CN115340472B - Glutamic acid derivative and synthesis method and application thereof - Google Patents
Glutamic acid derivative and synthesis method and application thereof Download PDFInfo
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- CN115340472B CN115340472B CN202211135753.4A CN202211135753A CN115340472B CN 115340472 B CN115340472 B CN 115340472B CN 202211135753 A CN202211135753 A CN 202211135753A CN 115340472 B CN115340472 B CN 115340472B
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- 150000002306 glutamic acid derivatives Chemical class 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 57
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 21
- 229920001184 polypeptide Polymers 0.000 claims abstract description 17
- 125000006239 protecting group Chemical group 0.000 claims abstract description 16
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 claims abstract description 9
- GOPWHXPXSPIIQZ-HXUWFJFHSA-N (4r)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-HXUWFJFHSA-N 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 93
- 238000006243 chemical reaction Methods 0.000 claims description 26
- -1 1- (tert-butyl) 5- (2- (4-methoxyphenyl) -2-oxo-ethyl) (((9H-fluoren-9-yl) methoxy) carbonyl) Chemical group 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 229960002989 glutamic acid Drugs 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000007790 solid phase Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract description 6
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 229920005989 resin Polymers 0.000 description 31
- 239000011347 resin Substances 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 4
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 4
- OJGYAUWOAQHIQD-UHFFFAOYSA-N 4-methoxy-7-nitro-2,3-dihydro-1h-indole Chemical compound COC1=CC=C([N+]([O-])=O)C2=C1CCN2 OJGYAUWOAQHIQD-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229920003180 amino resin Polymers 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 102000000470 PDZ domains Human genes 0.000 description 2
- 108050008994 PDZ domains Proteins 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101000925646 Enterobacteria phage T4 Endolysin Proteins 0.000 description 1
- 241000701533 Escherichia virus T4 Species 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a glutamic acid derivative, a synthesis method and application thereof, wherein the molecular structure of the glutamic acid derivative is shown as follows: The invention firstly carries out substitution reaction on commercially purchased N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester and alpha-bromo-4-methoxyacetophenone, and then removes tert-butyl ester serving as carboxyl protecting group of main glutamic acid chain, thus obtaining the glutamic acid derivative with photosensitive groups on side chains. The glutamic acid derivative disclosed by the invention can be compatible with polypeptide solid-phase synthesis and is used for preparing and producing various polypeptides requiring light-operated protecting groups.
Description
Technical Field
The invention relates to a glutamic acid derivative compatible with solid phase synthesis and provided with a photosensitive p-methoxybenzoyl group on a side chain, and a synthesis method and application thereof, and belongs to the technical field of protein synthesis.
Background
The biological functions of the light cage peptide and the protein are inhibited by the photocleavable protecting group, and the activity of the light cage peptide and the protein can be recovered under the irradiation of light. These compounds are widely used to detect and elucidate complex biological processes because illumination can be precisely controlled in a non-invasive manner in terms of space, time and amplitude. Side chain cage forms of serine, threonine, tyrosine, cysteine, lysine, arginine, glutamine, aspartic acid, and glutamic acid (Glu) have been reported. Among these functions, carboxylic acid groups play an important role in protein activity and protein interactions with other biological macromolecules or small molecules. Peptide and protein derivatives that are carboxylic acid moiety-entrapped have been developed to study biochemical mechanisms and protein-protein/ligand interactions.
For example, the article (J.am.chem.Soc.1991, 113, 2758-2760.) reports a method for triggering an enzymatic reaction by photoactivatable phage T4 lysozyme containing aspartyl b-nitrobenzyl ester in the active site Asp 20. Also, the article (J.am.chem.Soc.2013, 135, 4580-4583.) reports methods of introducing a photolabile blocking group into the basic C-terminal carboxylate of a PDZ domain ligand to take advantage of synaptic PDZ domain-mediated interactions.
In general, caged peptides are synthesized by standard Solid Phase Peptide Synthesis (SPPS) methods, which provides maximum flexibility in designing caged peptides and protein derivatives. Articles (J.biomed. Mater. Res. PartA 2013,101A, 787-796) produced a photoactivatable peptide containing "RGD" by modifying the carboxylic acid of Asp with 2-nitrobenzyl (2-NB). However, the photochemical and photophysical properties of 2-NB limit its further application in biological processes. 4, 5-Dimethoxynitrobenzyl (DMNB) reported in the article (Peptides 2007,28,1074-1082.) has improved photochemical properties, but it was not incorporated into side chain carboxylic acids during Fmoc SPPS due to the formation of asparagine and pyrrolidone side reactions by Asp (ODMNB) and Glu (ODMNB). The article (Tetrahedron letters, 56 (2015), pp.4582-4585) reports a method for synthesizing a light cage peptide by modification of 4-methoxy-7-nitroindoline (MNI) to derive Asp and Glu. MNI cages have excellent photochemical properties and rapid photolytic kinetics, but the synthesis steps are cumbersome.
Thus, there remains a need for new Fmoc-compatible methods to simply and quickly generate side chain carboxyl blocking peptides/proteins with good photochemical properties.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a glutamic acid derivative compatible with solid phase synthesis and provided with a photosensitive p-methoxybenzoyl group on a side chain, and a synthesis method and application thereof.
The invention firstly carries out substitution reaction on commercially purchased N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester and alpha-bromo-4-methoxyacetophenone, and then removes tert-butyl ester serving as carboxyl protecting group of main glutamic acid chain, thus obtaining the glutamic acid derivative with photosensitive groups on side chains. The glutamic acid derivative disclosed by the invention can be compatible with polypeptide solid-phase synthesis and is used for preparing and producing various polypeptides requiring light-operated protecting groups.
The glutamic acid derivative is abbreviated as Fmoc-Glu (cage) -OH, and has the structural formula shown as follows:
The invention firstly carries out substitution reaction on commercially purchased N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester and alpha-bromo-4-methoxyacetophenone, and then removes tert-butyl ester serving as carboxyl protecting group of main glutamic acid chain, thus obtaining the glutamic acid derivative with photosensitive groups on side chains. The synthetic route is as follows:
The invention discloses a synthesis method of glutamic acid derivative Fmoc-Glu (cage) -OH, which specifically comprises the following steps:
Step 1: synthesis of Compound I
The compound I-1- (tert-butyl) 5- (2- (4-methoxyphenyl) -2-oxoethyl) (((9H-fluoren-9-yl) methoxy) carbonyl) -L-glutamic acid was isolated by dissolving commercially available 1-tert-butyl-D-glutamate with alpha-bromo-4-methoxyacetophenone in dry Dichloromethane (DCM) and adding solid particles of potassium carbonate under argon, stirring at 40 ℃ for 24 hours, concentrating in vacuo after completion of the reaction and purifying by column chromatography.
In the step 1, the molar ratio of the N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester, alpha-bromo-4-methoxyacetophenone and potassium carbonate is 1:1.2:1.5.
Step 2: synthesis of target product
Dissolving a compound I in Dichloromethane (DCM), placing in an ice bath, stirring and cooling to 0 ℃, slowly dropwise adding trifluoroacetic acid (TFA) solution into a reaction system, reacting for 1 hour, removing the ice bath, restoring to room temperature, and continuing stirring and reacting for 6 hours; after the reaction, the solvent is removed by vacuum concentration, and the pure target product (S) -2- (((((9H-fluorene-9-yl) methoxy) carbonyl) amino) -5- (2- (4-methoxyphenyl) -2-oxo ethoxy) -5-oxo valeric acid is obtained.
In step2, the molar ratio of compound I to trifluoroacetic acid (TFA) is 1:60.
In step2, the volume ratio of Dichloromethane (DCM) to trifluoroacetic acid (TFA) in the reaction system was 1:1.
The glutamic acid derivative is used as a special protected amino acid, and is connected to polypeptides by a common N-fluorenylmethoxycarbonyl (Fmoc) solid-phase polypeptide synthesis method, so that various polypeptides requiring light-operated protecting groups are obtained.
The reaction process is schematically as follows:
the beneficial effects of the invention are as follows:
the invention discloses a glutamic acid derivative with a photosensitive p-methoxybenzoyl group on a side chain, a synthesis method and application thereof, wherein the light-operated protection glutamic acid can be compatible with Fmoc solid-phase synthesis for chemically synthesizing polypeptide requiring light-operated protection, and the synthesis method has the characteristics of high synthesis efficiency, simple synthesis steps, high product purity and capability of mass preparation.
Drawings
FIG. 1 is a (Compound I) hydrogen spectrum of Compound I-1- (tert-butyl) 5- (2- (4-methoxyphenyl) -2-oxoethyl) (((9H-fluoren-9-yl) methoxy) carbonyl) -L-glutamic acid hydrogen spectrum-CDCl 3.
FIG. 2 is a hydrogen spectrum of the compound (S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- (2- (4-methoxyphenyl) -2-oxoethoxy) -5-oxopentanoic acid (Fmoc-Glu (cage) -OH).
FIG. 3 is a carbon spectrum of the compound (S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- (2- (4-methoxyphenyl) -2-oxoethoxy) -5-oxopentanoic acid (Fmoc-Glu (cage) -OH).
FIG. 4 is a high performance liquid chromatogram of linear polypeptide ARKGKIKPKA-NH 2 prior to ligation of Glu (cage) molecules.
FIG. 5 is a mass spectrum of linear polypeptide ARKGKIKPKA prior to ligation of Glu (cage) molecules.
FIG. 6 is a high performance liquid chromatogram of linear polypeptide GLE (cage) ARKGKIKPKA following ligation of Glu (cage) molecules.
FIG. 7 is a mass spectrum of linear polypeptide GLE (cage) ARKGKIKPKA following ligation of Glu (cage) molecules.
FIG. 8 is a high performance liquid chromatogram of a solid crude peptide SKGLE (cage) ARKGKIKPKA with photo-controlled molecules.
FIG. 9 is a mass spectrum of a solid crude peptide SKGLE (cage) ARKGKIKPKA with photo-controlled molecules.
FIG. 10 is a high performance liquid chromatogram of photopheresis peptide SKGLEARKGKIKPKA.
FIG. 11 is a mass spectrum of photoperiod peptide SKGLEARKGKIKPKA.
FIG. 12 is a high performance liquid chromatogram of solid crude peptide AE (cage) FGLKLDRIG with photo-controlled molecules.
FIG. 13 is a mass spectrum of solid crude peptide AE (cage) FGLKLDRIG with photo-controlled molecules.
FIG. 14 is a high performance liquid chromatogram of photopheresis peptide AEFGLKLDRIG.
FIG. 15 is a mass spectrum of photoperiod peptide AEFGLKLDRIG.
FIG. 16 is a high performance liquid color chart comparing the solid crude peptide AE (cage) FGLKLDRIG before and after removal of the photo-control molecule.
Detailed Description
In order that the invention may be readily understood, a further description of the invention will be rendered by reference to specific embodiments that are merely provided to illustrate the features and advantages of the invention and are not to be construed as limiting the invention to the appended claims.
Example 1:
1. Commercially available N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester (850 mg,1.74 mmol) and alpha-bromo-4-methoxyacetophenone (474 mg,2.08 mmol) were dissolved in 10mL of dried Dichloromethane (DCM) and simultaneously potassium carbonate solid particles (312 mg,2.26 mmol) were added, the reaction was stirred at 40℃for 24 hours under argon, after completion of the reaction, the reaction solution was concentrated in vacuo and isolated by column chromatography purification to give compound I-1- (tert-butyl) 5- (2- (4-methoxyphenyl) -2-oxoethyl) (((9H-fluoren-9-yl) methoxy) carbonyl) -L-glutamic acid (897.6 mg,1.57 mmol) in 90% yield.
2. Compound I (897.6 mg,1.57 mmol) was dissolved in 7mL of Dichloromethane (DCM), placed in an ice bath and stirred to cool to 0℃and 7mL of trifluoroacetic acid (TFA) solution was slowly added dropwise to the reaction system, after 1 hour of reaction, the ice bath was removed and the temperature was returned to room temperature and stirring was continued for 6 hours. After the reaction was completed, the solvent was removed by vacuum concentration to give the pure target product, (S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- (2- (4-methoxyphenyl) -2-oxoethoxy) -5-oxopentanoic acid (Fmoc-Glu (cage) -OH) (731 mg,1.42 mmol), in a yield of 90%.
Example 2:
263.15mg (0.1 mmol) of amino resin having a degree of substitution of 0.38mmol/g was weighed, 10ml of N, N-Dimethylformamide (DMF)/dichloromethane solution (DCM) was added to the resin, the resin was swollen, and the volume ratio of the added solution was: DMF: DCM=1:1, swelling time is 10 minutes, and the swelled product is pumped out by using a diaphragm pump as a power source to obtain the swelled resin.
20% Piperidine was added to the resin and reacted for 10 minutes to completely remove the Fmoc protecting group of the amino group on the resin, and then washed three times with DMF, DCM, DMF each to remove the residual piperidine and the detached small molecule protecting group after the reaction.
The first amino acid Fmoc-Ala-OH (124.53 mg,0.4mmol,4 eq.) and the condensing agent 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate (HCTU, 157.20mg,0.38mmol,3.8 eq.) were dissolved in 4ml DMF, activated for 1 min with N, N-diisopropylethylamine (DIEA, 132. Mu.l, 0.8mmol,8 eq.) and added to the above amino resin, and put into a shaker for 30min at ambient temperature; after completion of the reaction, each was washed three times with DMF, DCM, DMF. Fmoc-Ala-OH (124.53 mg,0.4mmol,4 eq.) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 144.49mg,0.38mmol,3.8 eq.) and N-hydroxy-7-azabenzotriazole (HOAt, 51.60mg,0.38mmol,3.8 eq.) were added and DIEA (132. Mu.l, 0.8mmol,8 eq.) were dissolved in DMF and put into the resin for 30 minutes; after the completion of the reaction, the resin was washed three times with DMF, DCM, DMF portions of each, then a DMF solution containing 20% (volume fraction) piperidine was added to the resin, and after 5 minutes of the reaction, the resin was washed three times with DMF, DCM, DMF portions of each, and then 20% piperidine was added to the resin again to react for 10 minutes to completely remove the Fmoc protecting group of the amino group on the resin, and then washed three times with DMF, DCM, DMF portions of each to remove the residual piperidine and the detached small molecule protecting group, and the resin was washed with DMF, DCM, DMF portions of each. The subsequent amino acid condensation proceeds similarly until all sequences complete solid phase condensation, ultimately obtaining a linear Fmoc-S (tBu) K (Boc) GLE (cage) AR (Pbf) K (Boc) GK (Boc) IK (Boc) PK (Boc) A-NH 2 resin. The Fmoc protecting group at the N-terminal was removed in two steps with a DMF solution containing 20% piperidine and washed three times with DMF, DCM, DMF, DCM portions each followed by removal of the residual DCM solvent from the resin under reduced pressure to give a dry resin.
Example 3:
To the resin obtained in example 2, 10ml of a pre-prepared cleavage reagent (a mixture of trifluoroacetic acid, phenol, water and triisopropylsilane in a volume ratio of trifluoroacetic acid to water to phenol to triisopropylsilane=88:5:5:2) was added, and the reaction was carried out at room temperature for 2.5 hours, the polypeptide chain was cleaved from the resin, and then the filtrate was collected into a centrifuge tube, and the cleavage liquid was concentrated by a nitrogen bubbling method. Finally, after the cleavage liquid was concentrated to 5ml or less, 30ml of glacial ethyl ether was added for sedimentation, and the crude peptide was allowed to settle to the bottom by centrifugation with a low-speed centrifuge (4500 rpm). Removing supernatant, adding glacial ethyl ether again, ultrasonic treating to form coarse peptide suspension, dissolving small molecule impurity into glacial ethyl ether, and centrifuging. After the completion of the two times, the solid precipitate was air-dried in the shade to obtain 150mg of a solid crude peptide (SKGLE (cage) ARKGKIKPKA) with a photo-controlled molecule.
A small amount of crude peptide was dissolved in pure water, and analyzed by reverse phase high performance liquid chromatography (RP-HPLC) after membrane filtration. The analytical gradient was 10% -70% acetonitrile concentration for 30min. And (3) carrying out ESI-MS identification on the main peak after chromatographic analysis to verify the correctness of the solid crude peptide. After verification, the solid crude peptide was isolated and purified (semi-preparative gradient 10% -70% acetonitrile concentration for 30 min) using a C18 semi-preparative column, and the correct product peak solution was collected and lyophilized in a lyophilizer to give a white flocculent SKGLE (cage) ARKGKIKPKA pure peptide product (112 mg).
Example 4:
The purified peptide product SKGLE (cage) ARKGKIKPKA obtained in example 3 was selected as the target short peptide for further light cage-removal experiments. 1mg SKGLE (cage) ARKGKIKPKA of the pure peptide product was dissolved in 200uL of buffer (6 MGn-HCl,200mM NaH 2 PO4, pH=7.0), placed in an ultraviolet cross-box, placed on flat ice and irradiated with 365nm light for 5min. The reaction was monitored by RP-HPLC. The analytical gradient was 10% -70% acetonitrile concentration for 30min. The main peak was subjected to ESI-MS identification after chromatographic analysis to verify the correctness of the product. The result shows that the pure peptide (CagedForm) of SKGLE (cage) ARKGKIKPKA is mostly converted into SKGLEARKGKIKPKA (NATIVEFORM), which proves that the side chain photosensitive protecting group of Fmoc-Glu (cage) -OH molecule can be well removed under 254nm illumination condition, and has good light cage removal efficiency (see figure 10 and figure 11).
Example 5:
312.5mg (0.1 mmol) of chlorine resin with the substitution degree of 0.32mmol/g is weighed, 10ml of N, N-Dimethylformamide (DMF) solution is added into the resin to swell the resin for 20 minutes, and a diaphragm pump is used as a power source to pump out the swelled product to obtain the swelled resin.
The first amino acid Fmoc-Gly-OH (118.92 mg,0.4mmol,4 eq.) was dissolved in 4ml DMF, N-diisopropylethylamine (DIEA, 132. Mu.l, 0.8mmol,8 eq.) was added to the amino resin after 1 min activation, and the mixture was placed in a shaker and shaken at ambient temperature for 12h; after the completion of the reaction, the resin was washed three times with DMF, DCM, DMF portions of each, a DMF solution containing 20% (volume fraction) piperidine was added to the resin, and after 5 minutes of the reaction, the resin was washed three times with DMF, DCM, DMF portions of each in sequence, and 20% piperidine was added to the resin again to react for 10 minutes to completely remove the Fmoc protecting group of the amino group on the resin. After completion of the reaction, the reaction mixture was washed three times with DMF, DCM, DMF a, fmoc-Ile-OH (141.36 mg,0.4mmol,4 eq.) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 144.49mg,0.38mmol,3.8 eq.) and N-hydroxy-7-azabenzotriazole (HOAt, 51.60mg,0.38mmol,3.8 eq.) were added and DIEA (132. Mu.l, 0.8mmol,8 eq.) were dissolved in DMF and reacted for 30 minutes; the latter amino acid condensation proceeds similarly until all sequences complete solid phase condensation, finally obtaining a linear Fmoc-AE (cage) FGLK (Boc) LD (OtBu) R (Pbf) IG-COOH resin. The Fmoc protecting group at the N-terminal was removed in two steps with a DMF solution containing 20% piperidine and washed three times with DMF, DCM, DMF, DCM portions each followed by removal of the residual DCM solvent from the resin under reduced pressure to give a dry resin.
Example 6:
To the resin obtained in example 5, 10ml of a pre-prepared cleavage reagent (a mixture of trifluoroacetic acid, phenol, water and triisopropylsilane in a volume ratio of trifluoroacetic acid to water to phenol to triisopropylsilane=88:5:5:2) was added, and the reaction was carried out at room temperature for 2.5 hours, the polypeptide chain was cleaved from the resin, and then the filtrate was collected into a centrifuge tube, and the cleavage liquid was concentrated by a nitrogen bubbling method. Finally, after the cleavage liquid was concentrated to 5ml or less, 30ml of glacial ethyl ether was added for sedimentation, and the crude peptide was allowed to settle to the bottom by centrifugation with a low-speed centrifuge (4500 rpm). Removing supernatant, adding glacial ethyl ether again, ultrasonic treating to form coarse peptide suspension, dissolving small molecule impurity into glacial ethyl ether, and centrifuging. After the completion of the two times, the solid precipitate was air-dried in the shade to obtain 118mg of a solid crude peptide (AE (cage) FGLKLDRIG) with a photo-controlled molecule.
A small amount of crude peptide was dissolved in pure water, and analyzed by reverse phase high performance liquid chromatography (RP-HPLC) after membrane filtration. The analytical gradient was 10% -70% acetonitrile concentration for 30min. And (3) carrying out ESI-MS identification on the main peak after chromatographic analysis to verify the correctness of the solid crude peptide. After verification, the solid crude peptide was isolated and purified (semi-preparative gradient 10% -70% acetonitrile concentration for 30 min) using a C18 semi-preparative column, and the correct product peak solution was collected and lyophilized in a lyophilizer to give a white flocculent AE (cage) FGLKLDRIG pure peptide product (76 mg).
Example 7:
The AE (cage) FGLKLDRIG pure peptide product obtained in example 6 was selected as the target short peptide for further light cage-removal experiments. 1mgAE (cage) FGLKLDRIG pure peptide product was dissolved in 200uL buffer (6M Gn-HCl,200mMNaH 2 PO4, pH=7.0) and placed in an ultraviolet cross-box on flat ice and irradiated with 365nm light for 5min. The reaction was monitored by RP-HPLC. The analytical gradient was 10% -70% acetonitrile concentration for 30min. The main peak was subjected to ESI-MS identification after chromatographic analysis to verify the correctness of the product. The result shows that AE (cage) FGLKLDRIG pure peptide (CagedForm) is mostly converted into AEFGLKLDRIG (NATIVEFORM), which proves that the side chain photosensitive protecting group of Fmoc-Glu (cage) -OH molecule can be well removed under 254nm illumination condition, and has good light cage removal efficiency (see figure 14, figure 15 and figure 16).
In summary, the invention discloses a glutamic acid derivative compatible with solid phase synthesis and provided with a photosensitive p-methoxybenzoyl group on a side chain, and a synthesis method and application thereof.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and the present invention is not limited thereto by the order of the examples, and any changes or substitutions easily suggested by those skilled in the art within the technical scope of the present invention should be included in the scope of the present invention.
Claims (2)
1. A synthesis method of glutamic acid derivatives is characterized in that:
firstly, carrying out substitution reaction on N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester and alpha-bromo-4-methoxyacetophenone, and then removing tert-butyl ester serving as a carboxyl protecting group of a glutamic acid main chain, thus obtaining a glutamic acid derivative with a photosensitive group on a side chain;
The synthetic route is as follows:
The synthesis method comprises the following steps:
Step 1: synthesis of Compound I
Dissolving N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester and alpha-bromo-4-methoxyacetophenone in dry dichloromethane, adding potassium carbonate solid particles, stirring at 40 ℃ for 24 hours under the protection of argon, concentrating in vacuo after the reaction is completed, and purifying and separating by column chromatography to obtain a compound I, namely 1- (tert-butyl) 5- (2- (4-methoxyphenyl) -2-oxo-ethyl) (((9H-fluoren-9-yl) methoxy) carbonyl) -L-glutamic acid;
Step 2: synthesis of target product
Dissolving a compound I in dichloromethane, placing in an ice bath, stirring and cooling to 0 ℃, slowly dropwise adding a trifluoroacetic acid solution into a reaction system, reacting for 1 hour, removing the ice bath, restoring the room temperature, and continuing stirring and reacting for 6 hours; after the reaction is finished, the solvent is removed by vacuum concentration, and the pure target product (S) -2- (((((9H-fluorene-9-yl) methoxy) carbonyl) amino) -5- (2- (4-methoxyphenyl) -2-oxo ethoxy) -5-oxo valeric acid is obtained;
in the step 1, the molar ratio of the N- (9-fluorenylmethoxycarbonyl) -D-glutamic acid 1-tert-butyl ester, alpha-bromo-4-methoxyacetophenone and potassium carbonate is 1:1.2:1.5;
in the step 2, the molar ratio of the compound I to the trifluoroacetic acid is 1:60;
in the step 2, the volume ratio of dichloromethane to trifluoroacetic acid in the reaction system is 1:1.
2. The use of the glutamic acid derivative produced by the synthetic method according to claim 1, characterized in that:
the glutamic acid derivative is connected to the polypeptide by an N-fluorenylmethoxycarbonyl Fmoc solid-phase polypeptide synthesis method, so that the polypeptide requiring the light-operated protecting group is obtained.
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