US3082203A - Novel nucleotide coenzymes - Google Patents
Novel nucleotide coenzymes Download PDFInfo
- Publication number
- US3082203A US3082203A US7744A US774460A US3082203A US 3082203 A US3082203 A US 3082203A US 7744 A US7744 A US 7744A US 774460 A US774460 A US 774460A US 3082203 A US3082203 A US 3082203A
- Authority
- US
- United States
- Prior art keywords
- adenosine
- nucleotide
- phosphate
- coenzymes
- imidazole
- 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.)
- Expired - Lifetime
Links
- 239000002773 nucleotide Substances 0.000 title claims description 27
- 239000005515 coenzyme Substances 0.000 title claims description 14
- 125000003729 nucleotide group Chemical group 0.000 title description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 235000011180 diphosphates Nutrition 0.000 description 10
- 239000002777 nucleoside Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 9
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 9
- 239000010452 phosphate Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 8
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 6
- -1 phosphate ester Chemical class 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001962 electrophoresis Methods 0.000 description 4
- MPUAUPQFSLHOHQ-UHFFFAOYSA-N 1,2-dicyclohexylguanidine Chemical compound C1CCCCC1NC(=N)NC1CCCCC1 MPUAUPQFSLHOHQ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 3
- 229950006790 adenosine phosphate Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004816 paper chromatography Methods 0.000 description 3
- TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 108010006591 Apoenzymes Proteins 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229930182474 N-glycoside Natural products 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-O acridine;hydron Chemical compound C1=CC=CC2=CC3=CC=CC=C3[NH+]=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-O 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 239000001226 triphosphate Substances 0.000 description 2
- 235000011178 triphosphate Nutrition 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- HSCJRCZFDFQWRP-JZMIEXBBSA-N UDP-alpha-D-glucose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-JZMIEXBBSA-N 0.000 description 1
- HSCJRCZFDFQWRP-UHFFFAOYSA-N Uridindiphosphoglukose Natural products OC1C(O)C(O)C(CO)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical compound [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 1
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 1
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical class OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002402 hexoses Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Description
United States Patent ice Patented idlifli The term nucleoside is used herein to include deoxy- 3,032,203 nuoleosides. Thus, nucleoside within the meaning of NOVEL NUCLEOTIDE; (FOENZYMES the present invention includes: Leon Goldman and Joseph William Marslco, Nanuet, (4) Thymidine (or thymine deOXyfibOSidC):
N.Y., and George Washington Anderson, Upper Saddle River, N.J., assignors to American Cyanamid Com- 5 pany, New York, N.Y., a corporation of Maine No Drawing. Filed Feb. 10, 1960, Ser. No. 7,744
4 Claims. (Cl. 260-211.5)
The present invention relates to a novel method of preparing nucleotide coenzymes of biological and medical significance.
In order to clarify the exact nature of the chemical compounds of the present invention a few definitions will first be given before proceeding with the description of th invention.
A nucleoside is an N-glycoside of 'a heterocyclic base, generally a pyrimidine or a purine. Examples of nucleosides are:
(1) Adenosine (or adenine riboside):
A nucleotide is a phosphate ester of a nucleoside and may be a nucleoside monophosphate or a nucleoside polyphosphate. Examples of nucleoside monophosphates are:
(l1) Adenosine-'5 phosphate (or muscle adenylic acid or adenosine monophosphate, the latter hereinafter termed AMP) (3) Cytidine-S phosphate:
ff H O-F-0H 3 (4) Thymidine-S phosphate:
Examples of nucleoside polyphosphates are: (l) Adenosine-S' diphosphate (hereinafter termed ADP):
(2) Adnosine-S' triphosphate (hereinafter termed ATP):
Originally, the term nucleotide referred only to phosphate esters of nucleosides. Today, the term nucleotide is applied to phosphate esters of N-glycosides of heterocyclic bases generally. The newer definition, thus, includes not only the simple nucleotides of the original definition, but also the nucleic acids (polynucleotides) and such substances as adenosine-S' triphosphate and nicotinamide nucleotide. Derivatives of riboflavin phosphate, although not glycosidic in nature, are commonly included among the nucleotides because of their similarity to, and association with, true nucleotides.
A nucleotide coenzyme is a compound including in its structure at least one simple nucleotide moiety. The term nucleotide coenzyme is applied to a large and growing group of substances which are vital components of many enzyme systems involved in metabolic processes. Nucleotide coenzymes function in association with specific proteins or apoenzymes, the complete enzyme system being made up of the combination apoenzyme plus coenzyme. Historically, the first nucleotide coenzyme discovered was cozyrnase, or diphosphopyridine nucleotide,
discovered by Harden and Young in 1904. Examples of nucleotide coenzymes are:
(1) Cozymase (or diphosphopyridine nucleotide):
(2) Flavin adenine dinucleotide:
Oil
(3) Uridine diphosphate glucose:
The preparation of adenosine-S' phosphoroimidazole from adenosine-5' phosphate, dicyclohexylcarbodiimide and imidazole was reported by R. W. Chambers and I. G. Moffatt [1. Am. Chem. Soc. 80, 3752 (1958)]. Thereafter, the more facile preparation of nucleotide imidazoles by the interaction of a salt of a nucleotide and a l,1-carbonyldiimidazole was discovered by L. Goldman et a1. as is more fully set forth in U.S. Patent No. 2,951,838.
The reactivity of phosphorylated imidazoles is much greater than that of the ordinary phosphoramidates which also contain a phosphorus-nitrogen linkage. It has been postulated that this is a result of electronic displacements associated in particular with the electron attraction of the unsubstituted nitrogen atom. Surprisingly, however, although the phosphorus-nitrogen bond in the nucleotide imidazoles is thus generally activated, it is nevertheless resistant to reaction with water. Hence, it is possible to prepare nucleotide coenzymes and related compounds such as the linear and cyclic oligonucleotides from the nucleotide imidazoles in the presence of water as a solvent without the starting material reacting with that solvent. This NHZ.
O RENE RC 02H II rrlsol ll RCHCOzH Base-sugar-O ROH Base-sugar-O ROP 0311 wherein the Base may be either a purine or a pyrimidine moiety, the Sugar may be either a pentose or a hexose moiety such as D-ribose, D-glucose, or 2-deoxy-D-rib-ose, and wherein imidazole is a by-product in each case. These nucleotide coenzymes may be prepared by the novel method of the present invention in aqueous or nonaqueous media, at temperatures of from C. up to 100 C., and over a period of time of from a few minutes up to 12 hours.
The nucleotide coenzymes produced by the novel method of the present invention are useful as vital components of many enzyme systems. They are useful as organic catalytic agents in that they are capable of altering the velocity of many chemical reactions.
The following examples illustrate the novel method of preparing nucleotide coenzymes of the present invention.
EXAMPLE 1 Preparation of l,3-Dicycl0hexylguanidinium Azlenosine-b" Phosphoramia'ate A solution of adenosine-S' phosphoroimidazole in anhydrous dimethylformamide (prepared from 1.00 g. of adenosine-S' phosphate hydrate, 0.586 g. of imidazole, and 1.38 g. of 1,l'-carbonyldiimidazole) was diluted with 2 N ammonium hydroxide and tert-butyl alcohol and heated in a stainless steel bomb at 92 C. for 11 hours.
6 To the bomb contents, 0.612 g. of 1,3-dicyclohexylguanidine was added and the resultant solution evaporated under reduced pressure to a gummy residue. Addition of acetone followed by filtration gave 1.55 g. of colorless crystals of 1,3-dicyclohexylguanidinium adenosine-S phosphoramidate (solvated with Water and dimethylformamide), melting point 211-214 C. dec. The product was homogeneous has shown by paper chromatography in isopropyl alcohol-ammonia-water (7-1-2) and by paper electrophoresis in pH 7.5 phosphate buffer. Recrystallization from aqueous acetone gave l,3-dicyclohexylguanidinium NHZ adenosine-S' phosphoramidate, melting point 236238 C. dec.
EXAMPLE2 Preparation of 1,3-Dicycl0hexylguanidinium Adenosine-S Phosphora midate A solution of adenosine-S phosphoroimidazole in 7.5 ml. of anhydrous dimethylformamide (prepared from 1.00 g. of adenosine-S phosphate hydrate, 0.586 g. of imidazole, and 0.92 g. of 1,l carbonyldiimidazole) was dissolved in 20 ml. of 0.46 N ammonium hydroxide and heated in a stainless steel bomb at 65 C. for 10 hours. To the bomb contents was added 0.612 gram of 1,3,- dicyclohexylguanidine and the solution was evaporated to dryness under reduced pressure. Recrystallization of the residue from aqueous acetone gave 1.41 g. of colorless crystals of 1,3-dicyclohexylguanidinium adenosine-S phosphoramidate (solvated with water and dimethylform amide), melting point 236-238 C. dec.
EXAMPLE 3 Preparation of Acridinium Aden0sine-5 Pyrophosphate To a stirred solution of adenosine-S' phosphoroimidazole in anhydrous dimethylforrnamide (prepared from 0.200 g. of adenosine-S' phosphate hydrate,-0.ll7 g. of imidazole, and 0.0886 g. of 1,1'-carbonyldiimidazole) at 10 C. to 20 C. was added dropwise a solution of 0.24 ml. of 85% phosphoric acid in dimethylformamide. The mixture was allowed to warm to room temperature during one-half hour. The gummy solid, which separated on chilling, was dissolved in dilute sulfuric acid and treated with ethanolic acridine to yield 0.222 gram of acridinium adenosine-S' pyrophosphate as yellow crystals, melting point 2l2-2l5 C. dec. Recrystallization from water gave yellow needles, melting point 216-217 C. dec. Paper chromatography in 5% disodium phosphateisoamyl alcohol and in isopropyl alcohol-|1% ammonium sulfate (3-2), and paper electrophoresis in 0.02 M potassium dihydrogen phosphate, showed as the only impurity a trace of adenosine-S phosphate.
EXAMPLE 4 Preparation of P P -DiQdBIZOSiIIE-S' Pyrophosphate To a stirred solution of 1.00 gram of adenosine-5 phosphate monohydrate and 0.586 gram of imidazole in 7.5 ml. of anhydrous dimethylformamide at to C. was added 0.922 gram of 1,1-carbonyldiimidazole. After five minutes the temperature of the reaction mixture was loweredo to -20 C., and after 10 minutes 1.00 gram of adenosine-S' phosphate was added, with stirring. After minutes the reaction mixture was warmed to room temperature, and after 26 hours 3 ml. of pyridine was added. After 47 hours the resulting solution was worked up by chromatography on Dowex-l (formate) [S. M. H. Christie, D. T. Elmore, G. W. Kenner, A. R. Rodd, and F. J. Weymouth, 1. Chem. Soc., 2947 (1953)] to yield, by evaporation of the 0.5 N formic acid eluate, 1.06 gram of P P -diadenosine-S' pyrophosphate sesquihydrate as colorless crystals, which were homogeneous by paper chromatography in 5% disodium phosphateisoamyl alcohol and in n-butyl alcohol-acetic acid-water (5-2-3), and by paper electrophoresis in 0.02 M potassium dihydrogen phosphate.
8 EXAMPLE 5 Preparation of P -Aden0sine-5' P -UridiMe-S Pyrophosphate A solution of adenosine-S' phosphoroimidazole in anhydrous dimethylformamide (prepared from 0.0903 g. of adenosine-5 phosphate hydrate, 0.0528 g. of imidazole, and 0.132 g. of 1,l carbonyldiimidazole) was added to 0.1045 g. of imidazolium uridine-S phosphate. The reaction was diluted with 1.0 ml. of anhydrous pyridine and stirred for 74 hours at room temperature. When an aliquot was removed and subjected to paper electrophoresis in an acetate buffer of pH 4.8, the major component, P -adenosine-5 P -uridine-S pyrophosphate, traveled 15.7 cm. towards the anode, whereas the minor components, adenosine-5' phosphate, uridine-S' phosphate, and P P -(diuridine-S') pyrophosphate traveled 9.3, 13.0 and 18.7 cm., respectively.
We claim:
1. The method of preparing nucleotide coenzymes which comprises reacting a nucleotide imidazole with a nucleophilic agent selected from the group consisting of ammonia, primary amines, secondary amines, carboxylic acids, sulfuric acid, carbonic acid, N-blocked a-amino acids, alcohols, phosphate esters and phosphoric acid.
2. The method of preparing adenosine-S phosphoramidate which comprises reacting adenosine-S phosphoroimidazole with aqueous ammonia at a temperature between C. and C.
3. The method of preparing adenosine-S pyrophosphate which comprises reacting adenosine-fi' phosphoroimidazole with phosphoric acid at a temperature between -20 C. and 30 C.
4. The method of preparing P W-diadenosine-S' pyrophosphate which comprises reacting adenosine-S phosphoroimidazole with adenosine-S' phosphate at :1 mm perature between 20 C. and 30 C.
No references cited.
Claims (1)
1. THE METHOD OF PREPARING NUCLEOTIDE COENZYMES WHICH COMPRISES REACTING A NUCLEOTIDE IMIDAZOLE WITH A NUCLEOPHILIC AGENT SELECTED FROM THE GROUP CONSISTING OF AMMONIA, PRIMARY AMINES, SECONDARY AMINES, CARBOXYLIC ACIDS, SLUFURIC ACID, CARBONIC ACID, N-BLOCKED A-AMINO ACIDS, ALCOHOLS, PHOSPHATE ESTERS AND PHOSPHORIC ACID.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7744A US3082203A (en) | 1960-02-10 | 1960-02-10 | Novel nucleotide coenzymes |
| GB3055/61A GB935509A (en) | 1960-02-10 | 1961-01-26 | Method of preparing nucleotides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7744A US3082203A (en) | 1960-02-10 | 1960-02-10 | Novel nucleotide coenzymes |
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| Publication Number | Publication Date |
|---|---|
| US3082203A true US3082203A (en) | 1963-03-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US7744A Expired - Lifetime US3082203A (en) | 1960-02-10 | 1960-02-10 | Novel nucleotide coenzymes |
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| Country | Link |
|---|---|
| US (1) | US3082203A (en) |
| GB (1) | GB935509A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3299042A (en) * | 1964-06-22 | 1967-01-17 | Lipkin David | Iodination of the heterocyclic bases in nucleosides, nucleotides, nucleoside-5'-polyphosphates, and nucleic acids |
| US3321462A (en) * | 1963-07-15 | 1967-05-23 | Syntex Corp | Process for the preparation of nucleoside polyphosphates |
| US3332935A (en) * | 1963-08-07 | 1967-07-25 | Ajinomoto Kk | Preparation of guanosine and intermediates therein |
| WO1990005736A2 (en) * | 1988-11-23 | 1990-05-31 | Medical Research Council | Nucleoside analogues |
-
1960
- 1960-02-10 US US7744A patent/US3082203A/en not_active Expired - Lifetime
-
1961
- 1961-01-26 GB GB3055/61A patent/GB935509A/en not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3321462A (en) * | 1963-07-15 | 1967-05-23 | Syntex Corp | Process for the preparation of nucleoside polyphosphates |
| US3332935A (en) * | 1963-08-07 | 1967-07-25 | Ajinomoto Kk | Preparation of guanosine and intermediates therein |
| US3299042A (en) * | 1964-06-22 | 1967-01-17 | Lipkin David | Iodination of the heterocyclic bases in nucleosides, nucleotides, nucleoside-5'-polyphosphates, and nucleic acids |
| WO1990005736A2 (en) * | 1988-11-23 | 1990-05-31 | Medical Research Council | Nucleoside analogues |
| WO1990005736A3 (en) * | 1988-11-23 | 1990-07-12 | Medical Res Council | Nucleoside analogues |
Also Published As
| Publication number | Publication date |
|---|---|
| GB935509A (en) | 1963-08-28 |
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