA F22T (sequence (FAM-
[(G3T2A) 3AG3]-TAMRA) melting temperature TmThe change of value.To reflect Different Complex to tetra- serobila DNA heat of G-
The difference of mechanics stabilization.FRET experiments carry out in PCR instrument, use dipotassium hydrogen phosphate or phosphorus containing 100mM KCl
F22T (250nM) and a certain concentration that annealing forms tetra- serobilas of G- is added in sour disodium hydrogen buffer solution (10mM, pH=7.0)
The complex of ratio, it is common to be incubated 1 hour, carry out TmValue measures as shown in Figure 3.
The result shows that in the presence of having complex (0.5uM G4,100mM NaCl), the Tm values of the F22T of tetra- serobilas of G- compared with
It is small；With the addition of complex and the increase of concentration, the Tm values of F22T gradually increase.Ultimately joining a concentration of 7 μM of complex makes
Tetra- serobila Tm values of G- increase 3 DEG C, therefore, under potassium buffer solution complex to the stabilization of tetra- serobilas of G- be with concentration according to
Rely property.
Embodiment 2
A kind of ruthenium (II) multi-pyridine ligand, the complex is with 2- (1,10- ferrosin -5- bases)-benzimidazole) based on match
Body, for complex with 1,10 '-phenanthroline for co-ligand, the chemical formula of complex is [Ru (phen)2pbi]2+, the complex
Structural formula be：
It is denoted as a2。
The complex is through the following steps that be made：
1. synthetic ligands pbi (pbi=2- (1,10-Phenanthrolin-5-yl)-benzo [d] imidazole) is obtained
Yellow powder：0.001mol o-phenylenediamines are added into single neck flask, 0.001mol 5- aldehyde radicals Phens and 0.002mol are sub-
Niter cake, and 3mL DMF dissolvings are added, 6 hours are heated to reflux at 150 DEG C, obtain brown solution, and have a small amount of precipitation production
It is raw.Into reaction solution plus 30mL water has a large amount of yellow mercury oxides to generate, and filters, filter cake is washed with water for several times, be dried in vacuo.Obtain Huang
Color powder 0.255g, yield 86%.
2. 6mmol ruthenium trichlorides (RuCl is added in three-neck flask3·3H2O), mono- chloride hydrate lithiums of 6mmol, and
12mmol Phens are dissolved in 10ml DMF, are heated to reflux under protection of argon gas in 140 DEG C 8 hours.It is cooled to room temperature, adds
50mL acetone, stirred with glass bar it is evenly dispersed to bottom solid, set refrigerator freezing stay overnight.Filter to obtain atropurpureus solid.By institute
There is the ethyl alcohol that 150mL is added in solid to be heated to reflux 0.5 hour, be cooled to room temperature, suction filtration obtains atropurpureus crystallite, is washed till with ice water
It is close colourless, it is dry.It is calculated with bipyridyl, yield about 65%.
3. accurately weighing 0.4mmol cis- [Ru (bpy)2Cl2]·2H2The product of O, 0.229g (0.6mmol) step 1,
It is dissolved in 35mL ethylene glycol and 5mL H2The mixed solvent of O flows back 6 hours in 120 DEG C under protection of argon gas.Reaction starts solution
In atropurpureus, gradually become red as reaction tends to perfect solution color.It is cooled to room temperature after reaction, adds 50mL water
Dilution filters and removes unreacted ligand, obtains claret clear filtrate.2g hexafluoros are added into filtrate and close ammonium phosphate, stirring obtains
Peony precipitates, and after standing a night, filters, washs filter cake for several times with water and ether respectively, is dried in vacuo.Crude product is crossed 200
~300 mesh neutral alumina columns are detached, with acetonitrile/toluene (5:1, v/v) it elutes, collects intermediate red zone eluent, use
Preservative film sealing, which is placed on draught cupboard, makes solvent volatilize, and can obtain product about 0.2~0.3g, yield about 50%.
To gained complex carried out hydrogen spectrum (1H NMR) and electrospray ionization mass spectrum (ES-MS) characterization, it is as a result as follows：
1H-NMR(DMSO-d6, TMS, 400Hz):13.46 (1H, s), 10.07 (1H, d), 8.95 (2H, s), 8.79 (5H,
S), 8.41 (4H, s), 8.18 (3H, s), 8.09 (2H, s), 7.79 (8H, m), 7.35 (2H, d), TOF-MS for a1:m/z
757.1(M-2PF6- H), 379.06 (M-2PF6/2)
Gained ruthenium (II) multi-pyridine ligand is used to be combined with tetra- serobilas of telomere G-, tetra- chains of telomere G- can be improved
The stability of body regulates and controls expression of proto-oncogenes to inhibit telomerase activation.Tetra- serobilas of telomere G- are tetra- chains of telomere G- of people
Body, tetra- serobilas of telomere G- include 22 bases.
The application of obtained ruthenium (II) complex is measured using method same as Example 1, as a result such as Fig. 4 and
Shown in Fig. 5.
Spectroscopic data peak value display has apparent hypochromic effect and red shift, illustrates that complex and tetra- serobila DNA effects of G- are strong
It is strong.But be between being inserted into two G- tetrads of tetra- serobilas of G- for the ligand of these four ruthenium complexes it is extremely difficult,
This is because four serobilas be a rigidity and stablize structure, if to destroy its structural intergrity need to consume it is relatively high
Energy.Therefore speculate complex a2It is to be acted on tetra- serobilas of G- by being stacked into tetra- serobila distal portions of G-, that is, be called
External accumulation mode.And compared by spectrogram, either in potassium ion or sodium ion buffer solution, four kinds of complexs and telomere
The effect power of tetra- serobilas of G- is all a2＞ a1。
Ruthenium (II) complex a obtained by the present embodiment2Stabilizing power research for tetra- serobila DNA of telomere G-, specifically
Steps are as follows：
Using FRET technologies, complex a2 is tested to fluorescent label DNA F22T (sequence (FAM- [(G3T2A) 3AG3]-
TAMRA melting temperature T)mThe change of value.To reflect what Different Complex acted on tetra- serobila DNA Thermodynamically stables of G-
Difference.FRET experiments carry out in PCR instrument, are buffered using the dipotassium hydrogen phosphate containing 100mM NaCl or disodium hydrogen phosphate molten
Liquid (10mM, pH=7.0) is added annealing and forms the F22T (250nM) of tetra- serobilas of G- and the complex of a certain concentration ratio,
It is common to be incubated 1 hour, carry out TmValue measures as shown in Figure 6.
The result shows that (0.5uM G4,100mM NaCl), the T of the F22T of tetra- serobilas of G- in the presence of having complexmValue compared with
It is small；With complex a2Addition and concentration increase, the T of F22TmValue gradually increases, as complex a2Concentration increases to 7 μM
When, tetra- serobila T of G-mValue improves 5 DEG C.Therefore, under potassium buffer solution complex to the stabilization of tetra- serobilas of G- be have it is dense
Spend dependence, and complex a2Tetra- serobilas of stabilization G- effect be more than complex a1。
Embodiment 3
Using preparation method similar to Example 1, following steps are specifically included：
1. synthetic ligands pbi (pbi=2- (1,10-Phenanthrolin-5-yl)-benzo [d] imidazole) is obtained
Yellow powder：0.001mol o-phenylenediamines are added into single neck flask, 0.001mol 5- aldehyde radicals Phens and 0.002mol are sub-
Niter cake, and 3mL DMF dissolvings are added, 12 hours are heated to reflux at 120 DEG C, obtain brown solution, and have a small amount of precipitation
It generates.The water for adding 5 times of liquor capacities into reaction solution, has a large amount of yellow mercury oxides to generate, and filters, filter cake is washed with water for several times, very
Sky is dry.Obtain yellow powder 0.255g, yield 86%.
2. 6mmol ruthenium trichlorides (RuCl is added in three-neck flask3·3H2O), mono- chloride hydrate lithiums of 6mmol, and
12mmol bipyridyls are dissolved in 10ml DMF, are heated to reflux under protection of argon gas in 130 DEG C 10 hours, are obtained solidliquid mixture,
It is cooled to room temperature, adds 4 times of volumes in the acetone of solidliquid mixture, stirred with glass bar evenly dispersed to bottom solid, be placed in -25
15h is preserved at DEG C.Filter to obtain atropurpureus solid.The ethyl alcohol that all solids are added to 150mL is heated to reflux 0.5 hour, is cooled to
Room temperature, suction filtration obtain atropurpureus crystallite, be washed till with ice water it is close colourless, it is dry, obtain cis- [Ru (bpy)2Cl2]·2H2O.With connection
Pyridine calculates, yield about 65%.
3. accurately weighing 0.4mmol cis- [Ru (bpy)2Cl2]·2H2The product of O, 0.229g (0.6mmol) step 1,
It is dissolved in 35mol ethylene glycol and 5mol H2The mixed solvent of O flows back 8 hours in 110 DEG C under protection of argon gas.Reaction starts molten
Liquid is in atropurpureus, gradually becomes red as reaction tends to perfect solution color.It is cooled to room temperature after reaction, adds 50mL
Water dilutes, and filters and removes unreacted ligand, obtains claret clear filtrate.2.33g hexafluoros are added into filtrate and close ammonium phosphate, stir
It mixes, obtains peony precipitation, after standing a night, filter, wash filter cake for several times with water and ether respectively, be dried in vacuo.By crude product
It crosses 200~300 mesh neutral alumina columns to be detached, with acetonitrile/toluene (3:1, v/v) it elutes, collects intermediate red zone elution
Liquid, being placed on draught cupboard with preservative film sealing makes solvent volatilize, and can obtain product about 0.2~0.3g, yield about 50%.
Embodiment 4
Using preparation method similar to Example 1, following steps are specifically included：
1. synthetic ligands pbi (pbi=2- (1,10-Phenanthrolin-5-yl)-benzo [d] imidazole) is obtained
Yellow powder：0.001mol o-phenylenediamines are added into single neck flask, 0.001mol 5- aldehyde radicals Phens and 0.002mol are sub-
Niter cake, and 3mL DMF dissolvings are added, 5 hours are heated to reflux at 180 DEG C, obtain brown solution, and have a small amount of precipitation production
It is raw.The water for adding 10 times of liquor capacities into reaction solution, has a large amount of yellow mercury oxides to generate, and filters, filter cake is washed with water for several times, vacuum
It is dry.Obtain yellow powder 0.255g, yield 86%.
2. 6mmol ruthenium trichlorides (RuCl is added in three-neck flask3·3H2O), mono- chloride hydrate lithiums of 6mmol, and
12mmol bipyridyls are dissolved in 10ml DMF, are heated to reflux under protection of argon gas in 150 DEG C 5 hours, are obtained solidliquid mixture,
It is cooled to room temperature, adds 6 times of volumes in the acetone of solidliquid mixture, stirred with glass bar evenly dispersed to bottom solid, be placed in -4
30h is preserved at DEG C.Filter to obtain atropurpureus solid.The ethyl alcohol that all solids are added to 150mL is heated to reflux 0.5 hour, is cooled to
Room temperature, suction filtration obtain atropurpureus crystallite, be washed till with ice water it is close colourless, it is dry, obtain cis- [Ru (bpy)2Cl2]·2H2O.With connection
Pyridine calculates, yield about 65%.
3. accurately weighing 0.4mmol cis- [Ru (bpy)2Cl2]·2H2The product of O, 0.229g (0.6mmol) step 1,
It is dissolved in 35mol ethylene glycol and 5mol H2The mixed solvent of O flows back 5 hours in 130 DEG C under protection of argon gas.Reaction starts molten
Liquid is in atropurpureus, gradually becomes red as reaction tends to perfect solution color.It is cooled to room temperature after reaction, adds 50mL
Water dilutes, and filters and removes unreacted ligand, obtains claret clear filtrate.1.75g sodium perchlorates are added into filtrate, stir,
Peony precipitation is obtained, after standing a night, filters, washs filter cake for several times with water and ether respectively, be dried in vacuo.By crude product mistake
200~300 mesh neutral alumina columns are detached, with acetonitrile/toluene (3:1, v/v) it elutes, collects intermediate red zone eluent,
Being placed on draught cupboard with preservative film sealing makes solvent volatilize, and can obtain product about 0.2~0.3g, yield about 50%.
Claims (9)
1. a kind of ruthenium (II) multi-pyridine ligand, which is characterized in that the complex is with 2- (1,10- ferrosin -5- bases)-benzo miaow
Azoles) it is main ligand, for complex with 2,2 '-bipyridyls or 1,10 '-phenanthrolines are co-ligand, the chemical formula of the complex
For [Ru (bpy)2pbi]2+Or [Ru (phen)2pbi]2+, the structural formula of the complex is：
Wherein, 2 bpy, 2 '-bipyridyls, 1,10 '-phenanthrolines of phen, pbi are 2- (1,10- ferrosin -5- bases)-benzo
Imidazoles).
2. a kind of preparation method of ruthenium as described in claim 1 (II) multi-pyridine ligand, which is characterized in that the preparation method packet
Include following steps：
(1) synthesis of pbi：By 1:1:2 molar ratio weighs o-phenylenediamine, 5- aldehyde radicals Phen and sodium hydrogensulfite, is added
DMF dissolves to obtain solution, is heated at reflux until starting to precipitate in solution, into solution, addition water obtains yellow mercury oxide, will
Yellow mercury oxide filters, washing, it is dry after up to pbi, for use, wherein the volume that water is added into solution be liquor capacity 5~
10 times, the temperature being heated at reflux described in step (1) is 120~180 DEG C, and the time being heated at reflux is 5~12h；
(2) 1 is pressed:1:2 molar ratio weighs RuCl3·3H2O, a chloride hydrate lithium and co-ligand, addition DMF dissolve to obtain molten
Liquid is heated at reflux to obtain solidliquid mixture under the protection of protection gas, and acetone is added after being cooled to room temperature, and stirring keeps solid uniform
Dispersion preserves 15~30h at -25~-4 DEG C, and suction filtration obtains purple black crystal, for use；
(3) purple black crystal obtained by pbi obtained by step (1) and step (2) is dissolved in the mixed solution of ethylene glycol and water, is being protected
It in being heated at reflux under the protection of gas, then cools to room temperature, water dilution is added, suction filtration obtains filtrate, is added in gained filtrate
Hexafluoro closes ammonium phosphate or sodium perchlorate, stirs to get precipitation, stands, filters, washing, vacuum drying obtains crude product；
(4) crude product obtained by step (3) is detached with silica gel chromatography, it is ruthenium (II) more pyrroles to obtain powdery product after dry
Pyridine complex.
3. a kind of preparation method of ruthenium (II) multi-pyridine ligand according to claim 2, which is characterized in that step (2)
The co-ligand includes bipyridyl or phenanthroline.
4. a kind of preparation method of ruthenium (II) multi-pyridine ligand according to claim 2, which is characterized in that step (2)
The amount that acetone is added is 4~6 times of the solidliquid mixture, the temperature being heated at reflux described in step (2) is 130~
150 DEG C, the time being heated at reflux is 5~10h.
5. a kind of preparation method of ruthenium (II) multi-pyridine ligand according to claim 2, which is characterized in that step (2),
Step (3) the protection gas is selected from argon gas, nitrogen or helium.
6. a kind of preparation method of ruthenium (II) multi-pyridine ligand according to claim 2, which is characterized in that step (3)
The ethylene glycol and H2The in the mixed solvent ethylene glycol and H of O2The molar ratio of O is 7：1, the hexafluoro of addition closes ammonium phosphate or perchloric acid
The ratio between the quality of sodium and the mole of ethylene glycol are 1g：(15~20) mol, the washing are to be washed at least with water and ether successively
3 times, it is 110~130 DEG C that temperature is heated at reflux described in step (3), and it is 5~8h to be heated at reflux the time.
7. a kind of preparation method of ruthenium (II) multi-pyridine ligand according to claim 2, which is characterized in that step (4)
The eluant, eluent with used in silica gel chromatography is acetonitrile and toluene, and the ratio of acetonitrile and toluene is acetonitrile：Toluene=3:1.
8. a kind of application of ruthenium as described in claim 1 (II) multi-pyridine ligand, which is characterized in that the complex is for making
It is ready for use on the drug for the stability that tetra- serobilas of telomere G- are combined, improved with tetra- serobilas of telomere G-.
9. a kind of application of ruthenium (II) multi-pyridine ligand according to claim 8, which is characterized in that the telomere G-
Four serobilas are tetra- serobilas of telomere G- of people, and tetra- serobilas of telomere G- include 22 bases.
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| CN107312023B (en) * | 2017-01-08 | 2019-07-09 | 河南城建学院 | Pyridine-benzimidazolyl polynuclear complex synthetic method and application |
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| CN111269268A (en) * | 2020-02-13 | 2020-06-12 | 湘潭大学 | Ru complex with dual-emission property, Ru complex with dual-emission property and blank coordination sites and dual-emission complex |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009050509A2 (en) * | 2007-10-15 | 2009-04-23 | University Of Sheffield | Colorimetric sensing and/or detection of dna sequences using ruthenium or osmium bipyridine complexes |
| CN102464676A (en) * | 2010-11-05 | 2012-05-23 | 同济大学 | Ruthenium (II)-polypyridine complex, and preparation method and application thereof |
| CN102942595A (en) * | 2012-11-22 | 2013-02-27 | 中山大学 | Ruthenium complexes, preparation method thereof and application |
| CN103788135A (en) * | 2014-01-24 | 2014-05-14 | 同济大学 | Ruthenium polypyridine complex and preparation method and application of [Ru(L)2(tppp)]<2+> thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009050509A2 (en) * | 2007-10-15 | 2009-04-23 | University Of Sheffield | Colorimetric sensing and/or detection of dna sequences using ruthenium or osmium bipyridine complexes |
| CN102464676A (en) * | 2010-11-05 | 2012-05-23 | 同济大学 | Ruthenium (II)-polypyridine complex, and preparation method and application thereof |
| CN102942595A (en) * | 2012-11-22 | 2013-02-27 | 中山大学 | Ruthenium complexes, preparation method thereof and application |
| CN103788135A (en) * | 2014-01-24 | 2014-05-14 | 同济大学 | Ruthenium polypyridine complex and preparation method and application of [Ru(L)2(tppp)]<2+> thereof |
Non-Patent Citations (2)
| Title |
|---|
| A ruthenium(II) complex capable of inducing and stabilizing bcl-2 G-quadruplex formation as a potential cancer inhibitor;Jingnan Zhang等，;《Journal of Inorganic Biochemistry》;20131224;第134卷;第1-11页 * |
| Ruthenium(II) polypyridyl complexes: Cellular uptake, cell image and apoptosis of HeLa cancer cells induced by double targets;Qianqian Yu;《European Journal of Medicinal Chemistry》;20140516;第82卷;第82-95页 * |
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