CN110317849B - 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 - Google Patents
一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 Download PDFInfo
- Publication number
- CN110317849B CN110317849B CN201810275135.7A CN201810275135A CN110317849B CN 110317849 B CN110317849 B CN 110317849B CN 201810275135 A CN201810275135 A CN 201810275135A CN 110317849 B CN110317849 B CN 110317849B
- Authority
- CN
- China
- Prior art keywords
- amino acid
- tetrahydroisoquinoline
- gly
- reaction system
- val
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- OXFGRWIKQDSSLY-VIFPVBQESA-N (1s)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Chemical compound C1=CC=C2[C@@H](C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-VIFPVBQESA-N 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 107
- 239000000758 substrate Substances 0.000 claims abstract description 59
- 108010003989 D-amino-acid oxidase Proteins 0.000 claims abstract description 58
- 102000004674 D-amino-acid oxidase Human genes 0.000 claims abstract description 53
- 239000002253 acid Substances 0.000 claims abstract description 26
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 19
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 96
- 102000004190 Enzymes Human genes 0.000 claims description 61
- 108090000790 Enzymes Proteins 0.000 claims description 61
- 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 claims description 39
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 claims description 39
- 239000011714 flavin adenine dinucleotide Substances 0.000 claims description 39
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 claims description 39
- 102000016938 Catalase Human genes 0.000 claims description 33
- 108010053835 Catalase Proteins 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- OCPCZCANFUBIEX-NSHDSACASA-N (1s)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1C[NH2+][C@H](C([O-])=O)C2=C1C=C(OC)C(OC)=C2 OCPCZCANFUBIEX-NSHDSACASA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- 239000005515 coenzyme Substances 0.000 claims description 16
- 241000894006 Bacteria Species 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 150000002466 imines Chemical class 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- -1 borane amines Chemical class 0.000 claims description 6
- 239000013604 expression vector Substances 0.000 claims description 6
- 239000008176 lyophilized powder Substances 0.000 claims description 6
- 241000427940 Fusarium solani Species 0.000 claims description 5
- 241001480015 Trigonopsis variabilis Species 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 4
- 241000223218 Fusarium Species 0.000 claims description 4
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 239000006174 pH buffer Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910000085 borane Inorganic materials 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 241000476619 Fusarium graminearum CS3005 Species 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- OXFGRWIKQDSSLY-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1=CC=C2C(C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-UHFFFAOYSA-N 0.000 abstract description 19
- OCPCZCANFUBIEX-UHFFFAOYSA-N 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1CNC(C(O)=O)C2=C1C=C(OC)C(OC)=C2 OCPCZCANFUBIEX-UHFFFAOYSA-N 0.000 abstract description 18
- 230000009471 action Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 23
- 239000000523 sample Substances 0.000 description 16
- 238000002156 mixing Methods 0.000 description 14
- 238000005070 sampling Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 150000001413 amino acids Chemical group 0.000 description 8
- 239000008055 phosphate buffer solution Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 7
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 108010037850 glycylvaline Proteins 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- OXFGRWIKQDSSLY-SECBINFHSA-N (1r)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Chemical compound C1=CC=C2[C@H](C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-SECBINFHSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 5
- OXHSZBRPUGNMKW-DCAQKATOSA-N Met-Gln-Arg Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OXHSZBRPUGNMKW-DCAQKATOSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- OCPCZCANFUBIEX-LLVKDONJSA-N (1r)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1C[NH2+][C@@H](C([O-])=O)C2=C1C=C(OC)C(OC)=C2 OCPCZCANFUBIEX-LLVKDONJSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- VOKCBYNCZVSILJ-KKUMJFAQSA-N His-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CN=CN2)N)O VOKCBYNCZVSILJ-KKUMJFAQSA-N 0.000 description 4
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 4
- 229910003203 NH3BH3 Inorganic materials 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 108010093581 aspartyl-proline Proteins 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 4
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 4
- 108010087823 glycyltyrosine Proteins 0.000 description 4
- 108010078274 isoleucylvaline Proteins 0.000 description 4
- 108010057821 leucylproline Proteins 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 108010064235 lysylglycine Proteins 0.000 description 4
- 108010048818 seryl-histidine Proteins 0.000 description 4
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 3
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 description 3
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 3
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 3
- VHAQSYHSDKERBS-XPUUQOCRSA-N Ala-Val-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O VHAQSYHSDKERBS-XPUUQOCRSA-N 0.000 description 3
- QHVRVUNEAIFTEK-SZMVWBNQSA-N Arg-Pro-Trp Chemical compound N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O QHVRVUNEAIFTEK-SZMVWBNQSA-N 0.000 description 3
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 3
- UBKOVSLDWIHYSY-ACZMJKKPSA-N Asn-Glu-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UBKOVSLDWIHYSY-ACZMJKKPSA-N 0.000 description 3
- YYSYDIYQTUPNQQ-SXTJYALSSA-N Asn-Ile-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YYSYDIYQTUPNQQ-SXTJYALSSA-N 0.000 description 3
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 3
- XDGBFDYXZCMYEX-NUMRIWBASA-N Asp-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)O XDGBFDYXZCMYEX-NUMRIWBASA-N 0.000 description 3
- USENATHVGFXRNO-SRVKXCTJSA-N Asp-Tyr-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(O)=O)CC1=CC=C(O)C=C1 USENATHVGFXRNO-SRVKXCTJSA-N 0.000 description 3
- 241000223195 Fusarium graminearum Species 0.000 description 3
- SMLDOQHTOAAFJQ-WDSKDSINSA-N Gln-Gly-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SMLDOQHTOAAFJQ-WDSKDSINSA-N 0.000 description 3
- DOQUICBEISTQHE-CIUDSAMLSA-N Gln-Pro-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O DOQUICBEISTQHE-CIUDSAMLSA-N 0.000 description 3
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 description 3
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 3
- DSPQRJXOIXHOHK-WDSKDSINSA-N Glu-Asp-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O DSPQRJXOIXHOHK-WDSKDSINSA-N 0.000 description 3
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 3
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 3
- ZIYGTCDTJJCDDP-JYJNAYRXSA-N Glu-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZIYGTCDTJJCDDP-JYJNAYRXSA-N 0.000 description 3
- ITVBKCZZLJUUHI-HTUGSXCWSA-N Glu-Phe-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ITVBKCZZLJUUHI-HTUGSXCWSA-N 0.000 description 3
- OCDLPQDYTJPWNG-YUMQZZPRSA-N Gly-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN OCDLPQDYTJPWNG-YUMQZZPRSA-N 0.000 description 3
- BPQYBFAXRGMGGY-LAEOZQHASA-N Gly-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN BPQYBFAXRGMGGY-LAEOZQHASA-N 0.000 description 3
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 3
- LPCKHUXOGVNZRS-YUMQZZPRSA-N Gly-His-Ser Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O LPCKHUXOGVNZRS-YUMQZZPRSA-N 0.000 description 3
- NSTUFLGQJCOCDL-UWVGGRQHSA-N Gly-Leu-Arg Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NSTUFLGQJCOCDL-UWVGGRQHSA-N 0.000 description 3
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 3
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 3
- PYFIQROSWQERAS-LBPRGKRZSA-N Gly-Trp-Gly Chemical compound C1=CC=C2C(C[C@H](NC(=O)CN)C(=O)NCC(O)=O)=CNC2=C1 PYFIQROSWQERAS-LBPRGKRZSA-N 0.000 description 3
- GNNJKUYDWFIBTK-QWRGUYRKSA-N Gly-Tyr-Asp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O GNNJKUYDWFIBTK-QWRGUYRKSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- LVQDUPQUJZWKSU-PYJNHQTQSA-N Ile-Arg-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N LVQDUPQUJZWKSU-PYJNHQTQSA-N 0.000 description 3
- FZWVCYCYWCLQDH-NHCYSSNCSA-N Ile-Leu-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N FZWVCYCYWCLQDH-NHCYSSNCSA-N 0.000 description 3
- QHUREMVLLMNUAX-OSUNSFLBSA-N Ile-Thr-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)O)N QHUREMVLLMNUAX-OSUNSFLBSA-N 0.000 description 3
- GVEODXUBBFDBPW-MGHWNKPDSA-N Ile-Tyr-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 GVEODXUBBFDBPW-MGHWNKPDSA-N 0.000 description 3
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 3
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 3
- ZQCVMVCVPFYXHZ-SRVKXCTJSA-N Lys-Asn-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN ZQCVMVCVPFYXHZ-SRVKXCTJSA-N 0.000 description 3
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 3
- VSJAPSMRFYUOKS-IUCAKERBSA-N Met-Pro-Gly Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O VSJAPSMRFYUOKS-IUCAKERBSA-N 0.000 description 3
- FZDOBWIKRQORAC-ULQDDVLXSA-N Met-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCSC)N FZDOBWIKRQORAC-ULQDDVLXSA-N 0.000 description 3
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 3
- AAERWTUHZKLDLC-IHRRRGAJSA-N Phe-Pro-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O AAERWTUHZKLDLC-IHRRRGAJSA-N 0.000 description 3
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 3
- HBBBLSVBQGZKOZ-GUBZILKMSA-N Pro-Met-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O HBBBLSVBQGZKOZ-GUBZILKMSA-N 0.000 description 3
- YIPFBJGBRCJJJD-FHWLQOOXSA-N Pro-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@@H]3CCCN3 YIPFBJGBRCJJJD-FHWLQOOXSA-N 0.000 description 3
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 3
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 3
- UJQVSMNQMQHVRY-KZVJFYERSA-N Thr-Met-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O UJQVSMNQMQHVRY-KZVJFYERSA-N 0.000 description 3
- BZTSQFWJNJYZSX-JRQIVUDYSA-N Thr-Tyr-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O BZTSQFWJNJYZSX-JRQIVUDYSA-N 0.000 description 3
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 3
- CSRCUZAVBSEDMB-FDARSICLSA-N Trp-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N CSRCUZAVBSEDMB-FDARSICLSA-N 0.000 description 3
- LTSIAOZUVISRAQ-QWRGUYRKSA-N Tyr-Gly-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)O LTSIAOZUVISRAQ-QWRGUYRKSA-N 0.000 description 3
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 3
- FBVUOEYVGNMRMD-NAKRPEOUSA-N Val-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N FBVUOEYVGNMRMD-NAKRPEOUSA-N 0.000 description 3
- SYOMXKPPFZRELL-ONGXEEELSA-N Val-Gly-Lys Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)O)N SYOMXKPPFZRELL-ONGXEEELSA-N 0.000 description 3
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 3
- RTJPAGFXOWEBAI-SRVKXCTJSA-N Val-Val-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RTJPAGFXOWEBAI-SRVKXCTJSA-N 0.000 description 3
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-N 0.000 description 3
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 3
- 108010047495 alanylglycine Proteins 0.000 description 3
- 108010087924 alanylproline Proteins 0.000 description 3
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 108010042598 glutamyl-aspartyl-glycine Proteins 0.000 description 3
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 3
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 3
- 108010028188 glycyl-histidyl-serine Proteins 0.000 description 3
- 108010040030 histidinoalanine Proteins 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 108010012581 phenylalanylglutamate Proteins 0.000 description 3
- 108010029020 prolylglycine Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- PAIHPOGPJVUFJY-WDSKDSINSA-N Ala-Glu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O PAIHPOGPJVUFJY-WDSKDSINSA-N 0.000 description 2
- WMYJZJRILUVVRG-WDSKDSINSA-N Ala-Gly-Gln Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O WMYJZJRILUVVRG-WDSKDSINSA-N 0.000 description 2
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 2
- OQWQTGBOFPJOIF-DLOVCJGASA-N Ala-Lys-His Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N OQWQTGBOFPJOIF-DLOVCJGASA-N 0.000 description 2
- PMQXMXAASGFUDX-SRVKXCTJSA-N Ala-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCCN PMQXMXAASGFUDX-SRVKXCTJSA-N 0.000 description 2
- HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 2
- MZRBYBIQTIKERR-GUBZILKMSA-N Arg-Glu-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MZRBYBIQTIKERR-GUBZILKMSA-N 0.000 description 2
- NIUDXSFNLBIWOB-DCAQKATOSA-N Arg-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NIUDXSFNLBIWOB-DCAQKATOSA-N 0.000 description 2
- MJINRRBEMOLJAK-DCAQKATOSA-N Arg-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N MJINRRBEMOLJAK-DCAQKATOSA-N 0.000 description 2
- OOXUBGLNDRGOKT-FXQIFTODSA-N Asn-Ser-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OOXUBGLNDRGOKT-FXQIFTODSA-N 0.000 description 2
- AECPDLSSUMDUAA-ZKWXMUAHSA-N Asn-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N AECPDLSSUMDUAA-ZKWXMUAHSA-N 0.000 description 2
- XMKXONRMGJXCJV-LAEOZQHASA-N Asp-Val-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XMKXONRMGJXCJV-LAEOZQHASA-N 0.000 description 2
- XLRHXNIVIZZOON-WFUPGROFSA-L Flavin adenine dinucleotide disodium Chemical compound [Na+].[Na+].C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP([O-])(=O)OP([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 XLRHXNIVIZZOON-WFUPGROFSA-L 0.000 description 2
- ATTWDCRXQNKRII-GUBZILKMSA-N Gln-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N ATTWDCRXQNKRII-GUBZILKMSA-N 0.000 description 2
- HTTSBEBKVNEDFE-AUTRQRHGSA-N Glu-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N HTTSBEBKVNEDFE-AUTRQRHGSA-N 0.000 description 2
- KUTPGXNAAOQSPD-LPEHRKFASA-N Glu-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O KUTPGXNAAOQSPD-LPEHRKFASA-N 0.000 description 2
- WNRZUESNGGDCJX-JYJNAYRXSA-N Glu-Leu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WNRZUESNGGDCJX-JYJNAYRXSA-N 0.000 description 2
- JBRBACJPBZNFMF-YUMQZZPRSA-N Gly-Ala-Lys Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN JBRBACJPBZNFMF-YUMQZZPRSA-N 0.000 description 2
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 2
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 2
- FSOXZQBMPBQKGJ-QSFUFRPTSA-N His-Ile-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]([NH3+])CC1=CN=CN1 FSOXZQBMPBQKGJ-QSFUFRPTSA-N 0.000 description 2
- MDOBWSFNSNPENN-PMVVWTBXSA-N His-Thr-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O MDOBWSFNSNPENN-PMVVWTBXSA-N 0.000 description 2
- JXMSHKFPDIUYGS-SIUGBPQLSA-N Ile-Glu-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N JXMSHKFPDIUYGS-SIUGBPQLSA-N 0.000 description 2
- CCYGNFBYUNHFSC-MGHWNKPDSA-N Ile-His-Phe Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CCYGNFBYUNHFSC-MGHWNKPDSA-N 0.000 description 2
- YWCJXQKATPNPOE-UKJIMTQDSA-N Ile-Val-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N YWCJXQKATPNPOE-UKJIMTQDSA-N 0.000 description 2
- WIDZHJTYKYBLSR-DCAQKATOSA-N Leu-Glu-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WIDZHJTYKYBLSR-DCAQKATOSA-N 0.000 description 2
- LIINDKYIGYTDLG-PPCPHDFISA-N Leu-Ile-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LIINDKYIGYTDLG-PPCPHDFISA-N 0.000 description 2
- WXUOJXIGOPMDJM-SRVKXCTJSA-N Leu-Lys-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O WXUOJXIGOPMDJM-SRVKXCTJSA-N 0.000 description 2
- KQFZKDITNUEVFJ-JYJNAYRXSA-N Leu-Phe-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CC=CC=C1 KQFZKDITNUEVFJ-JYJNAYRXSA-N 0.000 description 2
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 2
- LMKSBGIUPVRHEH-FXQIFTODSA-N Met-Ala-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(N)=O LMKSBGIUPVRHEH-FXQIFTODSA-N 0.000 description 2
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XWYXZPHPYKRYPA-GMOBBJLQSA-N Pro-Asn-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XWYXZPHPYKRYPA-GMOBBJLQSA-N 0.000 description 2
- FNGOXVQBBCMFKV-CIUDSAMLSA-N Pro-Ser-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O FNGOXVQBBCMFKV-CIUDSAMLSA-N 0.000 description 2
- 108010003201 RGH 0205 Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- PZZJMBYSYAKYPK-UWJYBYFXSA-N Ser-Ala-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PZZJMBYSYAKYPK-UWJYBYFXSA-N 0.000 description 2
- SVWQEIRZHHNBIO-WHFBIAKZSA-N Ser-Gly-Cys Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CS)C(O)=O SVWQEIRZHHNBIO-WHFBIAKZSA-N 0.000 description 2
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical class CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 2
- GKMYGVQDGVYCPC-IUKAMOBKSA-N Thr-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]([C@@H](C)O)N GKMYGVQDGVYCPC-IUKAMOBKSA-N 0.000 description 2
- VUVCRYXYUUPGSB-GLLZPBPUSA-N Thr-Gln-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O VUVCRYXYUUPGSB-GLLZPBPUSA-N 0.000 description 2
- XYFISNXATOERFZ-OSUNSFLBSA-N Thr-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N XYFISNXATOERFZ-OSUNSFLBSA-N 0.000 description 2
- BDENGIGFTNYZSJ-RCWTZXSCSA-N Thr-Pro-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O BDENGIGFTNYZSJ-RCWTZXSCSA-N 0.000 description 2
- JNKAYADBODLPMQ-HSHDSVGOSA-N Thr-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)[C@@H](C)O)=CNC2=C1 JNKAYADBODLPMQ-HSHDSVGOSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- JZSLIZLZGWOJBJ-PMVMPFDFSA-N Trp-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N JZSLIZLZGWOJBJ-PMVMPFDFSA-N 0.000 description 2
- YCQKQFKXBPJXRY-PMVMPFDFSA-N Trp-Tyr-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CCCCN)C(=O)O)N YCQKQFKXBPJXRY-PMVMPFDFSA-N 0.000 description 2
- NXRAUQGGHPCJIB-RCOVLWMOSA-N Val-Gly-Asn Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O NXRAUQGGHPCJIB-RCOVLWMOSA-N 0.000 description 2
- GVJUTBOZZBTBIG-AVGNSLFASA-N Val-Lys-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N GVJUTBOZZBTBIG-AVGNSLFASA-N 0.000 description 2
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 2
- MNSSBIHFEUUXNW-RCWTZXSCSA-N Val-Thr-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N MNSSBIHFEUUXNW-RCWTZXSCSA-N 0.000 description 2
- NLNCNKIVJPEFBC-DLOVCJGASA-N Val-Val-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O NLNCNKIVJPEFBC-DLOVCJGASA-N 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 2
- 229960000318 kanamycin Drugs 0.000 description 2
- 229930182823 kanamycin A Natural products 0.000 description 2
- 108010009298 lysylglutamic acid Proteins 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- IKWHIGGRTYBSIW-OBJOEFQTSA-N (2s)-2-[[(2s)-2-[[(2s)-1-(2-aminoacetyl)pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylbutanoic acid Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN IKWHIGGRTYBSIW-OBJOEFQTSA-N 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- ZLUUPCCXIKTEBG-UHFFFAOYSA-N 3,4-dihydro-2h-quinoline-1-carboxylic acid Chemical class C1=CC=C2N(C(=O)O)CCCC2=C1 ZLUUPCCXIKTEBG-UHFFFAOYSA-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
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- FJVAQLJNTSUQPY-CIUDSAMLSA-N Ala-Ala-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN FJVAQLJNTSUQPY-CIUDSAMLSA-N 0.000 description 1
- UCIYCBSJBQGDGM-LPEHRKFASA-N Ala-Arg-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N UCIYCBSJBQGDGM-LPEHRKFASA-N 0.000 description 1
- NXSFUECZFORGOG-CIUDSAMLSA-N Ala-Asn-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXSFUECZFORGOG-CIUDSAMLSA-N 0.000 description 1
- MBWYUTNBYSSUIQ-HERUPUMHSA-N Ala-Asn-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N MBWYUTNBYSSUIQ-HERUPUMHSA-N 0.000 description 1
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 1
- NJPMYXWVWQWCSR-ACZMJKKPSA-N Ala-Glu-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NJPMYXWVWQWCSR-ACZMJKKPSA-N 0.000 description 1
- LMFXXZPPZDCPTA-ZKWXMUAHSA-N Ala-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N LMFXXZPPZDCPTA-ZKWXMUAHSA-N 0.000 description 1
- NIZKGBJVCMRDKO-KWQFWETISA-N Ala-Gly-Tyr Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NIZKGBJVCMRDKO-KWQFWETISA-N 0.000 description 1
- FOHXUHGZZKETFI-JBDRJPRFSA-N Ala-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C)N FOHXUHGZZKETFI-JBDRJPRFSA-N 0.000 description 1
- TZDNWXDLYFIFPT-BJDJZHNGSA-N Ala-Ile-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O TZDNWXDLYFIFPT-BJDJZHNGSA-N 0.000 description 1
- LNNSWWRRYJLGNI-NAKRPEOUSA-N Ala-Ile-Val Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O LNNSWWRRYJLGNI-NAKRPEOUSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 1
- AWNAEZICPNGAJK-FXQIFTODSA-N Ala-Met-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O AWNAEZICPNGAJK-FXQIFTODSA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- IETUUAHKCHOQHP-KZVJFYERSA-N Ala-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)O)C(O)=O IETUUAHKCHOQHP-KZVJFYERSA-N 0.000 description 1
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VWVPYNGMOCSSGK-GUBZILKMSA-N Arg-Arg-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O VWVPYNGMOCSSGK-GUBZILKMSA-N 0.000 description 1
- PBSOQGZLPFVXPU-YUMQZZPRSA-N Arg-Glu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O PBSOQGZLPFVXPU-YUMQZZPRSA-N 0.000 description 1
- NKBQZKVMKJJDLX-SRVKXCTJSA-N Arg-Glu-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NKBQZKVMKJJDLX-SRVKXCTJSA-N 0.000 description 1
- YQGZIRIYGHNSQO-ZPFDUUQYSA-N Arg-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YQGZIRIYGHNSQO-ZPFDUUQYSA-N 0.000 description 1
- NGTYEHIRESTSRX-UWVGGRQHSA-N Arg-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NGTYEHIRESTSRX-UWVGGRQHSA-N 0.000 description 1
- FKQITMVNILRUCQ-IHRRRGAJSA-N Arg-Phe-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O FKQITMVNILRUCQ-IHRRRGAJSA-N 0.000 description 1
- UGZUVYDKAYNCII-ULQDDVLXSA-N Arg-Phe-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UGZUVYDKAYNCII-ULQDDVLXSA-N 0.000 description 1
- HNJNAMGZQZPSRE-GUBZILKMSA-N Arg-Pro-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O HNJNAMGZQZPSRE-GUBZILKMSA-N 0.000 description 1
- OVQJAKFLFTZDNC-GUBZILKMSA-N Arg-Pro-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O OVQJAKFLFTZDNC-GUBZILKMSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- DNLQVHBBMPZUGJ-BQBZGAKWSA-N Arg-Ser-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O DNLQVHBBMPZUGJ-BQBZGAKWSA-N 0.000 description 1
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 1
- MEFGKQUUYZOLHM-GMOBBJLQSA-N Asn-Arg-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MEFGKQUUYZOLHM-GMOBBJLQSA-N 0.000 description 1
- ZWASIOHRQWRWAS-UGYAYLCHSA-N Asn-Asp-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZWASIOHRQWRWAS-UGYAYLCHSA-N 0.000 description 1
- HCAUEJAQCXVQQM-ACZMJKKPSA-N Asn-Glu-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HCAUEJAQCXVQQM-ACZMJKKPSA-N 0.000 description 1
- AITGTTNYKAWKDR-CIUDSAMLSA-N Asn-His-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O AITGTTNYKAWKDR-CIUDSAMLSA-N 0.000 description 1
- RLHANKIRBONJBK-IHRRRGAJSA-N Asn-Met-Phe Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N RLHANKIRBONJBK-IHRRRGAJSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 1
- GHWWTICYPDKPTE-NGZCFLSTSA-N Asn-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N GHWWTICYPDKPTE-NGZCFLSTSA-N 0.000 description 1
- POTCZYQVVNXUIG-BQBZGAKWSA-N Asp-Gly-Pro Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O POTCZYQVVNXUIG-BQBZGAKWSA-N 0.000 description 1
- ZQFRDAZBTSFGGW-SRVKXCTJSA-N Asp-Ser-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZQFRDAZBTSFGGW-SRVKXCTJSA-N 0.000 description 1
- GWWSUMLEWKQHLR-NUMRIWBASA-N Asp-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O GWWSUMLEWKQHLR-NUMRIWBASA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- PRHGYQOSEHLDRW-VGDYDELISA-N Cys-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CS)N PRHGYQOSEHLDRW-VGDYDELISA-N 0.000 description 1
- BBQIWFFTTQTNOC-AVGNSLFASA-N Cys-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N BBQIWFFTTQTNOC-AVGNSLFASA-N 0.000 description 1
- NXQCSPVUPLUTJH-WHFBIAKZSA-N Cys-Ser-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O NXQCSPVUPLUTJH-WHFBIAKZSA-N 0.000 description 1
- AZDQAZRURQMSQD-XPUUQOCRSA-N Cys-Val-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AZDQAZRURQMSQD-XPUUQOCRSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 241001489200 Fusarium poae Species 0.000 description 1
- DLOHWQXXGMEZDW-CIUDSAMLSA-N Gln-Arg-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DLOHWQXXGMEZDW-CIUDSAMLSA-N 0.000 description 1
- MWLYSLMKFXWZPW-ZPFDUUQYSA-N Gln-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCC(N)=O MWLYSLMKFXWZPW-ZPFDUUQYSA-N 0.000 description 1
- JESJDAAGXULQOP-CIUDSAMLSA-N Gln-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N JESJDAAGXULQOP-CIUDSAMLSA-N 0.000 description 1
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 1
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 1
- SOEXCCGNHQBFPV-DLOVCJGASA-N Gln-Val-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SOEXCCGNHQBFPV-DLOVCJGASA-N 0.000 description 1
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 1
- HJIFPJUEOGZWRI-GUBZILKMSA-N Glu-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N HJIFPJUEOGZWRI-GUBZILKMSA-N 0.000 description 1
- ZWABFSSWTSAMQN-KBIXCLLPSA-N Glu-Ile-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O ZWABFSSWTSAMQN-KBIXCLLPSA-N 0.000 description 1
- ZCOJVESMNGBGLF-GRLWGSQLSA-N Glu-Ile-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZCOJVESMNGBGLF-GRLWGSQLSA-N 0.000 description 1
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 1
- BCYGDJXHAGZNPQ-DCAQKATOSA-N Glu-Lys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O BCYGDJXHAGZNPQ-DCAQKATOSA-N 0.000 description 1
- UDEPRBFQTWGLCW-CIUDSAMLSA-N Glu-Pro-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O UDEPRBFQTWGLCW-CIUDSAMLSA-N 0.000 description 1
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 1
- RMWAOBGCZZSJHE-UMNHJUIQSA-N Glu-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N RMWAOBGCZZSJHE-UMNHJUIQSA-N 0.000 description 1
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 1
- PYTZFYUXZZHOAD-WHFBIAKZSA-N Gly-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CN PYTZFYUXZZHOAD-WHFBIAKZSA-N 0.000 description 1
- RLFSBAPJTYKSLG-WHFBIAKZSA-N Gly-Ala-Asp Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O RLFSBAPJTYKSLG-WHFBIAKZSA-N 0.000 description 1
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 1
- OLPPXYMMIARYAL-QMMMGPOBSA-N Gly-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)CN OLPPXYMMIARYAL-QMMMGPOBSA-N 0.000 description 1
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 1
- IUKIDFVOUHZRAK-QWRGUYRKSA-N Gly-Lys-His Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IUKIDFVOUHZRAK-QWRGUYRKSA-N 0.000 description 1
- MHXKHKWHPNETGG-QWRGUYRKSA-N Gly-Lys-Leu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O MHXKHKWHPNETGG-QWRGUYRKSA-N 0.000 description 1
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 1
- GWCJMBNBFYBQCV-XPUUQOCRSA-N Gly-Val-Ala Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O GWCJMBNBFYBQCV-XPUUQOCRSA-N 0.000 description 1
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 1
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- DCRODRAURLJOFY-XPUUQOCRSA-N His-Ala-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)NCC(O)=O DCRODRAURLJOFY-XPUUQOCRSA-N 0.000 description 1
- QMUHTRISZMFKAY-MXAVVETBSA-N His-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N QMUHTRISZMFKAY-MXAVVETBSA-N 0.000 description 1
- FFYYUUWROYYKFY-IHRRRGAJSA-N His-Val-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O FFYYUUWROYYKFY-IHRRRGAJSA-N 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- PHIXPNQDGGILMP-YVNDNENWSA-N Ile-Glu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N PHIXPNQDGGILMP-YVNDNENWSA-N 0.000 description 1
- NZOCIWKZUVUNDW-ZKWXMUAHSA-N Ile-Gly-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O NZOCIWKZUVUNDW-ZKWXMUAHSA-N 0.000 description 1
- SLQVFYWBGNNOTK-BYULHYEWSA-N Ile-Gly-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N SLQVFYWBGNNOTK-BYULHYEWSA-N 0.000 description 1
- YNMQUIVKEFRCPH-QSFUFRPTSA-N Ile-Ile-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)O)N YNMQUIVKEFRCPH-QSFUFRPTSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- BKPPWVSPSIUXHZ-OSUNSFLBSA-N Ile-Met-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N BKPPWVSPSIUXHZ-OSUNSFLBSA-N 0.000 description 1
- JZBVBOKASHNXAD-NAKRPEOUSA-N Ile-Val-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N JZBVBOKASHNXAD-NAKRPEOUSA-N 0.000 description 1
- YHFPHRUWZMEOIX-CYDGBPFRSA-N Ile-Val-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)O)N YHFPHRUWZMEOIX-CYDGBPFRSA-N 0.000 description 1
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 description 1
- HASRFYOMVPJRPU-SRVKXCTJSA-N Leu-Arg-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O HASRFYOMVPJRPU-SRVKXCTJSA-N 0.000 description 1
- KTFHTMHHKXUYPW-ZPFDUUQYSA-N Leu-Asp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KTFHTMHHKXUYPW-ZPFDUUQYSA-N 0.000 description 1
- HVJVUYQWFYMGJS-GVXVVHGQSA-N Leu-Glu-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVJVUYQWFYMGJS-GVXVVHGQSA-N 0.000 description 1
- FIYMBBHGYNQFOP-IUCAKERBSA-N Leu-Gly-Gln Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N FIYMBBHGYNQFOP-IUCAKERBSA-N 0.000 description 1
- OYQUOLRTJHWVSQ-SRVKXCTJSA-N Leu-His-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O OYQUOLRTJHWVSQ-SRVKXCTJSA-N 0.000 description 1
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 1
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 1
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-N 0.000 description 1
- ZDBMWELMUCLUPL-QEJZJMRPSA-N Leu-Phe-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 ZDBMWELMUCLUPL-QEJZJMRPSA-N 0.000 description 1
- PTRKPHUGYULXPU-KKUMJFAQSA-N Leu-Phe-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O PTRKPHUGYULXPU-KKUMJFAQSA-N 0.000 description 1
- YRRCOJOXAJNSAX-IHRRRGAJSA-N Leu-Pro-Lys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N YRRCOJOXAJNSAX-IHRRRGAJSA-N 0.000 description 1
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 1
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 1
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 1
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- JCFYLFOCALSNLQ-GUBZILKMSA-N Lys-Ala-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JCFYLFOCALSNLQ-GUBZILKMSA-N 0.000 description 1
- GQUDMNDPQTXZRV-DCAQKATOSA-N Lys-Arg-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GQUDMNDPQTXZRV-DCAQKATOSA-N 0.000 description 1
- PAMDBWYMLWOELY-SDDRHHMPSA-N Lys-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)C(=O)O PAMDBWYMLWOELY-SDDRHHMPSA-N 0.000 description 1
- UETQMSASAVBGJY-QWRGUYRKSA-N Lys-Gly-His Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 UETQMSASAVBGJY-QWRGUYRKSA-N 0.000 description 1
- IZJGPPIGYTVXLB-FQUUOJAGSA-N Lys-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IZJGPPIGYTVXLB-FQUUOJAGSA-N 0.000 description 1
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 1
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 1
- QAHFGYLFLVGBNW-DCAQKATOSA-N Met-Ala-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN QAHFGYLFLVGBNW-DCAQKATOSA-N 0.000 description 1
- PCTFVQATEGYHJU-FXQIFTODSA-N Met-Ser-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O PCTFVQATEGYHJU-FXQIFTODSA-N 0.000 description 1
- VYXIKLFLGRTANT-HRCADAONSA-N Met-Tyr-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N VYXIKLFLGRTANT-HRCADAONSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 238000005990 Petasis reaction Methods 0.000 description 1
- SZYBZVANEAOIPE-UBHSHLNASA-N Phe-Met-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O SZYBZVANEAOIPE-UBHSHLNASA-N 0.000 description 1
- SHUFSZDAIPLZLF-BEAPCOKYSA-N Phe-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N)O SHUFSZDAIPLZLF-BEAPCOKYSA-N 0.000 description 1
- APZNYJFGVAGFCF-JYJNAYRXSA-N Phe-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)C(C)C)C(O)=O APZNYJFGVAGFCF-JYJNAYRXSA-N 0.000 description 1
- WWAQEUOYCYMGHB-FXQIFTODSA-N Pro-Asn-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 WWAQEUOYCYMGHB-FXQIFTODSA-N 0.000 description 1
- OBVCYFIHIIYIQF-CIUDSAMLSA-N Pro-Asn-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OBVCYFIHIIYIQF-CIUDSAMLSA-N 0.000 description 1
- AHXPYZRZRMQOAU-QXEWZRGKSA-N Pro-Asn-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1)C(O)=O AHXPYZRZRMQOAU-QXEWZRGKSA-N 0.000 description 1
- LNICFEXCAHIJOR-DCAQKATOSA-N Pro-Ser-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LNICFEXCAHIJOR-DCAQKATOSA-N 0.000 description 1
- NBDHWLZEMKSVHH-UVBJJODRSA-N Pro-Trp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@@H]3CCCN3 NBDHWLZEMKSVHH-UVBJJODRSA-N 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 1
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 1
- MAWSJXHRLWVJEZ-ACZMJKKPSA-N Ser-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N MAWSJXHRLWVJEZ-ACZMJKKPSA-N 0.000 description 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- IFPBAGJBHSNYPR-ZKWXMUAHSA-N Ser-Ile-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O IFPBAGJBHSNYPR-ZKWXMUAHSA-N 0.000 description 1
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 1
- OVQZAFXWIWNYKA-GUBZILKMSA-N Ser-Pro-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CO)N OVQZAFXWIWNYKA-GUBZILKMSA-N 0.000 description 1
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- ZSDXEKUKQAKZFE-XAVMHZPKSA-N Ser-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N)O ZSDXEKUKQAKZFE-XAVMHZPKSA-N 0.000 description 1
- HKHCTNFKZXAMIF-KKUMJFAQSA-N Ser-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CC=C(O)C=C1 HKHCTNFKZXAMIF-KKUMJFAQSA-N 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- UDQBCBUXAQIZAK-GLLZPBPUSA-N Thr-Glu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UDQBCBUXAQIZAK-GLLZPBPUSA-N 0.000 description 1
- WYKJENSCCRJLRC-ZDLURKLDSA-N Thr-Gly-Cys Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)O WYKJENSCCRJLRC-ZDLURKLDSA-N 0.000 description 1
- JKGGPMOUIAAJAA-YEPSODPASA-N Thr-Gly-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O JKGGPMOUIAAJAA-YEPSODPASA-N 0.000 description 1
- GMXIJHCBTZDAPD-QPHKQPEJSA-N Thr-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N GMXIJHCBTZDAPD-QPHKQPEJSA-N 0.000 description 1
- ADPHPKGWVDHWML-PPCPHDFISA-N Thr-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N ADPHPKGWVDHWML-PPCPHDFISA-N 0.000 description 1
- NDLHSJWPCXKOGG-VLCNGCBASA-N Thr-Trp-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N)O NDLHSJWPCXKOGG-VLCNGCBASA-N 0.000 description 1
- YLGQHMHKAASRGJ-WDSOQIARSA-N Trp-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N YLGQHMHKAASRGJ-WDSOQIARSA-N 0.000 description 1
- ARKBYVBCEOWRNR-UBHSHLNASA-N Trp-Ser-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O ARKBYVBCEOWRNR-UBHSHLNASA-N 0.000 description 1
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 1
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 1
- SOEGLGLDSUHWTI-STECZYCISA-N Tyr-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 SOEGLGLDSUHWTI-STECZYCISA-N 0.000 description 1
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 1
- KKHRWGYHBZORMQ-NHCYSSNCSA-N Val-Arg-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KKHRWGYHBZORMQ-NHCYSSNCSA-N 0.000 description 1
- CVUDMNSZAIZFAE-TUAOUCFPSA-N Val-Arg-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N CVUDMNSZAIZFAE-TUAOUCFPSA-N 0.000 description 1
- GBESYURLQOYWLU-LAEOZQHASA-N Val-Glu-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N GBESYURLQOYWLU-LAEOZQHASA-N 0.000 description 1
- PMXBARDFIAPBGK-DZKIICNBSA-N Val-Glu-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PMXBARDFIAPBGK-DZKIICNBSA-N 0.000 description 1
- ZTKGDWOUYRRAOQ-ULQDDVLXSA-N Val-His-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N ZTKGDWOUYRRAOQ-ULQDDVLXSA-N 0.000 description 1
- JZWZACGUZVCQPS-RNJOBUHISA-N Val-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N JZWZACGUZVCQPS-RNJOBUHISA-N 0.000 description 1
- DJQIUOKSNRBTSV-CYDGBPFRSA-N Val-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](C(C)C)N DJQIUOKSNRBTSV-CYDGBPFRSA-N 0.000 description 1
- VVIZITNVZUAEMI-DLOVCJGASA-N Val-Val-Gln Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCC(N)=O VVIZITNVZUAEMI-DLOVCJGASA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- XPAWRVKFFVLAKU-UHFFFAOYSA-N ethyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate Chemical compound COC1=C(OC)C=C2C(C(=O)OCC)NCCC2=C1 XPAWRVKFFVLAKU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000012215 gene cloning Methods 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 108010090037 glycyl-alanyl-isoleucine Proteins 0.000 description 1
- 108010026364 glycyl-glycyl-leucine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010085109 glycyl-histidyl-arginyl-proline Proteins 0.000 description 1
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 108010016686 methionyl-alanyl-serine Proteins 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 108010025488 pinealon Proteins 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/04—Alpha- or beta- amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明公开了一种制备(S)‑1,2,3,4‑四氢异喹啉‑1‑甲酸及其衍生物的方法，其包括：以外消旋1,2,3,4‑四氢异喹啉‑1‑甲酸(1)或外消旋6,7‑二甲氧基‑1,2,3,4‑四氢异喹啉‑1‑甲酸(2)为底物，利用D‑氨基酸氧化酶立体选择性催化R型异构体，经氧化脱氢生成相应的亚胺酸，S型异构体未被催化保留在反应体系中，亚胺酸经亚胺酸还原剂作用生成外消旋底物，再在D‑氨基酸氧化酶的作用下被立体选择性催化其中的R型异构体，由此制备S型异构体。本发明方法产率可达75％～97.4％，ee值>99％，且具有反应条件温和、立体选择性强、反应效率高、产率高、工艺相对简单等特点。
Description
技术领域
本发明属于生物催化技术领域，具体涉及一种制备(S)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法。
背景技术
1,2,3,4-四氢异喹啉类化合物是一类非常重要的药物中间体，被广泛应用于多种药物的合成。近年来，Hu等(Discovery of a small-molecule inhibitor and cellularprobe of Keap1-Nrf2 protein-protein interaction[J].Bioorg Med Chem Lett,2013,23(10):3039-43.)以(S)-1,2,3,4-四氢异喹啉-1-甲酸为起始化合物，合成一种靶向Kelch-like ECH-associated protein 1(Keap1)的抑制剂，从而有望用于癌症，糖尿病，阿尔兹海默症，帕金森等疾病的治疗和预防。而大部分具有药用价值的异喹啉碱都含有6,7-二甲氧基(如罂粟碱、吐根碱等)，有利于降低药物分子的疏水性，提高成药性，如6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸。
现有技术中，制备光学纯(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的方法主要有两大类：化学手性合成和生物催化手性拆分。
化学手性合成法从手性原料出发合成(S)-1,2,3,4-四氢异喹啉-1-甲酸，如Kurata等光学纯烯烃异喹啉为起始原料经臭氧分解和NaBH4原位还原、四甲基哌啶氮氧化物(TEMPO)氧化以及三氟乙酸介导的N-叔丁氧羰基去保护作用三步不对成合成(S)-1,2,3,4-四氢异喹啉-1-甲酸(Synthesis of Optically Pure(R)-and(S)-Tetrahydroisoquinoline-1-and-3-Carboxylic Acids[J].Synthesis,2015,47(09):1238-44.)。该法产率低，步骤繁琐，不适于工业化应用。
等采用Petasis反应和Pomeranz–Fritsch–Bobbitt反应非对映体选择性全合成(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，ee值为90％(Synthesis of(+)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid,a DiastereoselectiveApproach[J].European Journal of Organic Chemistry,2015,2015(2):383-8.)。
相比之下，生物催化法具有立体选择性高、反应条件温和等优点，是制备(S)-1,2,3,4-四氢异喹啉-1-甲酸或其衍生物的潜在优势方法。Paál等利用枯草杆菌蛋白酶动态动力学拆分6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸乙酯制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，53g/L底物，加酶量为80mg/mL固定化酶，3℃，pH8.5条件下，反应3天，产率92％，产物ee值为93％(Directed(R)-or(S)-Selective Dynamic KineticEnzymatic Hydrolysis of 1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Esters[J].European Journal of Organic Chemistry,2008,2008(31):5269-76)。该法反应条件温和，立体选择性强，工艺相对简单，但所得产物的光学纯度还有待进一步提高。
发明内容
本发明的目的在于克服现有技术的不足，提供一种新的制备(S)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法。该方法具有反应条件温和、立体选择性强、反应效率高、产率高等特点，具有工业化应用前景。
为实现上述目的，本发明采取的技术方案如下：
一种制备如式(I)所示的化合物的方法，
式(I)中，R1，R2独立地选自氢、C1-C6烷基，C1-C6烷氧基，所述方法包括：
(1)以所述式(I)化合物的外消旋体或式(I)化合物的盐的外消旋体为底物，利用D-氨基酸氧化酶作为催化剂，选择性催化式(I)化合物的R型异构体进行氧化脱氢反应，生成亚胺酸，而式(I)化合物未被催化，保留在反应体系中；
其中，在进行所述氧化脱氢反应前、所述氧化脱氢反应过程中和所述氧化脱氢反应后中的一个或多个时间点向所述反应体系中加入亚胺酸还原剂，所述亚胺酸还原剂用于使所述氧化脱氢反应生成的所述亚胺酸被还原为所述式(I)化合物的外消旋体或式(I)化合物的盐的外消旋体；
(2)将所述式(I)化合物与反应体系分离。
根据本发明的一些优选方面，式(I)中，R1，R2独立地选自氢、甲基、乙基、异丙基、甲氧基或乙氧基。
根据本发明的一些优选方面，所述的盐为一价盐，具体优选碱金属盐或铵盐，其中碱金属盐可以为例如锂盐、钠盐、钾盐。
根据本发明的一些优选方面，所述的式(I)所示的化合物为(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸。
根据本发明，所述D-氨基酸氧化酶为选自如下D-氨基酸氧化酶中的一种或多种的组合：来源于三角酵母(Trigonopsis variabilis)CBS 4095的D-氨基酸氧化酶或其突变体或与其氨基酸序列同源性大于80％的其它D-氨基酸氧化酶、来自禾谷镰刀菌(Fusariumgraminearum)CS3005的D-氨基酸氧化酶或其突变体或与其氨基酸序列同源性大于80％的其它D-氨基酸氧化酶、来自梨孢镰刀菌(Fusarium poae)2516的D-氨基酸氧化酶或其突变体或与其氨基酸序列同源性大于80％的其它D-氨基酸氧化酶，来自茄病镰刀菌(Fusariumsolani)M-0718的D-氨基酸氧化酶或其突变体或与其氨基酸序列同源性大于80％的其它D-氨基酸氧化酶。
优选地，所述D-氨基酸氧化酶具有如SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3或SEQ ID NO.4所示的氨基酸序列。
根据本发明的一些具体且优选的方面，所述催化剂为含有离体的所述D-氨基酸氧化酶的粗酶液或胞内表达所述D-氨基酸氧化酶的细胞或者所述D-氨基酸氧化酶的纯酶或者所述D-氨基酸氧化酶的固定化酶。
进一步地，所述细胞为表达D-氨基酸氧化酶的工程菌，所述工程菌的宿主细胞为E.coliBL21(DE3)。
根据本发明的一个具体方面，所述工程菌含有表达载体pET-28a(+)，所述D-氨基酸氧化酶基因连接在表达载体pET-28a(+)上。
根据本发明的一些具体且优选的方面，所述催化剂的添加量以8000rpm离心10min后的细胞湿重计，所述细胞的添加量为所述反应体系重量的1～5％。
根据本发明的一些具体且优选的方面，使所述氧化脱氢反应在有氧环境中进行，所述氧化脱氢反应还生成有过氧化氢，所述方法还包括在进行所述氧化脱氢反应前、所述氧化脱氢反应过程中和所述氧化脱氢反应后中的一个或多个时间点还向所述反应体系中加入用于催化分解所述过氧化氢的过氧化氢酶。
进一步地，所述过氧化氢酶为牛肝过氧化氢酶冻干粉。根据本发明的一个具体方面，所述牛肝过氧化氢酶冻干粉的酶活为4000U/mg。
根据本发明的一些优选方面，所述过氧化氢酶与所述D-氨基酸氧化酶的酶活比为100～400：1。
根据本发明的一些优选方面，步骤(1)中，使所述反应在辅酶黄素腺嘌呤二核苷酸(FAD)存在下进行。使反应在FAD存在下进行，有助于进一步提高转化率。进一步地，FAD与所述的底物等当量或者是过量的。一般情况下，所制备的D-氨基酸氧化酶的粗酶液中已经含有足够量的FAD，在直接采用粗酶液的情况下，无需再另外添加FAD。在使用D-氨基酸氧化酶纯酶的情况下，可以根据需要再外加适量的FAD。
根据本发明的一些具体且优选的方面，步骤(1)中，首先构建所述反应体系，然后控制所述反应体系处于设定温度和有氧环境中进行反应，所述反应体系包括所述底物、所述催化剂、溶剂，所述反应体系还选择性的包括pH缓冲剂和/或pH调节剂。
进一步地，所述反应体系还包括所述的亚胺酸还原剂和/或用于催化分解过氧化氢的过氧化氢酶。
根据本发明的一个优选方面，所述溶剂是水，先将底物溶解于所述pH缓冲剂的水溶液中，再选择性的加入所述pH调节剂，配制pH值为6～9的底物溶液，然后加入所述催化剂、亚胺酸还原剂和/或过氧化氢酶，得到所述反应体系。更优选地，控制底物溶液的pH值为7～8。
根据本发明的一个具体且优选方面，所述pH缓冲剂为磷酸盐，将其溶于水可以配制成磷酸盐缓冲溶液。
根据本发明的一些优选方面，所述的pH调节剂为氨水、碱金属氢氧化物或其水溶液。
根据本发明的一个具体且优选方面，所述的pH调节剂为20wt％～35wt％氨水。
根据本发明的又一具体方面，所述的pH调节剂为氢氧化钠或氢氧化钾的水溶液。
根据本发明的一些具体且优选的方面，步骤(1)中，控制所述反应体系中起始底物的浓度为1～20g/L。
根据本发明的优选方面，所述设定温度为20～70℃。更优选地，所述设定温度为30～50℃。
根据本发明，所述的亚胺酸还原剂可以采用本领域熟知的还原剂。根据本发明的一些具体且优选的方面，所述亚胺酸还原剂为选自氰基硼氢化钠、硼烷胺和硼氢化钠中的一种或多种的组合，这些还原剂被证明对于亚胺酸具有非常好的反应活性。
根据本发明的一些具体且优选的方面，所述亚胺酸还原剂的添加量为所述底物投料摩尔量的3～10个当量。
进一步地，步骤(2)中，将反应体系的pH值调至5.0-6.0，加热使蛋白变性析出，抽滤，滤液浓缩后，冷却析晶，干燥，即得所述式(I)所示的化合物。
由于以上技术方案的实施，本发明与现有技术相比具有如下有益效果：
本发明意外发现D-氨基酸氧化酶可高效选择性催化(R)-1,2,3,4-四氢异喹啉-1-甲酸或(R)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸等进行氧化脱氢反应，而对于(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸基本无催化作用，同时结合亚胺酸还原剂的使用，进一步提高了产率。采用本发明方法来制备(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，反应效率高(1.5～5g/L的底物，2g/L干细胞或相对应的粗酶液，反应20～48小时，产率75％～97.4％)，反应条件温和，立体选择性强(ee值>99％)，工艺简单。
附图说明
图1为底物外消旋1,2,3,4-四氢异喹啉-1-甲酸的高效液相检测图谱(1g/L)；
其中，保留时间8.810min为(R)-1,2,3,4-四氢异喹啉-1-甲酸；保留时间12.685min为(S)-1,2,3,4-四氢异喹啉-1-甲酸；
图2为实施例3中反应体系中0小时取样检测的高效液相色谱检测图谱；
图3为实施例3中反应30小时取样检测的高效液相色谱检测图谱。
具体实施方式
本发明提供一种制备(S)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的新方法，以外消旋1,2,3,4-四氢异喹啉-1-甲酸或外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸为底物(或氨盐)为底物，利用离体的D-氨基酸氧化酶或胞内表达D-氨基酸氧化酶的细胞等作为催化剂，结合亚胺酸还原剂，进行氧化脱氢-化学还原反应，获得(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸。
具体原理为：以外消旋1,2,3,4-四氢异喹啉-1-甲酸(1)或外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸(2)为底物，利用D-氨基酸氧化酶立体选择性催化(R)-1,2,3,4-四氢异喹啉-1-甲酸或(R)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，经氧化脱氢生成相应的亚胺酸，(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸未被催化保留在反应体系中。亚胺酸经亚胺酸还原剂作用生成外消旋底物，再在D-氨基酸氧化酶的作用下被立体选择性催化其中的(R)-1,2,3,4-四氢异喹啉-1-甲酸或(R)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，可实现(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸产率的提高，且ee值>99％。其中生成的过氧化氢可经过氧化氢酶催化分解成水和氧气。反应过程示意如下：
进一步地，优选使反应在辅酶黄素腺嘌呤二核苷酸(FAD)存在下进行，在催化过程中，辅酶黄素腺嘌呤二核苷酸(FAD)被还原为FADH2，随后，一分子氧被还原为过氧化氢(H2O2)，而FADH2则被氧化为FAD。过氧化氢在过氧化氢酶的催化下分解成水和氧气。反应过程示意如下：
作为优选，所述D-氨基酸氧化酶来源于三角酵母、禾谷镰刀菌、梨孢镰刀菌、茄病镰刀菌。具体的，所述D-氨基酸氧化酶来源于三角酵母(Trigonopsis variabilis)CBS4095、禾谷镰刀菌(Fusarium graminearum)CS3005、梨孢镰刀菌(Fusarium poae)2516或茄病镰刀菌(Fusarium solani)M-0718。作为优选，所述细胞为表达D-氨基酸氧化酶的工程菌，所述工程菌的宿主细胞为E.coli BL21(DE3)。具体地，所述工程菌含有表达载体pET-28a(+)，所述D-氨基酸氧化酶基因连接在表达载体pET-28a(+)上。
反应体系中，D-氨基酸氧化酶的使用形式为粗酶液，或者表达重组酶的工程菌静息细胞，或者是纯酶，或者固定化酶。过氧化氢酶的使用形式为冻干粉末。
作为优选，反应体系中底物外消旋1,2,3,4-四氢异喹啉-1-甲酸或外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的浓度为1～20g/L。
作为一个具体且优选的方面，反应体系中，催化剂D-氨基酸氧化酶的添加量以8000rpm离心10min后的细胞湿重计，所述细胞的添加量为反应液重量的1～5％。
作为优选，反应体系中，亚胺酸还原剂可以是氰基硼氢化钠、硼烷胺、硼氢化钠或其它能够还原亚胺的化学试剂。反应体系中亚胺酸还原剂的添加量为底物投料摩尔量的3～10个当量。
作为优选，反应体系中，过氧化氢酶与D-氨基酸氧化酶的酶活比为100～400：1。
作为一个具体方面，过氧化氢酶为牛肝过氧化氢酶冻干粉末，酶活为4000U/mg。
作为优选，反应体系中，反应的温度为20～70℃，时间为6～72小时，反应液的pH值为6～9；更优选地，反应的温度为30～50℃，时间为12～48小时。作为一个具体且优选的方面，通过磷酸缓冲溶液控制反应的pH值为7～8。
以下结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围。
本发明实施例中的实验方法如无特别说明均为常规方法。
本发明实施例中所用基因由生工生物工程(上海)股份有限公司合成。E.coliBL21(DE3)菌种购自Novagen公司；DNA marker、PrimeStar DNA聚合酶、低分子量标准蛋白等分子生物学实验试剂购自TaKaRa。基因克隆及表达具体操作可参见J.萨姆布鲁克等编的《分子克隆实验指南》。
本发明通过高效液相色谱(HPLC)分析催化反应的各个产物和底物。外消旋1,2,3,4-四氢异喹啉-1-甲酸的HPLC分析方法为：色谱柱/
ZWIX(-)；柱温/25℃；流速/0.4mL/min；检测波长/UV220nm；流动相：HPLC级甲醇(加入50mM甲酸和25mM二已胺)。具体各相关物质出峰情况见附图1。外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的HPLC分析方法为：色谱柱/Chirobiotic TAG；柱温/25℃；流速/0.8mL/min；检测波长/UV220nm和232nm；流动相：HPLC级甲醇/水(1:1)(Directed(R)-or(S)-Selective DynamicKinetic Enzymatic Hydrolysis of 1,2,3,4-Tetrahydroisoquinoline-1-carboxylicEsters[J].European Journal of Organic Chemistry,2008,2008(31):5269-76)。
实施例1D-氨基酸氧化酶的筛选及表达D-氨基酸氧化酶的基因工程菌的构建
根据底物特异性的不同，微生物来源的D-氨基酸氧化酶可分为两大类:1)偏好底物侧链基团较小的氨基酸(如D-丙氨酸)，如尖孢镰刀菌(Fusarium oxysporum)来源的D-氨基酸氧化酶；2)偏好底物侧链基团较大的氨基酸(如D-苯丙氨酸)，如三角酵母(Trigonopsis variabilis)来源的D-氨基酸氧化酶(POLLEGIONI L,MOLLA G,SACCHI S,etal.Properties and applications of microbial D-amino acid oxidases:currentstate and perspectives[J].Appl Microbiol Biotechnol,2008,78(1):1-16.)。分别用这两种D-氨基酸氧化酶的氨基酸序列在美国国立生物技术信息中心(NCBI)数据库(https://www.ncbi.nlm.nih.gov/)中进行BLASTp分析，选取序列一致性不同的4种D-氨基酸氧化酶作进一步研究(如表1所示)。
表1四种不同来源的D-氨基酸氧化酶
将上述D-氨基酸氧化酶基因序列经密码子优化后送生工生物工程(上海)股份有限公司进行全基因合成，并克隆到重组表达质粒pET-28a(+)上。重组质粒转入表达宿主E.coliBL21(DE3)中，经测序验证无误后，向所得工程菌菌液中加入终浓度为25％的甘油并置于-80℃保藏备用。
实施例2
2.1微生物的培养
液体LB培养基组成：蛋白胨10g/L，酵母粉5g/L，NaCl 10g/L，用去离子水溶解后定容，121℃灭菌20min，待用。若为固体LB培养基，则另加15g/L琼脂。
将含有D-氨基酸氧化酶基因的工程菌接种于5mL液体LB(含50μg/ml卡那霉素)培养基中，37℃，200rpm振荡培养8小时左右。按1％(V/V)的接种量接种于100mL液体LB(含50μg/ml卡那霉素)培养基中培养，OD600达到0.6-0.8后，加入诱导剂异丙基硫代半乳糖苷(终浓度为0.1mM)，18℃诱导15h。培养结束后，将培养液倒入100mL离心管中4000rpm离心10min，弃上清，收集菌体细胞，用50mM磷酸缓冲液(pH＝8.0)洗涤细胞两次，放于-80℃超低温冰箱中保存，备用。
2.2粗酶液的制备
将菌体重悬于25mL磷酸缓冲液(50mM,pH＝8.0)中，超声破碎菌悬液，离心后得到的上清为含D-氨基酸氧化酶的粗酶液。
2.3高效液相色谱检测反应体系中各对映体含量
反应体系(1ml)：10g/L E1、E2、E3或E4湿菌体(超声波破碎)，5g/L底物外消旋1,2,3,4-四氢异喹啉-1-甲酸或外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸，反应介质为磷酸盐缓冲液(50mM,pH＝8.0)。将配好的反应体系置于30℃金属浴振荡反应器内反应10min。磷酸盐缓冲液代替粗酶液的反应体系作为对照。样品经流动相稀释10倍后用高效液相色谱进行定性分析。
结果表明：与对照相比，E1、E2、E3以及E4能够立体选择性催化(R)-1,2,3,4-四氢异喹啉-1-甲酸或(R)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸反应，而(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸含量基本保持不变。
实施例3 FsDAAO-NaCNBH3制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH8.0)配制10g/L外消旋1,2,3,4-四氢异喹啉-1-甲酸溶液并用30％氨水调节溶液pH至8.0。
向100mL反应器中加入20mL底物溶液，20mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应30小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。
0小时、30小时取样的检测结果分别如图2和图3所示，FsDAAO表现出严格的R-构型立体选择性，产率为78.8％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.2％。
实施例4 FsDAAO-NaCNBH3制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH8.0)配制3.4g/L外消旋1,2,3,4-四氢异喹啉-1-甲酸溶液并用30％氨水调节溶液pH至8.0。
向100mL反应器中加入20mL底物溶液，20mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应20小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为97.4％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.7％。
实施例5 FgDAAO-NaBH4制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
按实施例3的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL FgDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.35gNaBH4。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应30小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为76.3％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.1％。
实施例6 FpDAAO-NH3BH3制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
按实施例3的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL FpDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.29gNH3BH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应30小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为77.1％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.6％。
实施例7 TvDAAO-NaCNBH3制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
按实施例3的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL TvDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应40小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为75.6％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.1％。
实施例8 FsDAAO-NaCNBH3制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH＝8.0)配制10g/L的外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸溶液并用30％氨水调节溶液pH至8.0。
向100mL反应器中加入20mL底物溶液，20mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应40小时，取样。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为76.4％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.3％。
实施例9 FgDAAO-NaBH4制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸
按实施例8的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL FgDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.35gNaBH4。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应40小时，取样。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为75.8％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.3％。
实施例10 FpDAAO-NH3BH3制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸
按实施例8的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL FpDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.29gNH3BH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应40小时，取样。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为76.9％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.2％。
实施例11 TvDAAO-NaCNBH3制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸
按实施例8的方法配制底物溶液。
向100mL反应器中加入20mL底物溶液，20mL TvDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应48小时，取样。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为76.1％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.1％。
实施例12 纯酶FsDAAO-NaCNBH3制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
按实施例3的方法配制底物溶液。
取1ml底物溶液加入到5mL反应管中，再加入FsDAAO纯酶液，黄素腺嘌呤二核苷酸钠盐，过氧化氢酶，NaCNBH3，并用磷酸盐缓冲溶液(50mM,pH＝8.0)将反应总体积补到2ml，FsDAAO纯酶的终浓度为0.74mg/ml，FAD终浓度为100μM，NaCNBH3(5个当量)，过氧化氢酶终浓度为0.01mg/ml。混匀后，取出10μL，作为“0小时”并进行HPLC分析。将反应管置于30℃恒温水浴中，磁力搅拌，反应5小时。反应结束后用高效液相色谱检测反应体系中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为82.5％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.4％。
实施例13 纯酶FsDAAO-NaCNBH3制备(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸
按实施例8的方法配制底物溶液。
取1ml底物溶液加入到5mL反应管中，再加入FsDAAO纯酶液以及黄素腺嘌呤二核苷酸钠盐，过氧化氢酶，NaCNBH3，并用磷酸盐缓冲溶液(50mM,pH＝8.0)将反应总体积补到2ml，FsDAAO纯酶的终浓度为0.72mg/ml，FAD终浓度为100μM，NaCNBH3(5个当量)，过氧化氢酶终浓度为0.01mg/ml。混匀后，取出10μL，作为“0小时”并进行HPLC分析。将反应管置于30℃恒温水浴中，磁力搅拌，反应5小时。反应结束后用高效液相色谱检测反应体系中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为80.2％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.5％。
实施例14 FsDAAO-NaCNBH3制备(S)-1,2,3,4--四氢异喹啉--1--甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH＝8.0)配制10g/L的外消旋1,2,3,4-四氢异喹啉-1-甲酸溶液并用5M氢氧化钠溶液调节底物溶液pH至8.0。
向100mL反应器中加入20mL底物溶液，20mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应30小时，取样。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为78.6％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值为99.4％。
实施例15 FsDAAO-NaCNBH3制备(S)-6,7--二甲氧基--1,2,3,4--四氢异喹啉--1--甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH＝8.0)配制10g/L的外消旋6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸溶液并用5M氢氧化钾溶液调节底物溶液pH至8.0。
向100mL反应器中加入20mL底物溶液，20mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)，8mg过氧化氢酶冻干粉末和0.3gNaCNBH3。混匀后，立即取样，作为“0小时”。将反应体系置于30℃恒温水浴中，磁力搅拌，反应30小时，取样。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为77.4％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.2％。
实施例16 (S)-1,2,3,4-四氢异喹啉--1--甲酸的制备与分离
底物溶液及反应体系如实施例3。
反应结束后，将反应体系的pH值调至5.0-6.0。99℃水浴，待蛋白变性析出后，抽滤。取滤液于65℃条件下旋蒸，将反应体积浓缩10倍。置于冰上，冷却后，抽滤。将析出的白色晶体，小心刮下，置于烘箱中，烘干并称重。称取0.2g白色烘干晶体，用50mM磷酸盐缓冲溶液(pH＝8.0)定容至50ml。高效液相色谱检测所取样品中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为75.8％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.4％。
实施例17 (S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的制备与分离
底物溶液及反应体系如实施例8。
反应结束后，将反应体系的pH值调至5.0-6.0。99℃水浴，待蛋白变性析出后，抽滤。取滤液于65℃条件下旋蒸，将反应体积浓缩10倍。置于冰上，冷却后，抽滤。将析出的白色晶体，小心刮下，置于烘箱中，烘干并称重。称取0.25g白色烘干晶体，用50mM磷酸盐缓冲溶液(pH＝8.0)定容至50ml。高效液相色谱检测所取样品中6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。产率为75.2％，(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99.2％以上。
对比例FsDAAO制备(S)-1,2,3,4-四氢异喹啉-1-甲酸
底物溶液的配制：用50mM的磷酸盐缓冲溶液(pH＝8.0)配制10g/L的外消旋1,2,3,4-四氢异喹啉-1-甲酸溶液并用30％氨水调节溶液pH至8.0。
取1ml底物溶液加入到5mL反应管中，再加入1mL FsDAAO粗酶液(粗酶液中已含有足量辅酶FAD，因此，粗酶液反应体系中不需额外添加FAD)。混匀后，取样，作为“0小时”并进行HPLC分析。将反应管置于30℃恒温水浴中，磁力搅拌，反应30小时。反应结束后用HPLC法检测反应体系中1,2,3,4-四氢异喹啉-1-甲酸两种构型的含量。
FsDAAO表现出严格的R-构型立体选择性，产率为49.9％，(S)-1,2,3,4-四氢异喹啉-1-甲酸的ee值达99％以上。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
序列表
<110> 苏州同力生物医药有限公司
<120> 一种制备(S)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法
<160> 4
<170> SIPOSequenceListing 1.0
<210> 1
<211> 361
<212> PRT
<213> 人(Homo)
<400> 1
Met Ser Asn Thr Ile Val Val Val Gly Ala Ile Val Ser Gly Leu Thr
1 5 10 15
Ser Ala Leu Leu Leu Ser Lys Asn Lys Gly Asn Lys Ile Thr Val Val
20 25 30
Ala Lys His Met Pro Gly Asp Tyr Asp Val Glu Tyr Ala Ser Pro Phe
35 40 45
Ala Gly Ala Asn His Ser Pro Met Ala Thr Glu Glu Ser Ser Glu Trp
50 55 60
Glu Arg Arg Thr Trp Tyr Glu Phe Lys Arg Leu Val Glu Glu Val Pro
65 70 75 80
Glu Ala Gly Val His Phe Gln Lys Ser Arg Ile Gln Arg Arg Asn Val
85 90 95
Asp Thr Glu Lys Ala Gln Arg Ser Gly Phe Pro Asp Ala Leu Phe Ser
100 105 110
Lys Glu Pro Trp Phe Lys Asn Met Phe Glu Asp Phe Arg Glu Gln His
115 120 125
Pro Ser Glu Val Ile Pro Gly Tyr Asp Ser Gly Cys Glu Phe Thr Ser
130 135 140
Val Cys Ile Asn Thr Ala Ile Tyr Leu Pro Trp Leu Leu Gly Gln Cys
145 150 155 160
Leu Lys Asn Gly Val Ile Val Lys Arg Ala Ile Leu Asn Asp Ile Ser
165 170 175
Glu Ala Lys Lys Leu Ser His Ala Gly Lys Thr Pro Asn Ile Ile Val
180 185 190
Asn Ala Thr Gly Leu Gly Ser Tyr Lys Leu Gly Gly Val Glu Asp Lys
195 200 205
Thr Met Ala Pro Ala Arg Gly Gln Ile Val Val Val Arg Asn Glu Ser
210 215 220
Ser Pro Met Leu Leu Thr Ser Gly Val Glu Asp Gly Gly Ala Asp Val
225 230 235 240
Met Tyr Leu Met Gln Arg Ala Ala Gly Gly Gly Thr Ile Leu Gly Gly
245 250 255
Thr Tyr Asp Val Gly Asn Trp Glu Ser Gln Pro Asp Pro Asn Ile Ala
260 265 270
Asn Arg Ile Met Gln Arg Ile Val Glu Val Arg Pro Glu Ile Ala Asn
275 280 285
Gly Lys Gly Val Lys Gly Leu Ser Val Ile Arg His Ala Val Gly Met
290 295 300
Arg Pro Trp Arg Lys Asp Gly Leu Arg Ile Glu Glu Glu Lys Leu Asp
305 310 315 320
Asp Glu Thr Trp Ile Val His Asn Tyr Gly His Ser Gly Trp Gly Tyr
325 330 335
Gln Gly Ser Tyr Gly Cys Ala Glu Asn Val Val Gln Leu Val Asp Lys
340 345 350
Val Gly Lys Ala Ala Lys Ser Lys Leu
355 360
<210> 2
<211> 361
<212> PRT
<213> 人(Homo)
<400> 2
Met Ala Asn Thr Ile Ile Val Val Gly Ala Gly Val Ser Gly Leu Thr
1 5 10 15
Ser Ala Tyr Leu Leu Ser Lys Asn Lys Gly Asn Lys Ile Thr Val Val
20 25 30
Ala Lys His Met Pro Gly Asp Tyr Asp Ile Glu Tyr Ala Ser Pro Phe
35 40 45
Ala Gly Ala Asn Val Cys Pro Met Ala Thr Gln Glu Asn Ser Arg Trp
50 55 60
Glu Arg Arg Thr Trp Val Glu Phe Lys Arg Leu Cys Glu Gln Val Pro
65 70 75 80
Glu Ala Gly Ile His Phe Gln Lys Cys His Ile Ala Arg Arg Lys Lys
85 90 95
Asp Val Glu Glu Ala Lys Ser Ser Thr Phe Pro Asp Ala Leu Phe Gln
100 105 110
Glu Glu Pro Trp Tyr Lys Glu Leu Phe Glu Asp Phe Arg Glu Gln Asn
115 120 125
Pro Asn Glu Val Thr Arg Gly Tyr Asp Ser Gly Cys Glu Phe Thr Ser
130 135 140
Val Cys Ile Asn Thr Ala Ile Tyr Leu Pro Trp Leu Ala Gly Gln Cys
145 150 155 160
Leu Lys Asn Gly Val Val Leu Lys Arg Thr Ile Leu Thr Asp Ile Ser
165 170 175
Glu Ala Lys Lys Leu Ser His Thr Gly Lys Val Pro Asn Ile Ile Val
180 185 190
Asn Ala Thr Gly Leu Gly Ser Leu Lys Leu Gly Gly Val Lys Asp Glu
195 200 205
Thr Met Ala Pro Ala Arg Gly Gln Ile Val Val Val Arg Asn Glu Ser
210 215 220
Thr Pro Met Leu Ile Thr Ser Gly Val Glu Asp Gly Gly Ser Asp Val
225 230 235 240
Met Tyr Leu Met Gln Arg Ala Ala Gly Gly Gly Thr Ile Leu Gly Gly
245 250 255
Thr Tyr Asp Val Gly Asn Trp Glu Ser Gln Pro Asp Pro Asn Ile Ala
260 265 270
Gln Arg Ile Met Gln Arg Ile Val Glu Ala Arg Pro Glu Val Ala Asp
275 280 285
Gly Lys Gly Val Lys Gly Leu Ser Ile Ile Arg His Ala Val Gly Leu
290 295 300
Arg Pro Trp Arg Lys Gly Gly Leu Arg Leu Glu Glu Glu Lys Leu Asp
305 310 315 320
Asp Glu Thr Trp Ile Val His Asn Tyr Gly His Ser Gly Trp Gly Tyr
325 330 335
Gln Gly Ser Tyr Gly Cys Ala Glu Gly Val Val Glu Leu Val Asp Lys
340 345 350
Val Gly Lys Gly Ala Lys Ala Lys Leu
355 360
<210> 3
<211> 361
<212> PRT
<213> 人(Homo)
<400> 3
Met Ala Asn Thr Ile Val Val Val Gly Ala Gly Val Ser Gly Leu Thr
1 5 10 15
Ser Ala Tyr Leu Leu Ser Lys Asn Lys Gly Asn Lys Ile Thr Val Val
20 25 30
Gly Lys His Met Pro Gly Asp Tyr Asp Ile Glu Tyr Ala Ser Pro Phe
35 40 45
Ala Gly Ala Asn Val Cys Pro Met Ala Thr Gln Glu Asn Ser Arg Trp
50 55 60
Glu Arg Arg Thr Trp Val Glu Phe Lys Arg Leu Cys Glu Gln Val Pro
65 70 75 80
Glu Ala Gly Ile His Phe Gln Lys Cys His Ile Ala Arg Arg Lys Lys
85 90 95
Asp Val Glu Glu Ala Lys Ser Asn Thr Phe Pro Asp Ala Leu Phe Gln
100 105 110
Glu Glu Pro Trp Tyr Lys Glu Leu Phe Glu Asp Phe Arg Glu Leu Asn
115 120 125
Pro Ser Glu Val Thr Arg Gly Tyr Asp Thr Gly Cys Glu Phe Thr Ser
130 135 140
Val Cys Ile Asn Thr Ala Ile Tyr Leu Pro Trp Leu Ala Gly Gln Cys
145 150 155 160
Leu Lys Lys Gly Val Val Ile Lys Arg Ala Ser Leu Thr Asp Ile Ser
165 170 175
Glu Ala Lys Lys Leu Ser His Thr Gly Asn Val Pro Asn Ile Ile Val
180 185 190
Asn Ala Thr Gly Leu Gly Ser Leu Lys Leu Gly Gly Val Lys Asp Glu
195 200 205
Thr Met Ala Pro Ala Arg Gly Gln Ile Val Val Val Arg Asn Glu Ser
210 215 220
Thr Pro Met Leu Ile Thr Ser Gly Val Glu Asp Gly Gly Ser Asp Val
225 230 235 240
Met Tyr Leu Met Gln Arg Ala Ala Gly Gly Gly Thr Ile Leu Gly Gly
245 250 255
Thr Tyr Asp Ile Gly Asn Trp Glu Ser Gln Pro Asp Pro Asn Val Ala
260 265 270
Gln Arg Ile Leu Gln Arg Ile Val Glu Ala Arg Pro Glu Val Ala Asp
275 280 285
Gly Lys Gly Val Lys Gly Leu Ser Ile Ile Arg His Ala Val Gly Leu
290 295 300
Arg Pro Trp Arg Lys Asp Gly Leu Arg Leu Glu Glu Glu Lys Leu Asp
305 310 315 320
Asp Glu Thr Trp Ile Val His Asn Tyr Gly His Ser Gly Trp Gly Tyr
325 330 335
Gln Gly Ser Tyr Gly Cys Ala Glu Gly Val Val Glu Leu Val Asp Lys
340 345 350
Val Gly Lys Gly Ala Lys Ala Lys Leu
355 360
<210> 4
<211> 356
<212> PRT
<213> 人(Homo)
<400> 4
Met Ala Lys Ile Val Val Ile Gly Ala Gly Val Ala Gly Leu Thr Thr
1 5 10 15
Ala Leu Gln Leu Leu Arg Lys Gly His Glu Val Thr Ile Val Ser Glu
20 25 30
Phe Thr Pro Gly Asp Leu Ser Ile Gly Tyr Thr Ser Pro Trp Ala Gly
35 40 45
Ala Asn Trp Leu Thr Phe Tyr Asp Gly Gly Lys Leu Ala Asp Tyr Asp
50 55 60
Ala Val Ser Tyr Pro Ile Leu Arg Glu Leu Ala Arg Ser Ser Pro Glu
65 70 75 80
Ala Gly Ile Arg Leu Ile Ser Gln Arg Ser His Val Leu Lys Arg Asp
85 90 95
Leu Pro Lys Leu Glu Val Ala Met Ser Ala Ile Cys Gln Arg Asn Pro
100 105 110
Trp Phe Lys Asn Thr Val Asp Ser Phe Glu Ile Ile Glu Asp Arg Ser
115 120 125
Arg Ile Val His Asp Asp Val Ala Tyr Leu Val Glu Phe Arg Ser Val
130 135 140
Cys Ile His Thr Gly Val Tyr Leu Asn Trp Leu Met Ser Gln Cys Leu
145 150 155 160
Ser Leu Gly Ala Thr Val Val Lys Arg Arg Val Asn His Ile Lys Asp
165 170 175
Ala Asn Leu Leu His Ser Ser Gly Ser Arg Pro Asp Val Ile Val Asn
180 185 190
Cys Ser Gly Leu Phe Ala Arg Phe Leu Gly Gly Val Glu Asp Lys Lys
195 200 205
Met Tyr Pro Ile Arg Gly Gln Val Val Leu Val Arg Asn Ser Leu Pro
210 215 220
Phe Met Ala Ser Phe Ser Ser Thr Pro Glu Lys Glu Asn Glu Asp Glu
225 230 235 240
Ala Leu Tyr Ile Met Thr Arg Phe Asp Gly Thr Ser Ile Ile Gly Gly
245 250 255
Cys Phe Gln Pro Asn Asn Trp Ser Ser Glu Pro Asp Pro Ser Leu Thr
260 265 270
His Arg Ile Leu Ser Arg Ala Leu Asp Arg Phe Pro Glu Leu Thr Lys
275 280 285
Asp Gly Pro Leu Asp Ile Val Arg Glu Cys Val Gly His Arg Pro Gly
290 295 300
Arg Glu Gly Gly Pro Arg Val Glu Leu Glu Lys Ile Pro Gly Val Gly
305 310 315 320
Phe Val Val His Asn Tyr Gly Ala Ala Gly Ala Gly Tyr Gln Ser Ser
325 330 335
Tyr Gly Met Ala Asp Glu Ala Val Ser Tyr Val Glu Arg Ala Leu Thr
340 345 350
Arg Pro Asn Leu
355
Claims (17)
1.一种制备如式(I)所示的化合物的方法，
式(I)中，R1，R2独立地选自氢、C1-C6烷基，C1-C6烷氧基，其特征在于，所述方法包括：
(1)以所述式(I)化合物的外消旋体或式(I)化合物的盐的外消旋体为底物，利用D-氨基酸氧化酶作为催化剂，选择性催化式(I)化合物的R型异构体进行氧化脱氢反应，生成亚胺酸，而式(I)化合物未被催化，保留在反应体系中；
其中，在进行所述氧化脱氢反应前、所述氧化脱氢反应过程中和所述氧化脱氢反应后中的一个或多个时间点向所述反应体系中加入亚胺酸还原剂，所述亚胺酸还原剂用于使所述氧化脱氢反应生成的所述亚胺酸被还原为所述式(I)化合物的外消旋体或式(I)化合物的盐的外消旋体；
所述D-氨基酸氧化酶为选自如下D-氨基酸氧化酶中的一种或多种的组合：来源于三角酵母(Trigonopsis variabilis)CBS 4095的D-氨基酸氧化酶、来自禾谷镰刀菌(Fusariumgraminearum)CS3005的D-氨基酸氧化酶、来自梨孢镰刀菌(Fusarium poae)2516的D-氨基酸氧化酶、来自茄病镰刀菌(Fusarium solani)M-0718的D-氨基酸氧化酶；
(2)将所述式(I)化合物与反应体系分离。
2.如权利要求1所述的方法，其特征在于，式(I)中，R1，R2独立地选自氢、甲基、乙基、异丙基、甲氧基或乙氧基，所述的盐为碱金属盐或铵盐。
3.如权利要求1所述的方法，其特征在于，所述的式(I)所示的化合物为(S)-1,2,3,4-四氢异喹啉-1-甲酸或(S)-6,7-二甲氧基-1,2,3,4-四氢异喹啉-1-甲酸。
4.如权利要求1所述的方法，其特征在于，所述催化剂为含有离体的所述D-氨基酸氧化酶的粗酶液或胞内表达所述D-氨基酸氧化酶的细胞或者所述D-氨基酸氧化酶的纯酶或者所述D-氨基酸氧化酶的固定化酶。
5.如权利要求4所述的方法，其特征在于，所述细胞为表达D-氨基酸氧化酶的工程菌，所述工程菌的宿主细胞为E.coliBL21(DE3)。
6.如权利要求5所述的方法，其特征在于，所述工程菌含有表达载体pET-28a(+)，所述D-氨基酸氧化酶基因连接在表达载体pET-28a(+)上。
7.如权利要求1所述的方法，其特征在于，使所述氧化脱氢反应在有氧环境中进行，所述氧化脱氢反应还生成过氧化氢，所述方法还包括在进行所述氧化脱氢反应前、所述氧化脱氢反应过程中和所述氧化脱氢反应后中的一个或多个时间点还向所述反应体系中加入用于催化分解所述过氧化氢的过氧化氢酶。
8.如权利要求7所述的方法，其特征在于，所述过氧化氢酶为牛肝过氧化氢酶冻干粉。
9.如权利要求7所述的方法，其特征在于，所述过氧化氢酶与所述D-氨基酸氧化酶的酶活比为100～400：1。
10.如权利要求1所述的方法，其特征在于，步骤(1)中，使所述反应在辅酶黄素腺嘌呤二核苷酸存在下进行。
11.如权利要求1所述的方法，其特征在于，步骤(1)中，首先构建所述反应体系，然后控制所述反应体系处于设定温度和有氧环境中进行反应，所述反应体系包括所述底物、所述催化剂、溶剂，所述反应体系还选择性的包括pH缓冲剂和/或pH调节剂。
12.如权利要求11所述的方法，其特征在于，步骤(1)中，所述反应体系还包括所述的亚胺酸还原剂和/或用于催化分解过氧化氢的过氧化氢酶。
13.如权利要求11所述的方法，其特征在于，所述溶剂是水，先将底物溶解于所述pH缓冲剂的水溶液中，再选择性的加入所述pH调节剂，配制pH值为6～9的底物溶液，然后加入所述催化剂、亚胺酸还原剂和/或过氧化氢酶，得到所述反应体系。
14.如权利要求11所述的方法，其特征在于，步骤(1)中，控制所述反应体系中起始底物的浓度为1～20g/L。
15.如权利要求11所述的方法，其特征在于，所述设定温度为20～70℃。
16.如权利要求1所述的方法，其特征在于，所述亚胺酸还原剂为选自氰基硼氢化钠、硼烷胺和硼氢化钠中的一种或多种的组合。
17.如权利要求1或16所述的方法，其特征在于，所述亚胺酸还原剂的添加量为所述底物投料摩尔量的3～10个当量。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810275135.7A CN110317849B (zh) | 2018-03-30 | 2018-03-30 | 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 |
| PCT/CN2019/079814 WO2019184936A1 (zh) | 2018-03-30 | 2019-03-27 | 一种制备(s)-1，2，3，4-四氢异喹啉-1-甲酸及其衍生物的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810275135.7A CN110317849B (zh) | 2018-03-30 | 2018-03-30 | 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110317849A CN110317849A (zh) | 2019-10-11 |
| CN110317849B true CN110317849B (zh) | 2020-12-08 |
Family
ID=68062557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810275135.7A Active CN110317849B (zh) | 2018-03-30 | 2018-03-30 | 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110317849B (zh) |
| WO (1) | WO2019184936A1 (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5955471A (en) * | 1998-01-13 | 1999-09-21 | Sk Corporation | Tetrahydroisoquinolinealkanol derivatives and pharmaceutical compositions containing same |
| CN104557911A (zh) * | 2013-10-17 | 2015-04-29 | 苏州同力生物医药有限公司 | 一种左旋吡喹酮的制备方法 |
| CN105237532A (zh) * | 2014-12-05 | 2016-01-13 | 苏州同力生物医药有限公司 | 一种左旋吡喹酮的合成方法及其中间体 |
| CN107384885A (zh) * | 2017-09-05 | 2017-11-24 | 武汉大学 | 亚胺还原酶及其突变体在合成(s)‑1‑芳基‑1，2，3，4‑四氢异喹啉中的应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1900821A4 (en) * | 2005-06-09 | 2011-12-21 | Daicel Chem | PROCESS FOR THE PRODUCTION OF L-FORM AMINO ACID |
| EP1918375B1 (en) * | 2005-08-02 | 2015-03-11 | Kaneka Corporation | D-amino acid oxidase, and method for production of l-amino acid, 2-oxo acid or cyclic imine |
-
2018
- 2018-03-30 CN CN201810275135.7A patent/CN110317849B/zh active Active
-
2019
- 2019-03-27 WO PCT/CN2019/079814 patent/WO2019184936A1/zh active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5955471A (en) * | 1998-01-13 | 1999-09-21 | Sk Corporation | Tetrahydroisoquinolinealkanol derivatives and pharmaceutical compositions containing same |
| CN104557911A (zh) * | 2013-10-17 | 2015-04-29 | 苏州同力生物医药有限公司 | 一种左旋吡喹酮的制备方法 |
| CN105237532A (zh) * | 2014-12-05 | 2016-01-13 | 苏州同力生物医药有限公司 | 一种左旋吡喹酮的合成方法及其中间体 |
| CN107384885A (zh) * | 2017-09-05 | 2017-11-24 | 武汉大学 | 亚胺还原酶及其突变体在合成(s)‑1‑芳基‑1，2，3，4‑四氢异喹啉中的应用 |
Non-Patent Citations (3)
| Title |
|---|
| Deracemisation methods;Nicholas J Turner;《Current Opinion in Chemical Biology》;20100430;第14卷(第2期);全文 * |
| Engineering an Enantioselective Amine Oxidase for the Synthesis of Pharmaceutical Building Blocks and Alkaloid Natural Products;Diego Ghislieri,等;《Journal of the American Chemical Society》;20180628;第135卷(第29期);第10866页第3段和图4，第10867页第2段和方案2 * |
| 基于各种拆分方法的四氢异喹啉生物_省略_性亚磺酰胺和顺式哌虫啶的合成研究;朱瑞恒;《中国博士学位论文全文数据库》;20140615;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2019184936A1 (zh) | 2019-10-03 |
| CN110317849A (zh) | 2019-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2017119731A1 (ko) | Co 수화효소 및 이를 이용한 개미산의 제조방법 | |
| CN110628841B (zh) | 酶催化不对称合成右美沙芬关键中间体的新方法 | |
| CN109971802B (zh) | 一种酶法拆分制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 | |
| CN110184288A (zh) | 没食子酸和原儿茶酸的制备方法及其反应催化剂的制备方法 | |
| CN110835639B (zh) | 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 | |
| CN111254181B (zh) | 一种化学酶法制备(s)-1,2,3,4-四氢异喹啉-3-甲酸的方法 | |
| CN111254180B (zh) | 一种酶法拆分制备(s)-1,2,3,4-四氢异喹啉-3-甲酸的方法 | |
| KR101803174B1 (ko) | 코돈 최적화된 사이클로스포린 특이적 p450 수산화효소 및 이를 이용한 대장균 기반의 최적화된 사이클로스포린 생전환 방법 | |
| CN110317849B (zh) | 一种制备(s)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 | |
| CN111254170B (zh) | 一种多酶耦合制备(s)-1,2,3,4-四氢异喹啉-3-甲酸的方法 | |
| CN114891707B (zh) | 重组菌株及其全细胞催化生产胆红素的方法 | |
| CN110643650B (zh) | （s）-1-苄基-1，2，3，4，5，6，7，8-八氢异喹啉类化合物的制备方法 | |
| CN112442523B (zh) | 一种酶法拆分制备(r)-1,2,3,4-四氢异喹啉-1-甲酸及其衍生物的方法 | |
| AU2020103435A4 (en) | Method for preparing (s)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and derivatives thereof | |
| CN114480315B (zh) | 一种Baeyer-Villiger单加氧酶及其在布立西坦合成中的应用 | |
| Carminati et al. | Strategies for the expression and characterization of artificial myoglobin-based carbene transferases | |
| CN114736882B (zh) | 一种单胺氧化酶及其应用 | |
| CN110004119B (zh) | ε-酮酯还原酶突变体及其催化合成(R)-α-硫辛酸前体的应用 | |
| CN114317631B (zh) | 单胺氧化酶在制备托品酮中的应用 | |
| CN112852768B (zh) | 羰基还原酶突变体及其应用 | |
| CN109722456B (zh) | 一种丙烯酸的生物合成方法及应用 | |
| CN115109760A (zh) | 单胺氧化酶及其在制备药物中间体中的应用 | |
| CN116790686A (zh) | 一种生物酶法催化合成(r)-2-(1-氨乙基)-4-氟苯酚的方法 | |
| CN117448294A (zh) | 一组单萜合成酶及其应用与一种催化合成d-柠檬烯的方法 | |
| CN116710549A (zh) | 使用苯丙氨酸氨裂合酶的链状不饱和羧酸化合物的制造方法 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |