CN108938658A - 2’-氟-4’-叠氮核苷在制备病毒感染因子蛋白抑制剂中应用 - Google Patents
2’-氟-4’-叠氮核苷在制备病毒感染因子蛋白抑制剂中应用 Download PDFInfo
- Publication number
- CN108938658A CN108938658A CN201810633797.7A CN201810633797A CN108938658A CN 108938658 A CN108938658 A CN 108938658A CN 201810633797 A CN201810633797 A CN 201810633797A CN 108938658 A CN108938658 A CN 108938658A
- Authority
- CN
- China
- Prior art keywords
- nucleosides
- hiv
- compound
- drug
- vif
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002777 nucleoside Substances 0.000 title claims abstract description 21
- 229940121649 protein inhibitor Drugs 0.000 title claims abstract description 6
- 239000012268 protein inhibitor Substances 0.000 title claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 title abstract description 10
- 230000001524 infective effect Effects 0.000 title abstract description 9
- 230000003612 virological effect Effects 0.000 title abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 5
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 22
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 39
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 230000005764 inhibitory process Effects 0.000 abstract description 10
- 238000002474 experimental method Methods 0.000 abstract description 6
- 102000004169 proteins and genes Human genes 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 4
- 101710201961 Virion infectivity factor Proteins 0.000 description 26
- 102000002797 APOBEC-3G Deaminase Human genes 0.000 description 22
- 108010004483 APOBEC-3G Deaminase Proteins 0.000 description 22
- 230000000694 effects Effects 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 10
- 125000003835 nucleoside group Chemical group 0.000 description 9
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 230000034512 ubiquitination Effects 0.000 description 7
- 238000010798 ubiquitination Methods 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 6
- 238000001962 electrophoresis Methods 0.000 description 6
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 5
- 239000002850 integrase inhibitor Substances 0.000 description 5
- 229940124524 integrase inhibitor Drugs 0.000 description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 5
- -1 small molecule compounds Chemical class 0.000 description 5
- 238000001089 thermophoresis Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 229960002555 zidovudine Drugs 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- 229940124321 AIDS medicine Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101710117545 C protein Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102100034343 Integrase Human genes 0.000 description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 3
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 3
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 3
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 3
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 239000005549 deoxyribonucleoside Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 239000002342 ribonucleoside Substances 0.000 description 2
- 229960004556 tenofovir Drugs 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- QHRCVGXBBIRPTE-UHFFFAOYSA-N 5-ethyl-4-(4-methoxyphenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC(OC)=CC=2)=C1CC QHRCVGXBBIRPTE-UHFFFAOYSA-N 0.000 description 1
- 102000012758 APOBEC-1 Deaminase Human genes 0.000 description 1
- 108010079649 APOBEC-1 Deaminase Proteins 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 108010013534 Auxilins Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 101000807306 Homo sapiens Ubiquitin-like modifier-activating enzyme 1 Proteins 0.000 description 1
- 108010042653 IgA receptor Proteins 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- 101100351501 Mus musculus Cbfb gene Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 102100034014 Prolyl 3-hydroxylase 3 Human genes 0.000 description 1
- 102100023874 RING-box protein 2 Human genes 0.000 description 1
- 101710178917 RING-box protein 2 Proteins 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100037160 Ubiquitin-like modifier-activating enzyme 1 Human genes 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 101150003556 cul-5 gene Proteins 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical group OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 229940125777 fusion inhibitor Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- IKKXOSBHLYMWAE-QRPMWFLTSA-N islatravir Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@H]1C[C@H](O)[C@](CO)(C#C)O1 IKKXOSBHLYMWAE-QRPMWFLTSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 230000017156 mRNA modification Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 102200089571 rs104893827 Human genes 0.000 description 1
- 102220080214 rs149830675 Human genes 0.000 description 1
- 102220097967 rs876660873 Human genes 0.000 description 1
- 102220119628 rs886044790 Human genes 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- AIDS & HIV (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了2’‑氟‑4’‑叠氮核苷在制备病毒感染因子蛋白抑制剂中应用，属药物化学领域。其具有如式I所示结构，实验证明该化合物具有显著的抑制病毒感染因子蛋白活性，对耐药性HIV病毒也显示显著的抑制作用。本发明公开了将该化合物及其前药、或其盐、或其组合物用于抑制病毒感染因子蛋白和耐药性HIV变异体药物的制备。I。
Description
技术领域
本发明涉及核苷类病毒感染因子蛋白抑制剂及其前药、或其组合物的用途，属药物化学领域。
背景技术
从1981年美国发现第一例艾滋病患者，到目前世界上大约有三千九百万艾滋病病人。艾滋病感染已成为人类健康的一个重大威胁。人类免疫缺陷病毒(HumanImmunodeficiency Virus，HIV)的感染引起艾滋病发作。艾滋病病毒(HIV-1)复制经过吸附、侵入和脱壳、逆转录、整合病毒RNA和蛋白质的合成、装配、释放和成熟等过程完成。其中每个环节均可作为抗HIV药物的靶点。经过三十多年的研究，包括合并用药在内，已有40个(Medicines in Development HIV/AIDS 2014)抗艾滋病药被美国FDA批准用于临床。根据药物的作用机理，它们可以分为：核苷和非核苷类逆转录酶抑制剂，蛋白酶抑制剂，侵入抑制剂和整合酶抑制剂等几大类。这些药物能有效地抑制HIV的复制，但都不能治愈艾滋病。长期使用这些药物，仍可能因新耐药性的不断产生和药物的毒副作用使现有药物治疗失去作用。因此仍有继续寻找具有新作用机理的抑制HIV治疗药物的紧急需求。
2’-脱氧核苷是用于临床的主要一类HIV抑制剂，它们通过抑制逆转录酶发挥药物作用。其作用机理如下：核苷首先被磷酸酯酶转化成活性成分核苷三磷酸酯。后者在逆转录酶作用下被HIV的DNA结合。由于目前的核苷类HIV抑制剂大多是3'-脱氧核苷，因为没有3'-OH，使HIV的DNA合成不能完成，从而达到抑制HIV的复制(其过程如下)。核苷1和3在磷酸酯酶的作用下被分别转化成相应的核苷三磷酸酯2和4。而2和4在逆转录酶的作用下与HIV的DNA片段结合分别生成新的HIV DNA片段6和7。带有改良核苷的DNA片断6因其没有3'-OH而不能继续延长下去；而DNA片断7也因为改良核苷有4'-位取代基的立体位阻而使新的DNA片段7不利于进一步延长。因此，这两种HIV抑制剂都属于HIV的DNA合成终止剂。
固有免疫在机体抵御HIV-1感染过程中发挥重要作用。近年来，研究人员发现载脂蛋白B mRNA编辑酶催化多肽样蛋白(apolipoprotein B mRNA-editing enzyme catalyticpolypeptide protein,APOBEC)家族的成员APOBEC3G(A3G)可以通过胞嘧啶脱氨机制抑制HIV的复制,发挥固有免疫的作用。病毒感染因子(Virion infectivity factor,Vif)是HIV的六个辅助蛋白之一，能与A3G结合并引发A3G的降解而失去抗病毒作用,使HIV-1的感染率增加100倍以上。因此，可以通过抑制Vif蛋白这一新途径抑制HIV复制。所以，Vif抑制剂可能成为艾滋病治疗药物的新选择。到目前为止，已有一些小分子化合物被发现具有抑制Vif的活性(Chemmedchem 2012,7,1217；Chem.Biol.Drug Design 2013,81,730；ACSMed.Chem.Lettt.2012,3,465；J.Biol.Chem.2015,290,10504)，但都处于非常早期发现阶段，这些化合物的抗病毒活性也不高(IC50在4μM以上)。目前，核苷类的Vif抑制剂还未见报道。
发明内容
本发明目的在于提供一种核苷类病毒感染因子蛋白抑制剂在制备治疗病毒感染因子有关疾病药物中的应用。
本发明所述2’-氟-4’-叠氮核苷具有如下结构：包括核苷式I及其磷酸酯类前药、医药上可接受的盐或其组合物；可选地，其组合物包括核苷抑制剂、非核苷类反转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂和/或医药上可接受的辅料。
化合物I的制备采用CN2007101375480所述方法或根据文献方法(J.Wu et alEuopean J.Med.Chem,2013,63,739)。
为实现本发明目的，本发明使用微量热泳动仪测量核苷式I化合物(CL002)与Vif-CBFb(1-170)-ElonginB-Elongin C蛋白质复合物之间的相互作用情况。使用染料标记蛋白复合物并梯度稀释化合物后，计算其亲和力大小，发现CL-002与Vif复合物之间有显著的亲和力，其KD值约为57.5μM。分别转染HEK293T细胞和Hela-APOBEC3G细胞并用化合物CL-002处理，发现化合物CL-002抑制Vif对APOBEC3G(A3G)的降解，并且CL-002对Vif降解A3G的抑制作用具有剂量依赖性。A3G体外泛素化实验也说明CL-002在体外也具有一定的抑制Vif对A3G的泛素化的活性，并且具有剂量依赖性。
核苷式I化合物可以与其它HIV抑制剂联用，可选地，但不限于下列：所述其它HIV抑制剂包括：核苷抑制剂、非核苷类反转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂；比如：可选地，所述核苷抑制剂包括：齐多夫定(AZT)、去羟肌苷(ddI)、扎西他滨(ddC)、司他夫定(d4T)、拉米夫定(3TC)、阿巴卡韦(Abacavir)、恩曲他滨(FTC)、替诺福韦(TDF)，EFdA(MK-8591)；可选地，所述非核苷类反转录酶抑制剂包括：奈韦拉平、地拉韦定、依非韦仑、依曲韦仑；可选地，所述蛋白酶抑制剂包括：沙奎那韦、茚地那韦、利托那韦、奈非那韦、氨普那韦、洛匹那韦、阿扎那韦、福沙普利那韦、替拉那韦、大诺那韦；可选地，所述整合酶抑制剂包括：雷特格韦、埃替拉韦、度鲁特韦。
结果表明：本发明提供的核苷式I化合物及其前药或其医药上可接受的盐或其组合物可以作为抑制病毒感染因子蛋白的治疗药物。尤其是作为抑制对AZT，Tenofovir,3CT和FTC耐药的HIV病毒株的治疗药物。
除非另外定义，否则本文所用的所有化学术语都采用所属领域技术人员所了解的它们的一般含义。
“医药学上可接受的盐”包括本申请提供的化合物的任何盐，它保留所述化合物的生物学性质并且无毒或不在其它方面是医药用途所不希望的，例如钠盐、钾盐、铵盐等。
本发明所述“前药”是指当投予生物系统时由于自发的化学反应、酶催化反应和/或代谢过程或任一者的组合而产生生物学活性化合物的任何化合物。标准的前药是使用连接到例如-OH、-NH2等官能团、与药物缔合并在体内裂解的基团形成。前药的例子包括酯等，优选磷酸酯。能够与本发明核苷I形成“酯”的化合物包括各种有机酸，如乙酸与3’-OH可形成乙酸酯，丙酸与3’-OH可形成丙酸酯。在本发明中描述的前药是例示性的，但不是限制性的，并且所属领域的技术人员可以制备其它已知种类的前药。
本发明所述磷酸酯选单磷酸酯基团、二磷酸酯基团、三磷酸酯基团，结构分别如下所示
本发明优点：所述核苷式I化合物(CL002)具有非常好的Vif蛋白抑制作用，对现有艾滋病治疗药物(如AZT，Tenofov ir,3TC，FTC和整合酶抑制剂度鲁特韦等)的耐药HIV病毒株也有显著的抑制作用，是治疗艾滋病的一个新选择。
附图说明
图1为转染HEK293T细胞并用本发明化合物CL-002处理后的电泳结果：发现化合物CL-002抑制Vif对APOBEC3G的降解(见中间一排黑点)，并且CL-002对Vif降解APOBEC3G的抑制作用具有剂量依赖性。
图2为转染Hela-APOBEC3G细胞并用本发明化合物CL-002处理的电泳结果：发现化合物CL-002抑制Vif对APOBEC3G的降解(见中间一排黑点)，并且CL-002对Vif降解APOBEC3G的抑制作用具有剂量依赖性。
图3为APOBEC3G体外泛素化实验的电泳结果：说明本发明化合物CL-002在体外也具有一定的抑制Vif对APOBEC3G的泛素化的活性，并且具有剂量依赖性。
图4为使用微量热泳动仪测量本发明化合物CL-002与
Vif-CBFb(1-170)-ElonginB-Elongin C蛋白质复合物之间的相互作用情况；使用染料标记蛋白复合物并梯度稀释化合物后计算其亲和力大小，发现CL-002与Vif复合物之间有显著的亲和力，其KD值约为57.5μM。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
实施例1、化合物CL-002的制备：
CL-002根据文献方法制备(J.Wu et al Euopean J.Med.Chem,2013,63,739)。
实施例2、抗病毒活性的测定
材料和方法
2.1鉴定CL-002细胞水平的作用：
1)第一天铺HEK293T或者Hela-APOBEC3G细胞(12孔板)。
2)第二天用lipofactamin2000转染：
HEK293T细胞：(pCDNA3-Flag-APOBEC3G：1.7μg/孔)
Hela-APOBEC3G细胞：
3)转染后4小时，换培养基(DMEM+10％FBS)同时加入化合物CL-002，CL-002浓度梯度：0μM，50μM，100μM，200μM(如上面表格所示)。
4)转染后48小时收细胞，western blot检测。
2.2体外泛素化实验：
将体外纯化的蛋白：vif E3(vif/CBFβ/ELOBC/Cul5/RBX2)复合物，UBE1，UbcH5b，Ub和APOBEC3G在存在ATP的条件下与CL-002在室温反应1.5小时后用western blot检测。
2.3微量热泳动实验
使用Monolith NT.115热泳动仪检测CL-002与纯化的蛋白质复合物Vif-CBFb(1-170)-ElonginB-ElonginC之间的亲和力。
第一步先用NT-647-NHS荧光染料标记蛋白质复合物，其浓度固定为1uM。CL-002的浓度按照2倍梯度稀释为5000uM到153nM之间。第二步把荧光染料标记的Vif-CBFb(1-170)-ElonginB-ElonginC蛋白复合物与稀释好的CL-002室温混合15分钟，这一步骤中所使用的缓冲液成分为20mM Tris pH 7.5和100mM NaCl。第三步，在24℃条件下选取疏水性毛细管进行测定，测定过程中使用参数20％LED power和40％MST power。最后数据分析使用仪器自带软件NanoTemper analysis software。
2.4结果
本发明化合物CL-002抑制HIV-1及抑制HIV-1耐药株的活性见表1和表2。
表1.核苷I式化合物(CL-002)抑制HIV-1的活性
| 化合物 | EC50 |
| 本发明化合物I(CL-002) | 0.01nM |
表2.核苷I式化合物(CL002)抑制HIV-1耐药株的活性
*EC50是抑制病毒50％所需要的药物浓度，EC90是抑制病毒90％所需的药物浓度；
HIV-174V：核苷类逆转录酶抑制剂ddI/ddC耐药株；
HIV-1L10R/M46I/L63P/V82T/I84V：为蛋白酶抑制剂耐药株；
pNL4-3gp41(36G)V38A/42T：融合抑制剂T-20耐药株。
表1结果表明，本发明化合物I因可以通过抑制Vif而使其具有极强的抑制HIV-1的活性。
表2结果表明，本发明化合物I对耐药性HIV-1病毒株的抑制作用十分显著。
图1为转染HEK293T细胞并用本发明化合物CL-002处理后的电泳结果：发现化合物CL-002抑制Vif对APOBEC3G的降解(见中间一排黑点)，并且CL-002对Vif降解APOBEC3G的抑制作用具有剂量依赖性。
图2为转染Hela-APOBEC3G细胞并用本发明化合物CL-002处理的电泳结果：发现化合物CL-002抑制Vif对APOBEC3G的降解(见中间一排黑点)，并且CL-002对Vif降解APOBEC3G的抑制作用具有剂量依赖性。
图3为APOBEC3G体外泛素化实验的电泳结果：说明本发明化合物CL-002在体外也具有一定的抑制Vif对APOBEC3G的泛素化的活性，并且具有剂量依赖性。
图4为使用微量热泳动仪测量本发明化合物CL-002与Vif-CBFb(1-170)-ElonginB-Elongin C蛋白质复合物之间的相互作用情况；使用染料标记蛋白复合物并梯度稀释化合物后计算其亲和力大小，发现CL-002与Vif复合物之间有显著的亲和力，其KD值约为57.5μM。
本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
Claims (2)
1.具有如下结构的2’-氟-4’-叠氮核苷I、或其盐、或其前药在制备药物中的应用，其特征在于，作为活性成分，将其应用于制备抗HIV病毒感染因子蛋白抑制剂；
I
其前药选其5’-磷酸酯前药。
2.如权利要求1所述2’-氟-4’-叠氮核苷I、或其盐、或其前药、或其组合物在制备药物中的应用，其特征在于，将其用于抑制耐药性HIV突变体药物的制备。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710499293 | 2017-06-27 | ||
| CN2017104992936 | 2017-06-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108938658A true CN108938658A (zh) | 2018-12-07 |
Family
ID=64491757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810633797.7A Pending CN108938658A (zh) | 2017-06-27 | 2018-06-20 | 2’-氟-4’-叠氮核苷在制备病毒感染因子蛋白抑制剂中应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108938658A (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177442A (zh) * | 2007-07-16 | 2008-05-14 | 郑州大学 | 2’-氟-4’-取代-核苷类似物、其制备方法及其应用 |
-
2018
- 2018-06-20 CN CN201810633797.7A patent/CN108938658A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177442A (zh) * | 2007-07-16 | 2008-05-14 | 郑州大学 | 2’-氟-4’-取代-核苷类似物、其制备方法及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| WANG Q等: "Synthesis of new 20-deoxy-20-fluoro-40-azido nucleoside analogues as potent anti-HIV agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US12239655B2 (en) | Combined modalities for nucleosides and/or NADPH oxidase (NOX) inhibitors as myeloid-specific antiviral agents | |
| US11963972B2 (en) | Antiviral agents and nucleoside analogs for treatment of Zika virus | |
| US20120107274A1 (en) | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment | |
| WO2022217155A2 (en) | Thionucleosides as antiviral agents | |
| ZA200400925B (en) | Novel virus proliferation inhibition/virucidal method and novel pyradine nucleotide/pyradine nucleoside analogue | |
| RU2609512C2 (ru) | Производные ингенола для реактивации латентного вируса вич | |
| SG186830A1 (en) | Methods and compounds for treating paramyxoviridae virus infections | |
| Anindita et al. | Ribavirin-related compounds exert in vitro inhibitory effects toward rabies virus | |
| CN109893536A (zh) | 4’-取代核苷的晶型、制备和应用 | |
| Wen et al. | Flavonoids derived from licorice suppress LPS-induced acute lung injury in mice by inhibiting the cGAS-STING signaling pathway | |
| US9872875B2 (en) | Component and method for treating viral disease | |
| JPH07507770A (ja) | Ｎ−（ホスホノアセチル）−ｌ−アスパラギン酸組成物，および広域抗ウイルス剤としてのその使用方法 | |
| US7049303B2 (en) | Inhibition of viruses | |
| JPH10507771A (ja) | Ｌ−エリトロシル ヌクレオシド | |
| Wen et al. | Synthesis and anti-SARS-CoV-2 evaluation of lipid prodrugs of β-D-N4-hydroxycytidine (NHC) and a 3′-fluoro-substituted analogue of NHC | |
| CN111374985B (zh) | 盐酸非那吡啶的医药用途 | |
| CN108938658A (zh) | 2’-氟-4’-叠氮核苷在制备病毒感染因子蛋白抑制剂中应用 | |
| DE19813802A1 (de) | Anti-virale Wirkung von Propolis durch Inhibition viraler Nukleinsäure Polymerasen | |
| JP4986617B2 (ja) | ヘテロアリール化合物のプロドラッグ | |
| US7572827B2 (en) | Use of angelicin and of its structural analogues for the treatment of thalassemia | |
| Mukusheva et al. | Synthesis and structure of new modified derivatives based on the quinine molecule and their biological activity | |
| CN114762694A (zh) | 寡糖转移酶抑制剂在预防和/或治疗新型冠状病毒感染中的应用 | |
| CN115708833A (zh) | 吉西他滨在制备抗肝包虫药物中的应用 | |
| CN105884826B (zh) | 抗病毒药物 | |
| CN104211748B (zh) | 6‑羟基双脱氧鸟嘌呤核苷磷酸酯制备和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181207 |