CN109824581A - A kind of class peptides containing alanine with and its preparation method and application - Google Patents
A kind of class peptides containing alanine with and its preparation method and application Download PDFInfo
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- CN109824581A CN109824581A CN201910049081.7A CN201910049081A CN109824581A CN 109824581 A CN109824581 A CN 109824581A CN 201910049081 A CN201910049081 A CN 201910049081A CN 109824581 A CN109824581 A CN 109824581A
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- Prior art keywords
- bromo
- alanine
- added
- class peptides
- peptides containing
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 title claims abstract description 43
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 43
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 43
- 235000004279 alanine Nutrition 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 23
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 23
- 230000000694 effects Effects 0.000 claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 117
- 239000000243 solution Substances 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 18
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical class NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 claims description 17
- -1 (4- chloro- 3- (trifluoromethyl) phenyl) amino Chemical group 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- FQIUCPGDKPXSLL-UHFFFAOYSA-N 5-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(Br)=C1 FQIUCPGDKPXSLL-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- 238000004176 ammonification Methods 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- 230000006837 decompression Effects 0.000 claims description 9
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 claims description 8
- KWNPRVWFJOSGMZ-UHFFFAOYSA-N 2-boronobenzoic acid Chemical compound OB(O)C1=CC=CC=C1C(O)=O KWNPRVWFJOSGMZ-UHFFFAOYSA-N 0.000 claims description 8
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- ASPDJZINBYYZRU-UHFFFAOYSA-N 5-amino-2-chlorobenzotrifluoride Chemical compound NC1=CC=C(Cl)C(C(F)(F)F)=C1 ASPDJZINBYYZRU-UHFFFAOYSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 150000001805 chlorine compounds Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 229960003512 nicotinic acid Drugs 0.000 claims description 5
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 102000001253 Protein Kinase Human genes 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 108060006633 protein kinase Proteins 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- XSAYDZQYEBSZFM-UHFFFAOYSA-N benzoic acid;boron Chemical compound [B].OC(=O)C1=CC=CC=C1 XSAYDZQYEBSZFM-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 30
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 abstract description 17
- 238000012360 testing method Methods 0.000 abstract description 6
- 229940124290 BCR-ABL tyrosine kinase inhibitor Drugs 0.000 abstract description 5
- 230000004663 cell proliferation Effects 0.000 abstract description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 abstract description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 abstract description 5
- LQWHPYPUHPQSRX-UHFFFAOYSA-N 1,1'-biphenyl;pyridine Chemical compound C1=CC=NC=C1.C1=CC=CC=C1C1=CC=CC=C1 LQWHPYPUHPQSRX-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009510 drug design Methods 0.000 abstract description 3
- 230000000857 drug effect Effects 0.000 abstract description 3
- 239000012634 fragment Substances 0.000 abstract description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 abstract description 3
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 239000011799 hole material Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 6
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 210000000349 chromosome Anatomy 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 241000220324 Pyrus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- KZXYTQOZYCREPI-UHFFFAOYSA-N 2-propan-2-ylbenzamide Chemical compound CC(C)C1=CC=CC=C1C(N)=O KZXYTQOZYCREPI-UHFFFAOYSA-N 0.000 description 2
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 2
- XHXCJDZLPRFWMV-UHFFFAOYSA-N 4-(6-acetamidopyridin-3-yl)benzoic acid Chemical compound C(C)(=O)NC1=CC=C(C=N1)C1=CC=C(C(=O)O)C=C1 XHXCJDZLPRFWMV-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 235000014443 Pyrus communis Nutrition 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000005554 pickling Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012048 reactive intermediate Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- DGRVQOKCSKDWIH-UHFFFAOYSA-N 1-chloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Cl DGRVQOKCSKDWIH-UHFFFAOYSA-N 0.000 description 1
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 description 1
- 101000783817 Agaricus bisporus lectin Proteins 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101000588130 Homo sapiens Microsomal triglyceride transfer protein large subunit Proteins 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001294 alanine derivatives Chemical class 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000003995 blood forming stem cell Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- 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
Abstract
A kind of class peptides and its preparation method and application containing alanine, using the drug design strategies based on segment, using biphenyl pyridine as hinge area binding fragment, introducing l-Alanine is flexibility Linker, to construct the class peptides library with kinase inhibiting activity, and the tyrosine kinase inhibitor for being found to have Bcr-Abl kinase inhibiting activity is screened by the kinase activity of ADP-Glo.The compound can be used in preparing in anti-tumor drug, has and inhibits Bcr-Abl, Bcr-AblT315IKinase activity has cell proliferation inhibitory activity to K562 cell.Introduce alanine, the structure diversity of Bcr-Abl kinase inhibitor can be extended, activity test shows that alanine Linker plays a significant role the inhibitory activity of compound, can be improved the affinity between receptor and compound, can be used as the drug effect segment of Bcr-Abl tyrosine kinase inhibitor.
Description
Technical field
The present invention relates to a kind of class peptides containing alanine with and its preparation method and application.
Background technique
Chronic myelocytic leukemia (CML) is a kind of malignant clone proliferative disease for betiding marrow hemopoietic stem cells,
Proportion is up to 15%~20% in adult leukaemic, it is characterized in that CML patient's body can detect Ph chromosome.
Ph chromosome is the breaking point aggregation cluster-Ai Erbei formed by No. 22 chromosomes and No. 9 chromosome reciprocal translocations of human normal
Inferior (BCR-ABL) fusion, the Bcr-Abl that this fusion coding generates tyrosine kinase activity sustained activation merge egg
It is white.Have listed currently on the market for Bcr-Abl be target small molecule tyrosine kinase inhibitors, but all exist drug resistance with
And the problems such as other clinical adverses.Therewith, the novel Bcr-Abl tyrosine kinase inhibitor of research and development has become medicine
One of the hot spot in field.
Summary of the invention
The purpose of the present invention is to provide a kind of class peptides containing alanine with and its preparation method and application.
To achieve the above object, the present invention adopts the following technical scheme that:
A kind of class peptides containing alanine, the structural formula of such compound are as follows:
Wherein, R is-NH2、
A kind of preparation method of the class peptides containing alanine, comprising the following steps:
1) the acylated bromo- 2-aminopyridine of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5- and chloride compounds；
2)N2Under protection, 5- bromo-nicotinic acid, thionyl chloride and aminated compounds, which react, prepares the 5- bromo-nicotinic acid of ammonification；
3) tetra-triphenylphosphine palladium catalysis under, the 5- bromo-nicotinic acid of the bromo- 2-aminopyridine of acylated 5- or ammonification with to carboxyl
Suzuki coupling reaction occurs for phenyl boric acid, obtains biphenol compound；
4) Boc-L- alanine and the condensation of 3- trifluoromethyl -4- chloroaniline generate tert-butyl-(R)-(1- ((chloro- 3- (three of 4-
Methyl fluoride) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate；
5) tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamic acid
Ester takes off Boc protecting group and generates (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide；
6) biphenol compound generates with the condensation of (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and contains
The class peptides of alanine.
A further improvement of the present invention lies in that the step 1) detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in nothing
In water methylene chloride, triethylamine is added, under condition of ice bath, chloride compounds is added dropwise and removes ice bath after being added dropwise and rises to
After reacting at room temperature 12h, is post-processed, obtain the bromo- 2-aminopyridine of acylated 5-.
A further improvement of the present invention lies in that the step 2) detailed process are as follows: in N2Under protection, thionyl chloride is dripped
It is added in 5- bromo-nicotinic acid, after dripping, is heated to reflux 2-3h and is clarified to solution, decompression rotation removes thionyl chloride, obtains faint yellow
The faint yellow solid is added in anhydrous methylene chloride by solid, and the two of aminated compounds is then added drop-wise under condition of ice bath
In chloromethanes solution；After dripping, it is warmed to room temperature reaction 12h and is post-processed after reaction, obtain the bromo- cigarette of 5- of ammonification
Acid.
A further improvement of the present invention lies in that the step 3) detailed process are as follows: by the acylated bromo- 2-aminopyridine of 5-
It is added in reaction vessel with to Carboxybenzeneboronic acid, or the bromo- niacin of the 5- of ammonification is reacted into appearance with being added to Carboxybenzeneboronic acid
In device, cesium carbonate and tetra-triphenylphosphine palladium are sequentially added；Then the mixed solution of acetonitrile and water, N are added2Protection, heating
To 90 DEG C of reaction 48h；After reaction, it is post-processed, obtains biphenol compound.
A further improvement of the present invention lies in that the detailed process of the step 4) are as follows: be dissolved in Boc-L- alanine anhydrous
In methylene chloride, -20 DEG C are cooled to, stirs 5-10min, triethylamine is added, the methylene chloride of isobutyl chlorocarbonate is then added dropwise
Solution, drop reacts 10-20min after finishing, and after having reacted, the dichloromethane solution of 3- trifluoromethyl -4- chloroaniline is added dropwise, after drop finishes
2h is reacted, is post-processed, obtains tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2-
Base) carbamate.
A further improvement of the present invention lies in that the detailed process of the step 5) are as follows: at 0 DEG C, by tert-butyl-(R)-
(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate is dissolved in anhydrous methylene chloride,
The dichloromethane solution of trifluoroacetic acid is added dropwise, after dripping, after being warmed to room temperature reaction 12h, is post-processed, obtains (R) -2- ammonia
Base-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.
A further improvement of the present invention lies in that the detailed process of the step 6) are as follows: biphenol compound is dissolved in anhydrous four
In hydrogen furans, 4- methyl morpholine is added, under condition of ice bath, the anhydrous tetrahydrofuran solution of isobutyl chlorocarbonate is added dropwise, drips
Afterwards, ice bath reacts 30-40min, is post-processed, obtains the class peptides containing alanine.
A kind of class peptides containing alanine, such compound is in preparation for inhibiting Abl kinases, T315I prominent
Become the application in Abl kinase activity drug.
A kind of class peptides containing alanine, such peptides application in preparation of anti-tumor drugs.
Compared with prior art, the invention has the benefit that the present invention utilizes acylated, Suzuki coupling, condensation etc.
Synthesising target compound is reacted, and constructs compound library, such compound is that have small point of the Bcr-Abl of new molecular architecture
Sub- tyrosine kinase inhibitor, and characterize by means such as MS, NMR the structure of target compound.The present invention is based on to early period
Bcr-Abl tyrosine kinase inhibitor and Bcr-Abl albumen and ligand the research such as transactional analysis, using being based on piece
The drug design strategies of section, using biphenyl pyridine as hinge area binding fragment, introducing l-Alanine is flexibility Linker, to construct tool
There is the class peptides small molecule compound library of kinase inhibiting activity, and Bcr- is found to have by the screening of the kinase activity of ADP-Glo
The tyrosine kinase inhibitor of Abl kinase inhibiting activity.Kinases screening test shows that such compound is prominent to Abl kinases, T315I
Become Abl kinases and all have certain inhibitory activity, wherein R isWhen it is best to the activity of Abl kinases.Cell Proliferation examination
It tests and shows that majority of compounds has certain inhibitory activity to K562 cell.Wherein when R is N, N- dimethyl second dinicotinoyl amine
When antiproliferative activity it is best.Structure-activity analysis discovery: the sky of the derivative of l-Alanine and the site ATP of Abl kinases is introduced
Between match good, binding mode is consistent with referring to small molecule Imatinib, illustrates inhibition of the introducing to compound of l-Alanine
Activity plays a significant role.Amide side chains are introduced on pyridine ring to improve the affinity of small molecule and receptor, can be used as with
Bcr-Abl is the novel drug effect segment that the tyrosine kinase of target inhibits.
Detailed description of the invention
Fig. 1 is synthetic route chart of the invention.
Specific embodiment
The present invention is described in detail with reference to the accompanying drawing.
Referring to Fig. 1, a kind of structural formula of class peptides containing alanine of the invention are as follows:
Wherein, R is specific as follows, is shown in Table 1:
Group representated by table 1R
It is illustrated below by specific embodiment.
Referring to Fig. 1, the preparation method of the class peptides containing alanine of above structure, comprising the following steps:
1) with corresponding chloride compounds the acylated bromo- 2- amino of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5-
Pyridine；
2)N2Under protection, 5- bromo-nicotinic acid reacts with thionyl chloride and corresponding aminated compounds and prepares the 5- of ammonification
Bromo-nicotinic acid；
3) tetra-triphenylphosphine palladium catalysis under, the 5- bromo-nicotinic acid of the bromo- 2-aminopyridine of acylated 5- or ammonification respectively with it is right
Suzuki coupling reaction occurs for Carboxybenzeneboronic acid, obtains biphenol compound；
4) Boc-L- alanine and the condensation of 3- trifluoromethyl -4- chloroaniline generate tert-butyl-(R)-(1- ((chloro- 3- (three of 4-
Methyl fluoride) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate；
5) tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamic acid
Ester takes off Boc protecting group and generates (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide；
6) biphenol compound generates with the condensation of (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and contains
The class peptides of alanine.
Step 1) the detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in anhydrous methylene chloride, three second are added
Corresponding chloride compounds are slowly dropped in above-mentioned solution by amine under condition of ice bath, after being added dropwise, remove ice bath
It is warmed to room temperature reaction 12h.After reaction, methylene chloride dilution, washing is added, saturated sodium bicarbonate water is washed, saturated sodium-chloride
Washing, anhydrous sodium sulfate is dry, and vacuum distillation, pillar layer separation obtains white solid, the bromo- 2- amino of the 5- being as acylated
Pyridine.
Step 2) the detailed process are as follows: in N2Under protection, thionyl chloride is added dropwise in 5- bromo-nicotinic acid, is dripped
Afterwards, it is heated to reflux 2-3h to clarify to solution, decompression rotation removes thionyl chloride, obtains faint yellow solid, which is dissolved in
The two of corresponding aminated compounds is slowly dropped under condition of ice bath into anhydrous methylene chloride, and by this reactive intermediate solution
In chloromethanes solution；After dripping, it is warmed to room temperature reaction 12h and K is added into reaction system after reaction2CO3Solution, point
Liquid takes methylene chloride phase, and water phase is extracted with dichloromethane, and merges organic phase, anhydrous Na2SO4It is dry；Column chromatography separating purification obtains
White solid, as by the bromo- niacin of the 5- of ammonification.
Step 3) the detailed process are as follows: by the acylated bromo- 2-aminopyridine of 5- and pears are added to Carboxybenzeneboronic acid
In shape bottle, or by the bromo- niacin of the 5- of ammonification and Carboxybenzeneboronic acid is added in pear shape bottle, sequentially adds cesium carbonate and four or three
Phenylphosphine palladium；The mixed solution of acetonitrile/water, N are added into said mixture2Protection, oil bath are warming up to 90 DEG C of reaction 48h；Instead
After answering, reaction solution is down to room temperature, is filtered.Filtrate is adjusted to pH4 with hydrochloric acid, and white solid is precipitated, and filters, and filter cake vacuum is dry
It is dry to obtain product, as biphenol compound.
The detailed process of the step 4) are as follows: Boc-L- alanine is dissolved in anhydrous methylene chloride, is cooled to -20 DEG C,
5-10min is stirred, triethylamine is added, then the dichloromethane solution of isobutyl chlorocarbonate is added drop-wise in above-mentioned solution, is reacted
After having reacted, the dichloromethane solution of 3- trifluoromethyl -4- chloroaniline is added drop-wise in above-mentioned solution by 10-20min, reacts 2h,
TLC detection；After reaction, 5%NaHCO is added3Solution (100ml/50mmol), is warming up to room temperature 30min, liquid separation, water phase
It is extracted with dichloromethane.Merge organic phase, 5%NaHCO3Solution is washed, 5% (volumetric concentration) salt pickling, anhydrous Na2SO4It is dry；
Pillar layer separation obtains product, as tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -
2- yl) carbamate.
The detailed process of the step 5) are as follows: at 0 DEG C, by tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) benzene
Base) amino) -1- Ethylene Oxide -2- base) carbamate is dissolved in anhydrous methylene chloride, and the methylene chloride that trifluoroacetic acid is added dropwise is molten
Liquid after dripping, removes ice bath, is warmed to room temperature reaction 12h；After having reacted, suitable quantity of water is added, liquid separation discards methylene chloride phase；
Water phase saturation Na2CO3Solution tune pH to 8, ethyl acetate extract, and merge organic phase, washing, saturation NaCl solution is washed, anhydrous
Na2SO4It is dry, it filters, decompression rotation removes solvent, and residue remains to react in next step.
The detailed process of the step 6) are as follows: biphenol compound is dissolved in anhydrous tetrahydro furan, 4- methyl morpholine is added,
Under condition of ice bath, the anhydrous tetrahydrofuran solution of isobutyl chlorocarbonate is added dropwise, after dripping, ice bath reacts 30-40min, TLC prison
It surveys.After having reacted, the tetrahydro of (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and 4- methyl morpholine is added dropwise
Tetrahydrofuran solution after dripping, is warmed to room temperature reaction 12h.After having reacted, decompression rotation removes tetrahydrofuran, and acetic acid is added in residue
Ethyl ester dissolution, washing, saturation NaCl solution are washed, anhydrous Na2SO4It is dry.Pillar layer separation.
A kind of class peptides containing alanine prepared such as the above method, such compound is for inhibiting Abl
Application in kinases, T315I mutation Abl kinase activity.
Such compound has antineoplastic action, can apply in the preparation of antitumor drugs.
Embodiment 1
A kind of class peptides containing alanine, R areWhen, the preparation method is as follows:
1) synthesis of N- (5- bromopyridine -2- base) acetamide: the bromo- 2-aminopyridine of 5- (5.19g, 30mmol) is dissolved in
In 100ml anhydrous methylene chloride, triethylamine 20ml is added.Under condition of ice bath, chloroacetic chloride (2.54ml) is slowly dropped to
It states in solution, after dripping, removes ice bath, be warmed to room temperature reaction (12h is reacted in reaction overnight in the present invention) overnight.Reaction
After, methylene chloride dilution is added, washes (30ml × 3), is saturated NaHCO3Solution is washed (30ml × 3), and saturation NaCl is washed
(30ml), organic phase anhydrous Na2SO4It is dry.Pillar layer separation obtains white solid 5.65g, yield 88%.Mp 78-81℃；EI-
MS(m/z):214[M]+。
2) synthesis of 4- (6- (acetylamino) pyridin-3-yl) benzoic acid: N- (5- bromopyridine -2- base) acetamide
(4.30g, 20mmol), Carboxybenzeneboronic acid (3.66g, 22mmol) is added in 250ml pear shape bottle, sequentially adds cesium carbonate
(13.0g, 40mmol), tetra-triphenylphosphine palladium (1.2g, 1mmol).Acetonitrile/water (V:V=3:2) is added into said mixture
200ml。N2Protection, oil bath are warming up to 90 DEG C of reaction 48h.After reaction, reaction solution is down to room temperature, filtered.Filtrate is used
6mol/L hydrochloric acid is adjusted to pH4, and white solid is precipitated, and filters, and filter cake is dried in vacuo to obtain product 3.89g, yield 76%.Mp 156-
158℃；EI-MS(m/z):256[M]+。
3) synthesis of Boc-L- alanine: the l-Alanine of 7.14g is dissolved in NaOH (80ml) solution of 40mol/L,
80ml tetrahydrofuran is added, it is cooling in ice-water bath.Stirring is lower to be added dropwise (Boc)2The tetrahydrofuran solution of O 19.2g, wait be added dropwise
After complete, remove ice bath and be warmed to room temperature reaction, TLC monitors (ninhydrin colour developing).After reaction, decompression rotation removes tetrahydrofuran,
With citric acid solution tune reaction solution pH to 2-3 under condition of ice bath, ethyl acetate is added later and is extracted (60ml × 3).Merge
Organic phase, saturation NaCl solution washing, anhydrous Na2SO4Dry, ethyl acetate and petroleum ether recrystallization obtain product 13.6g, yield
90%.Mp 81-83℃.
4) tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamic acid
The synthesis of ester: Boc-L- alanine (1.9g, 10mmol) is dissolved in 50ml anhydrous methylene chloride, is cooled to -20 DEG C, stirs 5-
10min is added triethylamine (2.77ml, 20mmol), then that the methylene chloride of isobutyl chlorocarbonate (1.95ml, 15mmol) is molten
Drop is added in above-mentioned solution, reacts 10-20min.After having reacted, by 3- trifluoromethyl -4- chloroaniline (1.95g, 10mmol)
Dichloromethane solution be added drop-wise in above-mentioned solution, react 2h, TLC detection.After reaction, 5%NaHCO is added3Solution
(100ml/50mmol), is warming up to room temperature 30min, liquid separation, and water phase is extracted with dichloromethane.Merge organic phase, 5%NaHCO3It is molten
Liquid is washed, 5% (volumetric concentration) salt pickling, anhydrous Na2SO4It is dry.Pillar layer separation (petroleum ether: ethyl acetate=20:1), must produce
Product 3.23g, yield 88%.EI-MS(m/z):351[M-CH3]+。
5) synthesis of (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide: at 0 DEG C, by compound uncle
Butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate (3.23g,
It 8.8mmol) is dissolved in 100ml anhydrous methylene chloride, the dichloromethane solution of trifluoroacetic acid (6.5ml, 88mmol) is added dropwise, be added dropwise
After complete, ice bath is removed, is warmed to room temperature reaction overnight.After having reacted, suitable quantity of water is added, liquid separation discards methylene chloride phase.Water phase is used
It is saturated Na2CO3Solution tune pH to 8, ethyl acetate extract (60ml × 3), merge organic phase, washing, and saturation NaCl solution is washed, nothing
Water Na2SO4It is dry, it filters, decompression rotation removes solvent, and residue remains to react in next step.
6) (R) -4- (6- acetamido pyridin-3-yl)-N- (1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxygen
The synthesis of propane -2- yl-benzamide (M1): 4- (6- (acetylamino) pyridin-3-yl) benzoic acid (2.5mmol) is dissolved in anhydrous
In tetrahydrofuran, it is added 4- methyl morpholine (0.85ml, 7.5mmol), under condition of ice bath, dropwise addition isobutyl chlorocarbonate (0.55ml,
Anhydrous tetrahydrofuran solution 3.75mmol), after dripping, ice bath reacts 30-40min, TLC monitoring.After having reacted, it is added dropwise
(R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide (0.8g, 3mmol) and 4- methyl morpholine (0.85ml)
Tetrahydrofuran solution after dripping, is warmed to room temperature reaction overnight.After having reacted, decompression rotation removes tetrahydrofuran, is added in residue
Ethyl acetate dissolution, washing, saturation NaCl solution are washed, anhydrous Na2SO4It is dry.Pillar layer separation.(petroleum ether: ethyl acetate=
1:1), white solid 0.34g, yield 27% are obtained.Mp 224-225℃；EI-MS(m/z):505[M+H]+,503[M-H]-；1H
NMR(400MHz,DMSO-d6) δ 10.67 (s, 1H), 10.55 (s, 1H), 8.81 (d, J=6.6Hz, 1H), 8.74 (s, 1H),
8.25 (d, J=2.4Hz, 1H), 8.19 (s, 2H), 8.04 (d, J=8.4Hz, 2H), 7.90 (dd, J=8.8,2.3Hz, 1H),
7.86 (d, J=8.4Hz, 2H), 7.69 (d, J=8.8Hz, 1H), 4.63-4.56 (m, 1H), 2.13 (s, 3H), 1.47 (d, J=
7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ172.71,169.87,166.43,152.33,146.47,140.07,
139.04,136.79,133.08,132.60,130.33,128.85,127.32,127.02,126.42,124.55,124.44,
124.32,121.84,118.33,118.28,113.61,50.64,24.41,17.89。
Embodiment 2
A kind of class peptides containing alanine, R areWhen, the preparation method is as follows:
1) in N2Under protection, thionyl chloride (36ml, 494mmol) is added dropwise to 5- bromo-nicotinic acid (5.00g, 24.7mmol)
In, after dripping, it is heated to reflux 2-3h and is clarified to solution, decompression rotation removes thionyl chloride, obtains faint yellow solid.The solid is dissolved in
Cyclopropylamine is slowly dropped under condition of ice bath into 30ml anhydrous methylene chloride, and by this reactive intermediate solution
In (3.77ml) methylene chloride (30ml) solution.After dripping, it is warmed to room temperature reaction overnight.After reaction, to reaction system
Middle addition 2mol/L K2CO3Solution 20ml.Liquid separation takes methylene chloride phase, and water phase is extracted with dichloromethane (15ml × 3), is associated with
Machine phase, anhydrous Na2SO4It is dry.Column chromatography separating purification.(petroleum ether: ethyl acetate=1:1), obtains white solid 5.27g, yield
89%.Mp 140-142℃；EI-MS(m/z):240[M]+。
Step 2)~step 6) is same as Example 1, obtains compound (M5) white solid 0.59g, yield 44%.Mp
207-209℃；EI-MS(m/z):531[M+H]+,529[M-H]-；1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),
9.10 (d, J=2.1Hz, 1H), 8.99 (d, J=1.9Hz, 1H), 8.87 (d, J=6.6Hz, 1H), 8.77 (d, J=3.9Hz,
1H), 8.49-8.48 (m, 1H), 8.25 (d, J=2.4Hz, 1H), 8.10 (d, J=8.4Hz, 2H), 7.95 (d, J=8.4Hz,
2H), 7.90 (dd, J=8.8,2.3Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 4.68-4.53 (m, 1H), 2.93-2.88 (m,
1H), 1.48 (d, J=7.2Hz, 3H), 0.79-0.72 (m, 2H), 0.66-0.58 (m, 2H)；13C NMR(101MHz,DMSO-
d6)δ172.67,166.36,166.28,150.30,148.35,139.63,139.03,134.55,133.95,133.16,
132.58,130.37,128.92,127.30,127.03,124.55,124.43,124.35,121.84,118.34,118.28,
50.68,23.54,17.89,6.23。
The same M1 of the synthesis step of compound M2-M4.
Compound M2: white solid 0.29g, yield 21%.Mp 179-181℃；EI-MS(m/z):547[M+H]+,
545M-H]-；1H NMR(400MHz,DMSO-d6) δ 10.56 (s, 1H), 9.99 (s, 1H), 8.82 (d, J=6.6Hz, 1H),
8.76 (s, 1H), 8.25 (d, J=2.2Hz, 1H), 8.19 (s, 2H), 8.05 (d, J=8.3Hz, 2H), 7.90 (dd, J=9.0,
2.2Hz, 1H), 7.87 (d, J=8.3Hz, 2H), 7.68 (d, J=8.7Hz, 1H), 4.64-4.57 (m, 1H), 1.48 (d, J=
7.1Hz,3H),1.27(s,9H)；13C NMR(101MHz,DMSO-d6)δ177.78,172.72,166.42,152.59,
146.17,140.04,139.04,136.68,133.12,132.59,130.45,128.86,127.33,127.03,126.45,
124.52,124.42,124.32,121.84,118.33,118.27,114.38,50.64,39.91,27.34,17.90。
Compound M3: white solid 0.63g, yield 47%.Mp 155-157℃；EI-MS(m/z):541[M+H]+,539
[M-H]-；1H NMR(400MHz,DMSO-d6) δ 10.87 (s, 1H), 10.54 (s, 1H), 8.80 (d, J=6.7Hz, 1H), 8.68
(s, 1H), 8.24 (d, J=2.3Hz, 1H), 8.16 (dd, J=8.6,2.4Hz, 1H), 8.04 (d, J=8.4Hz, 2H), 7.90
(dd, J=8.8,2.3Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.69 (d, J=8.8Hz, 1H), 7.10 (d, J=8.6Hz,
1H), 4.66-4.54 (m, 1H), 1.47 (d, J=7.1Hz, 3H)；13C NMR(101MHz,DMSO-d6)δ172.70,166.45,
152.55,145.67,139.91,139.03,137.57,133.15,132.59,129.08,128.86,127.32,127.02,
126.41,124.55,124.43,124.32,121.84,118.34,118.28,112.73,50.64,42.23,17.89。
Compound M4: white solid 0.52g, yield 45%.Mp 137-138℃；EI-MS(m/z):464[M+H]+,462
[M-H]-；1H NMR(400MHz,DMSO-d6) δ 10.54 (s, 1H), 8.76 (d, J=6.6Hz, 1H), 8.68 (s, 2H), 8.24
(d, J=2.5Hz, 1H), 8.00 (d, J=8.3Hz, 2H), 7.90 (dd, J=8.8,2.5Hz, 1H), 7.77 (d, J=8.5Hz,
2H), 7.68 (d, J=8.8Hz, 1H), 6.91 (s, 2H), 4.62-4.55 (m, 1H), 1.47 (d, J=7.2Hz, 3H)；13C NMR
(101MHz,DMSO-d6)δ172.75,166.50,163.64,156.66,139.03,138.67,132.55,132.34,
128.84,127.32,127.02,125.12,124.54,124.42,124.31,121.83,121.45,118.33,118.28,
50.63,17.88。
The same M5 of the synthesis step of compound M6, M7.
Compound M6: white solid 0.38g, yield 28%.Mp 104-106℃；EI-MS(m/z):547[M+H]+,545
[M-H]-；1H NMR(400MHz,DMSO-d6) δ 10.56 (s, 1H), 9.05 (d, J=2.0Hz, 1H), 8.87 (d, J=6.6Hz,
1H), 8.60 (d, J=1.7Hz, 1H), 8.25 (d, J=2.1Hz, 1H), 8.18 (s, 1H), 8.07 (d, J=8.3Hz, 2H),
7.95 (d, J=8.3Hz, 2H), 7.90 (dd, J=8.8,2.0Hz, 1H), 7.69 (d, J=8.7Hz, 1H), 4.65-4.54 (m,
1H), 3.50 (d, J=6.4Hz, 2H), 3.25 (d, J=6.6Hz, 2H), 1.47 (d, J=7.1Hz, 3H), 1.19 (d, J=
6.9Hz,3H),1.09(s,3H)；13C NMR(101MHz,DMSO-d6)δ172.67,167.87,166.36,148.59,
146.48,139.49,139.03,134.74,133.95,133.71,132.58,132.36,128.91,127.31,127.02,
124.55,124.44,124.32,121.84,118.34,118.29,50.67,43.49,17.87,14.52,13.28。
Compound M7: white solid 0.26g, yield 18%.Mp 126-129℃；EI-MS(m/z):562[M+H]+,560
[M-H]-；1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.11(s,1H),9.02(s,1H),8.90(s,1H),
8.81 (s, 1H), 8.53 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=6.4Hz, 2H), 7.96 (d, J=7.0Hz, 2H), 7.91
(d, J=7.3Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 4.61 (s, 1H), 3.32-3.26 (m, 2H), 2.48 (s, 2H),
2.22 (s, 6H), 1.49 (d, J=5.5Hz, 3H)；13C NMR(101MHz,DMSO-d6)δ172.71,166.38,165.01,
150.32,148.39,139.62,139.04,134.59,133.97,133.23,132.60,130.46,128.93,127.32,
126.99,125.75,124.56,124.48,124.34,119.35,118.34,118.30,58.54,50.71,45.67,
37.91,17.89。
It is living that Bcr-Abl kinase inhibition is carried out to the derivative of alanine with anti-tumor activity produced by the present invention below
Property screening.
Measuring method is specific as follows:
Kinases ABL1, ABL (T315I) and substrate A bltide are purchased from Signal-Chem company, select Promega company
ADP-GloTMKinase Assays detection kit detects the Inhibiting enzyme activity of target compound, and operating method is said according to kit
Bright progress.
In Abl experiment, ATP (1mM) is used into buffer (2 ×) (Tris 80mM, MgCl2 20mM,BSA 0.2mg/ml,
DTT 2mM) dilute 80 times of buffer (2 ×) solution for being configured to ATP (125 μM)；125 μM of ATP solution and Abltide is molten
The mixed solution that liquid product 1:1 is hybridly prepared into ATP (62.5 μM)-Abltide (0.5 μ g/ μ l) is spare；ABL1 kinase solution is used
buffer(1×)(Tris 40mM,MgCl210mM, BSA 0.1mg/ml, DTT 1mM) dilution 100 times be configured to ABL1
Buffer (1 ×) solution for standby of (1ng/ μ l).
The preparation steps of ATP-Abltide and ABL1 (T315I) in Abl (T315I) experiment are same as above, unlike
ATP concentration is 12.5 μM, and the concentration of ABL1 (T315I) is 2ng/ μ l
Target compound and positive control drug (Imatinib) are configured to 1.5 × 10 with buffer (1 ×) respectively-5, 1.5
×10-6, 1.5 × 10-7, 1.5 × 10-8, 1.5 × 10-9, 1.5 × 10-10The sample solution of mol/L concentration gradient, in 384 orifice plates
Upper every hole sequentially adds the mixed solution of 2 μ l ATP-Abltide, 1 μ l sample solution, 2 μ l enzyme solutions；Blank well adds 3 μ l to buffer
The mixed solution of liquid and 2 μ lATP-Abltide；Control wells add the mixed solution of 2 μ l ATP-Abltide, 1 μ l buffer, 2 μ l
Enzyme solutions finish, and are incubated for 60min at 30 DEG C；5 μ l of ADP-Glo reagent is added, is incubated for 40min at 25 DEG C；Kinase is added
Detection reagent, then 30min is incubated at 25 DEG C.It is surveyed using the chemiluminescence module of PerkinElmer multi-function microplate reader
The luminous value in fixed every hole calculates compound to the inhibiting rate and IC of Abl50。
A kind of structural formula of class peptides containing alanine of the invention are as follows:
The kinase inhibiting activity of the class peptides containing alanine of structure above is as shown in table 2
Class peptides of the table 2 containing alanine are to Bcr-Abl/Bcr-AblT315IInhibitory activity IC50(μM)
As can be seen from Table 2, most compound has preferable inhibitory activity, compound to Bcr-Abl kinases
IC50Value is within the scope of 0.011 μM to 9.38 μM, wherein active most preferably compound M2 and M6, IC50Value is respectively 0.041
μM and 0.011 μM.To Bcr-AblT315Kinases, majority of compounds have certain inhibitory activity, IC50Value is arrived at 2.28 μM
Within the scope of 59.85 μM, part of compound (M2, M3, M4, M5) is to the half-inhibitory concentration of T315I mutation Abl kinases micro-
Mol level, activity is preferably.It is living to the inhibition of kinases that Activity Results show that the difference of substituent group will have a direct impact on compound
Property.
The class peptides containing alanine are measured below to the growth inhibitory activity of tumour cell.It is examined using mtt assay
The class peptides containing alanine are tested to act on the growth inhibitory activity of tumour cell.
Class peptides provided by the invention containing alanine have antineoplastic action.There is body to tumour cell
Outer inhibition increment active effect, has the increment active effect for inhibiting tumour cell in human leukemia cell (K562 cell),
It can be used for the treatment to leukaemia.
Human leukemia cell's (K562 cell) of logarithmic growth phase, is diluted to 10 with RPMI1640 culture medium4A/ml number
The cell solution of magnitude is inoculated in 96 well culture plates (2000-4000/hole) in parallel, and every hole inoculation volume is 180 μ l, and 37
DEG C, 5%CO212h is cultivated in incubator；
The 20 μ l of untested compound of various concentration is added in every hole, makes the final concentration of of compound in hole: 1.5 × 10-7mol/
L, 1.5 × 10-6Mol/L, 1.5 × 10-5Mol/L, 1.5 × 10-4Mol/L, each concentration set 3 multiple holes, negative control refinement born of the same parents
Compound is not added, if 6 multiple holes, nilotinib or Imatinib are positive control, continues to cultivate 48h；
MTT (5mg/ml) 20 μ l is added in every hole, makes the final concentration 0.5mg/ml of MTT in hole, 37 DEG C of incubators are incubated for 4h, small
The heart, which is inhaled, abandons supernatant, and every hole adds 150 μ l of DMSO, vibrates 15min, and enzyme-linked immunosorbent assay instrument measures the UV absorption at each hole 490nm
It is worth (OD value), then calculates cell inhibitory rate, and calculate the IC for finding out compound using linear regression method according to inhibiting rate50Value；
The calculation formula of cell inhibitory rate are as follows:
Inhibiting rate %=(control wells mean OD value-medication group mean OD value)/control wells mean OD value × 100%；
Testing result is shown: compared with negative control group, the class peptides containing alanine are to above-mentioned tumour cell
With different degrees of In-vitro Inhibitory Effect, as shown in table 3.
K562 cell-proliferation activity:
Class peptides of the table 3 containing alanine are to K562 cell inhibitory activity IC50(μM)
Cell activity screening test shows that compound has certain cell proliferation inhibitory activity to K562 cell.IC50Value
Range is 4.65 μM to 396.00 μM, wherein the preferable compound IC of activity50It is worth in micromolar levels, active most preferably M7,
IC50Value is 4.65 μM, and activity is suitable with Imatinib.For the class peptides containing alanine, on pyridine ring
Different substituent groups is introduced, there are biggish differences for the influence to bioactivity, and the position difference of substituent group is to bioactivity
Influence it is also different.Compound M2 and M6 is preferable to the inhibitory activity of Bcr-Abl kinases；Inhibition of the compound M7 to K562 cell
It is active to be preferably close with Imatinib, it is worth the further further investigation of expansion.
The present invention is based on to early period Bcr-Abl tyrosine kinase inhibitor and Bcr-Abl albumen and ligand it is mutual
The research such as function analysis, using biphenyl pyridine as hinge area binding fragment, introduces L- third using the drug design strategies based on segment
Propylhomoserin is flexibility Linker, to construct the class peptides library with kinase inhibiting activity, and it is living by the kinases of ADP-Glo
Property screening be found to have the tyrosine kinase inhibitor of Bcr-Abl kinase inhibiting activity.It is anti-swollen that the compound can be used in preparation
In tumor (chronic myelocytic leukemia) drug, has and inhibit Bcr-Abl, Bcr-AblT315IKinase activity, and to K562 cell
With cell proliferation inhibitory activity.Alanine structure is introduced, the structure diversity of Bcr-Abl kinase inhibitor can be extended, together
When activity test show alanine Linker play a significant role to the inhibitory activity of compound, can be improved receptor and compound
Between affinity.It can be used as the drug effect segment of Bcr-Abl tyrosine kinase inhibitor.
Claims (10)
1. a kind of class peptides containing alanine, which is characterized in that the structural formula of such compound is as follows:
Wherein, R is-NH2、
2. a kind of preparation method of the class peptides containing alanine as described in claim 1, which is characterized in that including
Following steps:
1) the acylated bromo- 2-aminopyridine of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5- and chloride compounds；
2)N2Under protection, 5- bromo-nicotinic acid, thionyl chloride and aminated compounds, which react, prepares the 5- bromo-nicotinic acid of ammonification；
3) tetra-triphenylphosphine palladium catalysis under, the 5- bromo-nicotinic acid of the bromo- 2-aminopyridine of acylated 5- or ammonification with to carboxyl benzene boron
Suzuki coupling reaction occurs for acid, obtains biphenol compound；
4) Boc-L- alanine and the condensation of 3- trifluoromethyl -4- chloroaniline generate tert-butyl-(R)-(1- ((chloro- 3- (fluoroform of 4-
Base) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate；
5) tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate is de-
Fall Boc protecting group and generates (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide；
6) biphenol compound and the condensation of (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide generate and contain the third ammonia
The class peptides of acid.
3. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
Step 1) detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in anhydrous methylene chloride, be added triethylamine, in condition of ice bath
Under, be added dropwise chloride compounds, after being added dropwise, remove ice bath be warmed to room temperature reaction 12h after, post-processed, be acylated
The bromo- 2-aminopyridine of 5-.
4. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
Step 2) detailed process are as follows: in N2Under protection, thionyl chloride is added dropwise in 5- bromo-nicotinic acid, after dripping, is heated to reflux
2-3h is clarified to solution, and decompression rotation removes thionyl chloride, obtains faint yellow solid, which is added to anhydrous dichloromethane
In alkane, in the dichloromethane solution that is then added drop-wise to aminated compounds under condition of ice bath；After dripping, it is warmed to room temperature reaction
12h is post-processed after reaction, obtains the bromo- niacin of 5- of ammonification.
5. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
Step 3) detailed process are as follows: by the acylated bromo- 2-aminopyridine of 5- and Carboxybenzeneboronic acid is added in reaction vessel, or will
The bromo- niacin of the 5- of ammonification and Carboxybenzeneboronic acid is added in reaction vessel, sequentially adds cesium carbonate and tetra-triphenylphosphine palladium；
Then the mixed solution of acetonitrile and water, N are added2Protection, is warming up to 90 DEG C of reaction 48h；After reaction, it is post-processed,
Obtain biphenol compound.
6. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
The detailed process of step 4) are as follows: Boc-L- alanine is dissolved in anhydrous methylene chloride, is cooled to -20 DEG C, stirs 5-10min,
Triethylamine is added, the dichloromethane solution of isobutyl chlorocarbonate is then added dropwise, drop reacts 10-20min after finishing, after having reacted, drop
2h is reacted after adding the dichloromethane solution of 3- trifluoromethyl -4- chloroaniline, drop to finish, is post-processed, obtains tert-butyl-(R) -
(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Ethylene Oxide -2- base) carbamate.
7. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
The detailed process of step 5) are as follows: at 0 DEG C, by tert-butyl-(R)-(1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxygen
Propane -2- base) carbamate is dissolved in anhydrous methylene chloride, and the dichloromethane solution of trifluoroacetic acid is added dropwise, after dripping, rise
To room temperature reaction 12h, is post-processed, obtain (R) -2- amino-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.
8. a kind of preparation method of the class peptides containing alanine as claimed in claim 2, which is characterized in that described
The detailed process of step 6) are as follows: biphenol compound is dissolved in anhydrous tetrahydro furan, addition 4- methyl morpholine, under condition of ice bath,
The anhydrous tetrahydrofuran solution of isobutyl chlorocarbonate is added dropwise, after dripping, ice bath reacts 30-40min, is post-processed, is obtained
Class peptides containing alanine.
9. a kind of class peptides containing alanine as described in claim 1, which is characterized in that such compound is being made
It is ready for use on and Abl kinases, T315I is inhibited to be mutated the application in Abl kinase activity drug.
10. a kind of class peptides containing alanine as described in claim 1, which is characterized in that such peptides chemical combination
Object application in preparation of anti-tumor drugs.
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