CN109232663A - A kind of preparation method and its HIV reverse transcriptase inhibition application of ruthenium complex - Google Patents
A kind of preparation method and its HIV reverse transcriptase inhibition application of ruthenium complex Download PDFInfo
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- CN109232663A CN109232663A CN201811322776.XA CN201811322776A CN109232663A CN 109232663 A CN109232663 A CN 109232663A CN 201811322776 A CN201811322776 A CN 201811322776A CN 109232663 A CN109232663 A CN 109232663A
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- bpy
- dppzi
- reverse transcriptase
- compound
- hiv
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- 108010078851 HIV Reverse Transcriptase Proteins 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 230000005764 inhibitory process Effects 0.000 title abstract description 7
- 239000012327 Ruthenium complex Substances 0.000 title description 7
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims abstract description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 62
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 16
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 14
- -1 Bipyridine compound Chemical class 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 6
- 239000012964 benzotriazole Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 6
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 238000007347 radical substitution reaction Methods 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910001410 inorganic ion Inorganic materials 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 abstract description 8
- 102100034343 Integrase Human genes 0.000 abstract description 7
- 230000003595 spectral effect Effects 0.000 abstract description 7
- 230000027455 binding Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 108020000999 Viral RNA Proteins 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000010839 reverse transcription Methods 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 208000030507 AIDS Diseases 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 6
- 101710149951 Protein Tat Proteins 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 108091034057 RNA (poly(A)) Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- HGVLGDABAFXIAQ-UHFFFAOYSA-N C(C)CC#N.[Br] Chemical compound C(C)CC#N.[Br] HGVLGDABAFXIAQ-UHFFFAOYSA-N 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000009137 competitive binding Effects 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NBPGPQJFYXNFKN-UHFFFAOYSA-N 4-methyl-2-(4-methylpyridin-2-yl)pyridine Chemical group CC1=CC=NC(C=2N=CC=C(C)C=2)=C1 NBPGPQJFYXNFKN-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- VQLYBLABXAHUDN-UHFFFAOYSA-N bis(4-fluorophenyl)-methyl-(1,2,4-triazol-1-ylmethyl)silane;methyl n-(1h-benzimidazol-2-yl)carbamate Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1.C=1C=C(F)C=CC=1[Si](C=1C=CC(F)=CC=1)(C)CN1C=NC=N1 VQLYBLABXAHUDN-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- JGBUYEVOKHLFID-UHFFFAOYSA-N gelred Chemical compound [I-].[I-].C=1C(N)=CC=C(C2=CC=C(N)C=C2[N+]=2CCCCCC(=O)NCCCOCCOCCOCCCNC(=O)CCCCC[N+]=3C4=CC(N)=CC=C4C4=CC=C(N)C=C4C=3C=3C=CC=CC=3)C=1C=2C1=CC=CC=C1 JGBUYEVOKHLFID-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 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
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002976 reverse transcriptase assay Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005758 transcription activity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to generation of HIV inhibitors to research and develop field, the preparation method for disclosing a kind of [Ru(bpy)2(dppzi) and its application in HIV reverse transcriptase inhibition.The present invention devises the synthetic method of new [Ru(bpy)2(dppzi), resulting compound purity height, high income, with good water-soluble and excellent spectral property.[Ru(bpy)2(dppzi) of the invention has the ability combined to the TAR regioselectivity on hiv rna, and reverse transcriptase can be blocked to inhibit the duplication of viral RNA to the process of reverse-transcription of viral RNA.The [Ru(bpy)2(dppzi) is the HIV reverse transcriptase inhibitor of a kind of the hiv rna selective binding reagent with high-affinity and high activity, is the AIDS virus drug of great application potential.
Description
Technical field
The invention belongs to HIV reverse transcriptase inhibitor and AIDS virus Field of Drug Discovery more particularly to more pyridines
The preparation method of ruthenium complex and its application in HIV reverse transcriptase inhibition.
Background technique
AIDS is a kind of disease of serious harm human health life.Report that HIV patient and patient are more in China
Up to 65.4 ten thousand, add up dead 20.1 ten thousand.AIDS death toll has been first of China's Death of Infectious Diseases number.Inhibit inverse
Reverse transcription of the transcriptase to viral RNA, so that it may the generation and diffusion of virus are controlled, to play temporary to AIDS etc.
Can not cure, and the disease closely related with reverse transcriptase and viral RNA treatment and early prevention and treatment effect (Science,
1992,256, 1783-1790；Biochemistry, 2011,50, 5042-5057).Therefore, HIV reverse transcriptase becomes
Current anti-AIDS drug design primary target spot (Curr. Top. Med. Chem., 2004,4, 1045-1057).
Currently, be broadly divided into two classes as the reverse transcriptase inhibitor that drug is applied in clinic, i.e. " ucleosides reverse transcription
Enzyme inhibitor " and " non-nucleoside reverse transcriptase inhibitor ".Efabirenz is nucleoside analog, with virus
The viral DNA competitive binding reverse transcriptase that RNA reverse transcription is formed makes the duplication of virus obtain inhibition to a certain extent.However,
The long term administration of efabirenz can generate serious toxic side effect (such as inhibition bone marrow growth) and occur bright
Aobvious resistance phenomena is faced with the destiny being eliminated.By the extensive screening active ingredients of a large amount of noval chemical compounds, people send out successively
The small molecule compound for having showed some configurations shows preferable reverse transcriptase inhibitory activity, is called the inverse of non-nucleoside
Transcripting enzyme inhibitor.The affinity that they compare enzyme to the affinity of " enzyme-substrate " compound is high, by with reverse transcriptase
Interaction can cause the change of configuration of enzyme, so that making the compatibility at substrate active position reduces.Since non-nucleoside reverses
Transcriptase inhibitors will not directly damage the function of substrate-binding region, therefore cytotoxicity is smaller, and in extremely low concentration
Inhibit retrovirus activity (Chem. Soc. Rev., 2012,41, 4657-4670).
TAR and RRE is the upper two important functional areas of AIDS virus RNA, is played to the reverse transcription activity of viral RNA
It is vital effect (Mol. Cell Biol., 1988,8, 2555-2561).Recently, a kind of aminothiazole class compound table
Revealed preferable TAR RNA selectivity (Chem. Eur. J., 2014,20, 2071-2079；Chem. Commun., 2010,46, 6162-6164).Such compound can exclude the influence of DNA and tRNA, the U-A base of selective combination TAR RNA
To position, inhibit the growth of HIV-1 bacterial strain, and the growth of normal cell is not influenced significantly.
The structure of [Ru(bpy)2(dppzi) is introduced above-mentioned thiazole compound by the present invention, further design and optimization point
Minor structure, obtained it is a kind of it is with good aqueous solubility and spectral property, with making to hiv rna with specific recognition
The [Ru(bpy)2(dppzi) of aminothiazole functional group, can selective binding hiv rna the region TAR,
And significantly inhibit the activity of HIV reverse transcriptase.The [Ru(bpy)2(dppzi) is not only the specificity knot of hiv rna
The specific inhibitor for closing reagent or HIV reverse transcriptase, is the AIDS specific drug of potential high activity.
Summary of the invention
It is an object of the invention to provide a kind of both with good water for the AIDS-treating medicine research currently not yet captured
Dissolubility and spectral property, and there is the hiv rna recognition reaction of specificity and outstanding HIV reverse transcriptase to inhibit
The [Ru(bpy)2(dppzi) of ability.
A second object of the present invention is to provide the preparation methods of the [Ru(bpy)2(dppzi).
Third object of the present invention is to provide the [Ru(bpy)2(dppzi)s in AIDS virus TAR RNA specific recognition
In application.
Fourth object of the present invention is to provide the [Ru(bpy)2(dppzi) in HIV reverse transcriptase inhibition
Using.
Above-mentioned purpose of the invention is achieved by following technical solution:
A kind of ruthenium complex is made of cation and anion, and the cationic structural formula such as Formulas I is shown:
Formula 1.
Complex of iridium of the present invention does not limit the type of anion, and this field conventional anion is able to achieve the present invention
Purpose, especially inorganic salt anionic, such as PF6 ?、ClO4 ?、Cl?Deng, as a kind of most preferably scheme, iridium cooperation of the present invention
The anion of object is PF6 ?。
The preparation method of above-mentioned complex of iridium, comprising the following steps:
S1. compound 4,4'- dimethyl -2,2'- bipyridyl first pass through selenium dioxide and are oxidized to aldehyde radical substitution bipyridyl, using
Silver nitrate is oxidized to carboxyl and replaces bipyridyl, and further with aminothiazole compounds in 1- hydroxyl -7- azo benzotriazole
(HOAt), it is condensed to yield under the action of 1- ethyl-phosphinylidyne diimmonium salt hydrochlorate (EDCI), 4-dimethylaminopyridine (DMAP)
Bipyridine ligand L1 containing aminothiazole functional group, as shown in Formula II:
Formula II.
S2. compound 4,4'- dimethyl -2,2'- bipyridyl under the action of lithium diisopropylamine respectively with bromoacetonitrile,
Bromine butyronitrile and the own nitrile reaction of bromine, obtain the Bipyridine compound of cyano substitution, hydrolyze by hydrochloric acid, generate the connection that carboxyl replaces
Pyridine compounds, further with aminothiazole compounds in 1- hydroxyl -7- azo benzotriazole (HOAt), 1- ethyl-phosphinylidyne
It is condensed to yield under the action of diimmonium salt hydrochlorate (EDCI), 4-dimethylaminopyridine (DMAP) containing aminothiazole function base
Bipyridine ligand L2, L3 and L4 of group.
S3. above-mentioned 1 ~ L4 of ligand L respectively with precursor compoundcis-[Ru(bpy)2Cl2]·2H2O flows back in ethylene glycol,
Ammonium hexafluorophosphate saturated aqueous solution, filtering gained precipitating, anhydrous ether washing, vacuum drying, neutral oxygen are added after reaction
Change aluminium column chromatography, acetonitrile washes lower unique red component to get the [Ru(bpy)2(dppzi) Ru1 ~ Ru4.
The invention has the following advantages:
The present invention provides a kind of novel [Ru(bpy)2(dppzi)s, can be used as hiv rna selective binding reagent and AIDS
Viral reverse transcriptase inhibitor.The [Ru(bpy)2(dppzi) stable structure that the present invention synthesizes, with good spectral property, well
Hiv rna selective binding and HIV reverse transcriptase rejection ability, be novel HIV reverse transcriptase suppression
Preparation.
A kind of application of the novel [Ru(bpy)2(dppzi) that the present invention synthesizes in HIV reverse transcriptase inhibitor, tool
There is following advantage: (1) there is good water-soluble and stability；(2) there is positive charge, be conducive to and negatively charged RNA phase
Interaction；(3) there is good spectral property, spectral response can be carried out to RNA；(4) with aminothiazole organic compounds
It compares, there is stronger HIV reverse transcriptase rejection ability.
Detailed description of the invention
Fig. 1 is the route of synthesis of [Ru(bpy)2(dppzi) Ru1 prepared by the present invention；
Fig. 2 is the route of synthesis of [Ru(bpy)2(dppzi) Ru2 ~ Ru4 prepared by the present invention；
Fig. 3 is the [Ru(bpy)2(dppzi) gel electrophoresis that TAR RNA is tested in conjunction with tat protein competition prepared by the present invention
Figure；
Fig. 4 is the enzyme linked immunological experimental data that [Ru(bpy)2(dppzi) prepared by the present invention inhibits HIV reverse transcriptase
Figure；
Fig. 5 is that the uv-vis spectra titration that [Ru(bpy)2(dppzi) prepared by the present invention and DNA interact is schemed；
Fig. 6 is that the uv-vis spectra titration that [Ru(bpy)2(dppzi) prepared by the present invention and total serum IgE interact is schemed；
Fig. 7 is that the uv-vis spectra titration that [Ru(bpy)2(dppzi) prepared by the present invention and tRNA interact is schemed；
Fig. 8 is the uv-vis spectra titration of [Ru(bpy)2(dppzi) prepared by the present invention and poly (A) RNA interaction
Figure.
Specific embodiment
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment.Embodiment is only to explain this hair
It is bright, the present invention is not limited in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus is these
Technical field conventional reagent, method and apparatus, agents useful for same and material are commercially available.
The preparation of 1 [Ru(bpy)2(dppzi) of embodiment
1, the preparation of [Ru(bpy)2(dppzi) Ru1:
It is synthesized according to approach shown in FIG. 1.By 4,4'- dimethyl -2,2'- bipyridyl (1.5 g, 8 mmol) and selenium dioxide
(887.68 mg, 8 mmol) flow back 24 hours in 100 ml Isosorbide-5-Nitraes-dioxane, are cooled to room temperature, filter out black solid,
Solvent is boiled off, white solid is obtained.100 ml ethyl acetate stirring and dissolvings of the solid, filter out insoluble matter, and filtrate is with 20 ml
Three times, organic phase is extracted three times with the sodium metabisulfite solution of 50 ml, 0.3 M for the sodium carbonate liquor washing of 1.0 M, merges water
Phase adjusts pH to 10 with sodium carbonate liquor, is extracted four times with 20 ml chloroforms, merges organic phase, and anhydrous sodium sulfate is dry, boils off
Solvent obtains crude product.Crude product utilizes column Chromatographic purification, is eluted with petrol ether/ethyl acetate (1:4), obtains aldehyde radical substitution
398 mg of bipyridyl, yield 25%.The bipyridyl that gained aldehyde radical replaces all is dissolved in 20 ml ethyl alcohol, 4 ml silver nitrate water are added
Solution stirring, is slowly added to the sodium hydrate aqueous solution of 10 ml, 1.0 M, reacts 15 hours at room temperature, boils off solvent, solid point
Not with the sodium hydroxide of 4 ml, 1.3 M and 4 ml water washings 2 times, combined filtrate is extracted three times with 10 ml chloroforms, and water phase is with 4
The hydrochloric acid pH to 3.5 of M filters the white solid of generation, and vacuum drying obtains 258 mg of bipyridyl of carboxyl substitution, yield 60%.
The bipyridyl (1.3 mmol) that gained carboxyl replaces all is dissolved in 20 ml DMF, aminothiazole compounds (300 are added
Mg, 1.3 mmol), 1- hydroxyl -7- azo benzotriazole (1.3 mmol, 177 mg), 4-dimethylaminopyridine (1.3
Mmol, 146 mg), 1- ethyl-phosphinylidyne diimmonium salt hydrochlorate (1.3 mmol, 87 mg), be stirred at room temperature 6 hours, filtering gained
Solid, with 25 ml water washing four times, vacuum drying obtains more pyridine ligands (L1) 457 of aminothiazole functional group substitution
Mg, yield 82%.By gained whole L1(1.06 mmol) and compoundcis-[Ru(bpy)2Cl2]·2H2O(442 mg, 0.85
Mmol it) flows back 8 hours, is cooled to room temperature under 20 ml ethylene glycol, argon gas protective condition, 10 ml are added and are saturated ammonium hexafluorophosphate
Aqueous solution, the orange precipitating of filtering gained is primary with 15 ml water washings, and 30 ml anhydrous ethers wash three times, and vacuum drying obtains slightly
Product.Crude product is chromatographed with neutral alumina column, and acetonitrile elutes unique orange component, obtains the target multi-pyridine ligand
Ru1,616 mg of yield, yield 64%.1H-NMR (300 MHz, DMSO-d 6): δ (ppm) 12.28 (s, 1H), 10.79
(s, 1H), 9.21 (d, J = 1.4 Hz, 1H), 8.95 – 8.79 (m, 5H), 8.41 (t, J = 1.9 Hz,
1H), 8.20 (ddt, J = 7.9, 6.5, 1.8 Hz, 4H), 7.99 – 7.85 (m, 2H), 7.85 – 7.66
(m, 5H), 7.66 – 7.48 (m, 7H), 7.49 – 7.38 (m, 2H), 2.58 (s, 3H), 2.18 (s,
3H)。ESI-MS[CH3CN, m/z]=421.6(theoretical value: 421.5, [M-2PF6]2+).
2, the preparation of [Ru(bpy)2(dppzi) Ru2:
It is synthesized according to approach shown in Fig. 2.Pre-dry 4,4'- dimethyl -2,2'- connection is added in the flask of flame drying
Pyridine (3.0 mmol, 552.7 mg) and 20 ml anhydrous tetrahydro furans, it is different to be slowly added to 1.8 ml, 2.0 M bis- at -78 DEG C
Propylcarbamic lithium seals reactor, reacts 1 hour at -78 DEG C.The bromoacetonitrile (3.6 of 5 ml anhydrous tetrahydro furans will be dissolved in
Mmol, 431.8 mg) it is slowly added in reactant with syringe, reactor is slowly restored to room temperature, the reaction was continued 12 hours
Afterwards, 20 ml water quenching reactions are added.After reaction solution is neutralized with dilute hydrochloric acid, three times with the extraction of 50 ml ethyl acetate, merge organic
Phase, with saturated common salt water washing, anhydrous sodium sulfate is dry, and solvent is evaporated off, and obtained crude product purified by silica gel carries out column chromatography, acetic acid
Ethyl ester/petroleum ether (1:2) washes lower main component, obtains cyano-containing bipyridyl.It is small to add it to reflux 12 in 6 ml concentrated hydrochloric acids
When, it is cooled to room temperature, adjusts pH to 4.5 with sodium hydroxide, three times with the extraction of 50 ml chloroforms, merge organic phase, use saturated common salt
Water washing, anhydrous sodium sulfate is dry, and solvent is evaporated off, obtains 393 mg of bipyridyl containing carboxyl.Further it is dissolved in 20 ml
DMF, be added aminothiazole compounds (454 mg, 1.95 mmol), 1- hydroxyl -7- azo benzotriazole (272 mg, 2
Mmol), 4-dimethylaminopyridine (224 mg, 2.0 mmol), 1- ethyl-phosphinylidyne diimmonium salt hydrochlorate (384 mg, 2.0
Mmol it) is stirred at room temperature 12 hours.Filtering precipitating, 25 ml wash vacuum drying three times, obtain the substitution of aminothiazole functional group
670 mg of more pyridine ligands (L2), three step total recoverys 49%.By 1.46 mmol of ligand L 2(667 mg) and compoundcis-
[Ru(bpy)2Cl2]·2H2O(632 mg, 1.22 mmol) it flows back 8 hours under 20 ml ethylene glycol, argon gas protective condition, it is cold
But to room temperature, 10 ml being added and are saturated hexafluorophosphoric acid aqueous ammonium, the orange precipitating of filtering gained is primary with 15 ml water washings, and 30
Ml anhydrous ether washs three times, and vacuum drying obtains crude product.Crude product is chromatographed with neutral alumina column, the unique orange of acetonitrile elution
Colour cell point, obtains the target multi-pyridine ligand Ru2,864 mg of yield, yield 61%.1H-NMR (300 MHz, DMSO-d 6): δ (ppm) 12.24 (s, 1H), 10.03 (s, 1H), 8.92 – 8.75 (m, 6H), 8.71 (d, J =
7.9 Hz, 1H), 8.28 – 8.02 (m, 5H), 7.71 (dt, J = 13.3, 6.2 Hz, 4H), 7.52 (tq,J = 20.0, 6.1 Hz, 12H), 7.36 (d, J = 8.3 Hz, 4H), 3.14 (t, J = 7.3 Hz, 2H),
2.83 (d, J = 7.6 Hz, 2H), 2.17 (s, 3H)。ESI-MS[CH3CN, m/z]=435.6(theoretical value:
435.6 [M-2PF6]2+).
3, the preparation of [Ru(bpy)2(dppzi) Ru3:
With the preparation of [Ru(bpy)2(dppzi) Ru2, difference is bromoacetonitrile therein being replaced by bromine butyronitrile preparation step
(3.6 mmol, 533 mg) obtain 626 mg of more pyridine ligands (L3), three step total recoverys 43%.Further with compoundcis-
[Ru(bpy)2Cl2]·2H2O(572 mg, 1.1 mmol) reaction obtain target multi-pyridine ligand Ru3,706 mg of yield, receive
Rate 54%.1H-NMR (300 MHz, DMSO-d 6): δ (ppm) 12.22 (s, 1H), 9.96 (s, 1H), 8.82 (d,J = 8.2 Hz, 4H), 8.75 (d, J = 7.6 Hz, 2H), 8.23 (s, 1H), 8.15 (t, J = 7.7 Hz,
4H), 7.83 – 7.62 (m, 4H), 7.54 (q, J = 5.7 Hz, 7H), 7.48 – 7.20 (m, 5H), 2.82
(t, J = 7.7 Hz, 2H), 2.39 (t, J = 7.6 Hz ,2H), 2.17 (s, 3H), 1.73 (m, 4H)。
ESI-MS[CH3CN, m/z]=449.6(theoretical value: 449.6, [M-2PF6]2+).
4, the preparation of [Ru(bpy)2(dppzi) Ru4:
With the preparation of [Ru(bpy)2(dppzi) Ru2, difference is for bromoacetonitrile therein to be replaced by bromine own nitrile preparation step
(3.6 mmol, 630 mg) obtain 585 mg of more pyridine ligands (L4), three step total recoverys 38%.Further with compoundcis-
[Ru(bpy)2Cl2]·2H2O(494 mg, 0.95 mmol) reaction obtain target multi-pyridine ligand Ru4,531 mg of yield, receive
Rate 46%.1H-NMR (300 MHz, DMSO-d 6): δ (ppm) 12.24 (s, 1H), 9.93 (s, 1H), 8.82 (d,J = 8.3 Hz, 4H), 8.76 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 8.15 (t, J = 7.9
Hz, 4H), 7.79 – 7.64 (m, 4H), 7.64 – 7.43 (m, 8H), 7.43 – 7.22 (m, 4H), 2.76
(d, J = 8.1 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.16 (s, 3H), 1.64 (d, J =
23.9 Hz, 4H), 1.38 (s, 4H)。ESI-MS[CH3CN, m/z]=463.6(theoretical value: 463.6, [M-2PF6]2+).
The electrophoresis experiment of 2 [Ru(bpy)2(dppzi) of embodiment identification AIDS virus TAR RNA
In the raw work biology in the AIDS virus Shanghai TAR RNA(of 1:1) and the Shanghai TAR binding protein tat(shine by force biology) in system,
The [Ru(bpy)2(dppzi) of various concentration is added, carries out polyacrylamide gel electrophoresis experiment, 4S Gel Red is dyed,
Gel imaging is carried out on FluorChemFC3.As shown in figure 3, combining tat egg with the raising of [Ru(bpy)2(dppzi) concentration
White TAR RNA is gradually decreased, and is finally completely disappeared, and illustrates ruthenium complex and the same site of tat competitive binding.Complex-bound
The ability of TAR RNA is followed successively by Ru1 > Ru2 > Ru3 > Ru4, illustrate with TAR RNA recognition group and ruthenium complex center away from
Increase from (length of connection chain), the ability of complex-bound TAR RNA can be made to reduce.On the other hand, ruthenium complex Ru1 is showed
The ability of combination TAR RNA more stronger than tat albumen out, illustrate to contain the ruthenium coordination center there are two positive charge enhances molecule
With the effect between electronegative RNA.
3 [Ru(bpy)2(dppzi) of embodiment inhibits the enzyme linked immunological experiment of HIV reverse transcriptase
Using Roche kit (Reverse Transcriptase Assay, colorimetric), to prepared by the present invention
[Ru(bpy)2(dppzi) has carried out the reality based on enzyme-linked immunization to the inhibitory activity of the HIV-1 HIV reverse transcriptase of recombination
Test is fixed, records the absorption value (being reference with the absorption value of 490 nm) of 405 nm.Through single index curve matching, more pyridine rutheniums are matched
It closes object Ru1 ~ Ru4 and inhibits the active concentration (IC of half HIV reverse transcriptase50) it is respectively 2.38,5.42,5.87,8.20 μ
M is significantly higher than the aminothiazole compounds of not connected ruthenium complex.Therefore, [Ru(bpy)2(dppzi) prepared by the present invention has
Very high HIV reverse transcriptase inhibitory activity is the potential drug of the disease closely related with reverse transcriptase such as AIDS.
The interaction of embodiment 4 complex and nucleic acid
Suitable calf thymus DNA is weighed, is dissolved in buffer, is filtered after supersonic oscillations 15 minutes, filtrate is on-demand
After diluting, the absorbance value of 260 nm and 280 nm are measured.A260/A280In 1.8 ~ 1.9 ranges, show to be substantially free of egg
White matter and RNA.Total serum IgE, yeast tRNA and poly (A) tri- kinds of different RNA solutions of RNA are matched with reference to DNA solution preparation method
System.Accurate nucleic acid concentration is calculated by the corresponding molar extinction coefficient of respective characteristic absorption peak.[Ru(bpy)2(dppzi) Ru1 ~
The ultraviolet spectra that three kinds of nucleic acid of Ru4 and calf thymus DNA (Fig. 5), total serum IgE (Fig. 6), yeast tRNA(Fig. 7) interact respectively
Titration figure is not lost lustre significantly or red shift, and complex Ru1 ~ Ru4 contains with calf thymus DNA, total serum IgE, tri- kinds of yeast tRNA
There is the binding mode of the nucleic acid of conjugate double bonds structure to may be by electrostatic interaction, hydrogen bond action etc., rather than passes through insertion alkali
The mode of base pair.Apparent spectral response is produced for single-stranded poly (A) RNA, complex Ru1, it is seen that Ru1 is to single stranded RNA
Recognition reaction with specificity.On the other hand, Ru2 ~ Ru4 and single-stranded poly (A) RNA effect front and back is without apparent spectrum
Variation.This is because Ru1 has π track conjugated structure, it can be by the variation of electronics and molecular orbit on hydrogen bonding sites
It is effectively transmitted on coordination center ruthenium, so as to cause the significant change of the charge transfer transition (MLCT) of ligand to metal.And
It, can not be such as the structure of conjugated pi track since connection chain is aliphatic chain although Ru2 ~ Ru4 may also have this recognition reaction
The energy level variations of Hydrogenbond front and back electronics and molecular orbit are equally effectively transmitted, therefore do not show apparent change spectrally
Change.
Therefore, [Ru(bpy)2(dppzi) prepared by the present invention is the RNA binding reagents of specificity, and can identify AIDS
On the malicious TAR RNA and protein bound site tat, and efficiently inhibit the activity of HIV reverse transcriptase, it is AIDS etc.
The potential high-activity drug molecule of presently relevant disease with reverse transcriptase.
Claims (6)
1. a kind of [Ru(bpy)2(dppzi), such compound is made of cation and anion two parts, which is characterized in that described
The structural formula of cationic portion is shown in formula I:
Formulas I.
2. [Ru(bpy)2(dppzi) according to claim 1, which is characterized in that the anion is inorganic ion.
3. [Ru(bpy)2(dppzi) according to claim 2, which is characterized in that the inorganic ion is PF6 ?, ClO4 ?Or
Cl?。
4. the preparation method of [Ru(bpy)2(dppzi) described in claim 1, which is characterized in that preparation step is as follows:
S1. compound 4,4'- dimethyl -2,2'- bipyridyl first pass through selenium dioxide and are oxidized to aldehyde radical substitution bipyridyl, using
Silver nitrate is oxidized to carboxyl and replaces bipyridyl, and further with aminothiazole compounds in 1- hydroxyl -7- azo benzotriazole
(HOAt), it is condensed to yield under the action of 1- ethyl-phosphinylidyne diimmonium salt hydrochlorate (EDCI), 4-dimethylaminopyridine (DMAP)
Bipyridine ligand L1 containing aminothiazole functional group, as shown in Formula II:
Formula II
S2. compound 4,4'- dimethyl -2,2'- bipyridyl under the action of lithium diisopropylamine respectively with bromoacetonitrile, bromine fourth
Nitrile and the own nitrile reaction of bromine, obtain the Bipyridine compound of cyano substitution, hydrolyze by hydrochloric acid, generate the bipyridyl that carboxyl replaces
Compound, it is further sub- in 1- hydroxyl -7- azo benzotriazole (HOAt), 1- ethyl-phosphinylidyne two with aminothiazole compounds
It is condensed to yield under the action of amine hydrochlorate (EDCI), 4-dimethylaminopyridine (DMAP) containing aminothiazole functional group
Bipyridine ligand L2, L3 and L4, as shown in Formula II；
S3. above-mentioned 1 ~ L4 of ligand L respectively with precursor compoundcis-[Ru(bpy)2Cl2]·2H2O flows back in ethylene glycol, reaction
After be added ammonium hexafluorophosphate saturated aqueous solution, filtering gained precipitating, anhydrous ether washing, vacuum drying, neutral alumina
Column chromatography, acetonitrile wash lower unique red component to get the [Ru(bpy)2(dppzi) Ru1 ~ Ru4.
5. [Ru(bpy)2(dppzi) described in claim 1 is in answering as AIDS virus TAR RNA Selective recognition reagent
With.
6. [Ru(bpy)2(dppzi) described in claim 1 is in the application as HIV reverse transcriptase inhibitor.
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