CN107400072A - 一种双乙烯磺酰胺连接子及其制备和应用 - Google Patents
一种双乙烯磺酰胺连接子及其制备和应用 Download PDFInfo
- Publication number
- CN107400072A CN107400072A CN201710529954.5A CN201710529954A CN107400072A CN 107400072 A CN107400072 A CN 107400072A CN 201710529954 A CN201710529954 A CN 201710529954A CN 107400072 A CN107400072 A CN 107400072A
- Authority
- CN
- China
- Prior art keywords
- double
- ethenesulfonamide
- connexons
- alkyl
- aromatic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 15
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 15
- 239000000700 radioactive tracer Substances 0.000 claims abstract description 12
- -1 nitro, hydroxyl Chemical group 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000000524 functional group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 9
- 229920001184 polypeptide Polymers 0.000 claims description 9
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 150000001924 cycloalkanes Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000002304 perfume Substances 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 4
- 150000001356 alkyl thiols Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- 229960001866 silicon dioxide Drugs 0.000 description 27
- 229910001868 water Inorganic materials 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 239000003480 eluent Substances 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 229940049595 antibody-drug conjugate Drugs 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- MAHNFPMIPQKPPI-UHFFFAOYSA-N disulfur Chemical compound S=S MAHNFPMIPQKPPI-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 101800000989 Oxytocin Proteins 0.000 description 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 8
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 description 8
- 230000005526 G1 to G0 transition Effects 0.000 description 8
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 description 8
- 102400000050 Oxytocin Human genes 0.000 description 8
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 7
- 229960001723 oxytocin Drugs 0.000 description 7
- 238000003825 pressing Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 229960002685 biotin Drugs 0.000 description 4
- 235000020958 biotin Nutrition 0.000 description 4
- 239000011616 biotin Substances 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 235000010378 sodium ascorbate Nutrition 0.000 description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 4
- 229960005055 sodium ascorbate Drugs 0.000 description 4
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- 239000000611 antibody drug conjugate Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009145 protein modification Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical class CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
- 150000005801 3-amino-2-chloropyridine Chemical class 0.000 description 1
- 150000005805 3-amino-4-chloropyridine Chemical class 0.000 description 1
- BOOMHTFCWOJWFO-UHFFFAOYSA-N 3-aminopyridine-2-carboxylic acid Chemical class NC1=CC=CN=C1C(O)=O BOOMHTFCWOJWFO-UHFFFAOYSA-N 0.000 description 1
- 150000003929 3-aminopyridines Chemical class 0.000 description 1
- LLIANSAISVOLHR-GBCQHVBFSA-N 5-[(3as,4s,6ar)-2-oxidanylidene-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 LLIANSAISVOLHR-GBCQHVBFSA-N 0.000 description 1
- 150000005815 5-amino-2-chloropyridine Chemical class 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 240000000233 Melia azedarach Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 241000830536 Tripterygium wilfordii Species 0.000 description 1
- XAQHXGSHRMHVMU-UHFFFAOYSA-N [S].[S] Chemical compound [S].[S] XAQHXGSHRMHVMU-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- KPNBUPJZFJCCIQ-LURJTMIESA-N methyl L-lysinate Chemical compound COC(=O)[C@@H](N)CCCCN KPNBUPJZFJCCIQ-LURJTMIESA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMXAIJCDNKFKPO-UHFFFAOYSA-N n-ethynylaniline Chemical compound C#CNC1=CC=CC=C1 VMXAIJCDNKFKPO-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000012868 site-directed mutagenesis technique Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical class CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- 235000015398 thunder god vine Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/11—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供了一种双乙烯磺酰胺连接子及其制备和应用。所述的双乙烯磺酰胺连接子的结构式为式I或式II。本发明提供的新型双乙烯磺酰胺连接子不仅一端可以偶联多肽或蛋白,另一端同时可以连接亲和标记物或示踪荧光物质或活性药物。
Description
技术领域
本发明属于生物制药及生物技术领域,具体涉及一种新型的连接子(linker)及其制备,及其应用于亲和标记物、示踪荧光物质及活性药物等特异性的偶联到多肽、蛋白质中可到达的硫-硫键上的方法。本发明涉及的连接子及偶联方法可用于制备靶向示踪诊断试剂、肿瘤靶向治疗药物等并可控制药物/靶向物比值(DAR)。
背景技术
蛋白质的选择性化学修饰在物化学和生物医学研究领域中非常重要。利用化学手段发展蛋白质修饰方法已成功的应用在多个领域中,如:蛋白质荧光标记,细胞内生物过程检测,蛋白质偶联物用于治疗、诊断等。近年来最热门和重要的应用领域为抗体药物偶联物(Antibody drug conjugation,ADCs)。抗体药物偶联物是将具有极高生物活性的药物分子修饰连接到抗体上。ADCs的诞生是基于一种理想的前药设计理念,希望将高活性药物分子和抗体两者的优点结合起来,利用抗体的特异专一性,有效输送高活性物质到特定靶标,提高药效,降低毒性。随着ADCs药物Adcetris和Kadcyla分别于2011和2013年上市,ADCs进入黄金发展期,目前共有超过40个ADCs药物正在进行临床研究。
ADCs由抗体(antibody)、连接子(linker)和细胞毒素(toxin)三部分组成。其中,连接子在ADC药物设计中非常重要,对于靶向药物的制备、功效等起着关键作用。早期的ADCs中的连接子多基于抗体内在的氨基酸残基进行修饰,如胺基、巯基等。但由于多个修饰位点的存在,导致抗体与高活性药物偶联时,化学选择性极差,药物的结合位点及结合数目极其复杂。这类均一性差的ADCs不仅会对药代动力学、药效和药物安全性产生很大的影响,同时对产品质量控制造成极大的挑战。其后,随着定点突变技术的发展,可以在蛋白的特定位点引入半胱氨酸(cysteine)或非天然氨基酸(叠氮,醛基等),进而进行化学选择性修饰。虽然这类方法对蛋白质的修饰特异性非常好,但突变的产率低,成本高,严重的制约了其发展和应用。
早期的研究认为蛋白质硫-硫键对其结构和功能非常重要,并不适合用来进行化学修饰,但近年来研究表明,硫-硫键修饰后,蛋白质的结构和生物活性都能够很好的保持。基于硫-硫键来发展蛋白质化学选择性修饰新方法,不仅对蛋白质本身的研究有非常积极的作用,同时将该方法用于ADCs的定位合成时也有着独特的优势:单抗中一般含有4对易于接近硫-硫键,如果通过硫-硫键定位偶联高活性物质,不仅可以实现化学选择性偶联,避免对抗体突变的改造,而且可以得到理想的DAR值产物。另外目前报道的技术已经可以实现选择性的对1对或2对硫-硫键偶联。由于蛋白质硫-硫键的修饰研究起步较晚,因此目前的方法并不多,将其用于ADCs的合成中的方法则更有限,目前主要侧重于两大类:(1)α,β-不饱和-β’单砜类化合物(α,β-Unsaturated-β’-monosulfones);(2)马来酰亚胺类化合物(Maleimides)。单砜类化合物的制备较为繁琐,而马来酰亚胺类化合物的稳定性并不理想。因此,发展新的简单、高效、实用的方法修饰蛋白质硫-硫键是非常有必要的。
发明内容
本发明的目的是提供一种双乙烯磺酰胺连接子及其制备,以及以该类连接子一端偶联亲和标记物或示踪荧光物质或活性药物等,另一端特异性偶联多肽或蛋白硫-硫键中的应用。
为达到上述发明目的,本发明采用的技术方案是:
一种双乙烯磺酰胺连接子,其结构式为式I或者式II:
式I中,X选自C或者N;R选自氢,硝基,羟基,烷基羟基,芳香基羟基,胺基,烷基胺基,芳香基胺基,巯基,烷基巯基,芳香基巯基,羧酸,烷基羧酸,芳香基羧酸,炔基,烷基炔基,芳香基炔基,叠氮,烷基叠氮,芳香基叠氮,羰基,烷基羰基,芳香基羰基,醛基,烷基醛基,芳香基醛基,或其中任意组合;式II中W选自直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合;R1选自氢,直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合;R2选自氢,直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合。
优选地,所述的双乙烯磺酰胺连接子的结构式为式1-式11(图1)、式16、式19、式22、式26以及式30中的至少一种。
上述的双乙烯磺酰胺连接子的制备方法,其特征在于,包括:以胺基化合物为起始物,在氯乙烷基磺酰氯和碱的作用下,反应得到乙烯磺酰胺连接子。
优选地,所述的胺基化合物包括直链、支链或环状烷基胺,苄基或其它芳香苄基胺,苯基或其它芳香基胺,或其中任意组合。
优选地,所述的碱包括三乙胺或其它有机碱,氢氧化钠或其它无机碱。
优选地,上述的双乙烯磺酰胺连接子的制备方法的具体步骤包括:将胺基化合物溶于溶剂中,冰浴下加入碱,充分冷却后加入氯乙烷基磺酰氯,在一定温度下进行反应一段时间,得到双乙烯磺酰胺连接子。
更优选地,所述的反应温度为0℃-45℃。
双乙烯磺酰胺连接子的制备的反应式如下:
本发明还提供了上述的双乙烯磺酰胺连接子的应用方法,其特征在于,包括:先在双乙烯磺酰胺连接子的所需官能团上接入Tag,再与多肽或蛋白偶联(方式a);或者,先将双乙烯磺酰胺连接子同多肽或蛋白偶联,然后再连接Tag(方式b);其中,所述的双乙烯磺酰胺连接子由在带有反应基团的胺基化合物引入所需官能团(FG)形成。
优选地,所述的胺基化合物包括直链、支链或环状烷基胺,苄基或其它芳香苄基胺,苯基或其它芳香基胺,或其中任意组合。
优选地,所述的所需官能团包括羟基,烷基羟基,芳香基羟基,胺基,烷基胺基,芳香基胺基,巯基,烷基巯基,芳香基巯基,羧酸,烷基羧酸,芳香基羧酸,炔基,烷基炔基,芳香基炔基,叠氮,烷基叠氮,芳香基叠氮,羰基,烷基羰基,芳香基羰基,醛基,烷基醛基,芳香基醛基,或其中任意组合。
优选地,所述的Tag包括亲和标记物(如biotin和folic acid中的至少一种)、示踪荧光物质(如有香豆素和荧光素中的至少一种)以及活性药物(如喜树碱类、美登醇类、抗生素类、毒素类和雷公藤类中的至少一种)中的至少一种。Tag不仅仅局限于上述提到的类别,还包括所有用于亲和标记,荧光失踪以及具有高活性的物质。
优选地,所述的多肽或蛋白包括可达到硫-硫键的多肽,蛋白或者抗体。
本发明同时提供了一种化合物,其特征在于,其结构式为式III:
P-(D-S)n
III
其中,P是多肽或者蛋白;D是上述的双乙烯磺酰胺连接子;S是亲和标记物或示踪荧光物质或活性药物;n是一个范围在0-4的整数。
上述反应的流程如图11所示。
与现有技术相比,本发明的有益效果是:
1.本发明提供了简单、高效的方法制备双乙烯磺酰胺连接子;
2.本发明提供的新型双乙烯磺酰胺连接子可选择性的修饰多肽或蛋白的硫-硫键;
3.本发明提供的新型双乙烯磺酰胺连接子不仅一端可以偶联多肽或蛋白,另一端同时可以连接亲和标记物或示踪荧光物质或活性药物。
4.本发明提供的新型双乙烯磺酰胺连接子可选择性在多肽或蛋白的硫-硫键上引入特定官能团后,进一步偶联亲和标记物或示踪荧光物质或活性药物。
5.本发明提供的新型双乙烯磺酰胺连接子可用于抗体药物偶联物,得到DAR(0-4间的整数)值较为均一的产物
附图说明
图1显示了本发明中涉及的典型的双乙烯磺酰胺连接子的结构。
图2显示双乙烯磺酰胺连接子同时含有可偶联的官能团炔基的制备路线。
图3显示双乙烯磺酰胺连接子一端已连接亲和标记物生物素(biotin)的制备路线。
图4显示双乙烯磺酰胺连接子一端已连示踪荧光物质香豆素的制备路线。
图5显示双乙烯磺酰胺连接子一端已连接活性药物喜树碱的制备路线。
图6显示双乙烯磺酰胺连接子对多肽上-SH和-NH2的选择性反应
图7显示一端已连接官能团炔基或亲和标记物生物素或示踪荧光物质香豆素或活性药物喜树碱的双乙烯磺酰胺连接子同多肽Oxytocin的偶联。
图8显示双乙烯磺酰胺连接子偶联多肽Oxytocin中硫-硫键后,引入特定官能团炔基进一步同示踪荧光物质香豆素和荧光素以及活性药物喜树碱偶联的制备路线。
图9显示双乙烯磺酰胺连接子同时偶联踪荧光物质香豆素和多肽Oxytocin的荧光测定结果。
图10显示一端为甲氧基或一端已连接官能团炔基或亲和标记物生物素双乙烯磺酰胺连接子同蛋白sCT的偶联。
图11显示双乙烯磺酰胺连接子偶联多肽或蛋白的实现方式。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
双乙烯磺酰胺连接子合成的通用步骤A:将胺类(1eq.,)溶于CH2Cl2(1mmol/6ml)中,冰浴下加入Et3N(3eq.,),充分冷却后缓慢滴加2-氯乙烷磺酰氯(2.2eq.,)到上述体系中,在一定温度下反应一段时间,反应温度视底物不同为0℃或者常温或者加热。加入等体积的水淬灭反应。用相等体积的CH2Cl2萃取3次。有机层合并后,等体积的饱和氯化钠洗2次后,无水硫酸钠干燥,过滤,减压旋蒸除去溶剂,加入CH2Cl2和60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚作为洗脱剂,快速柱层析。
合成化合物的核磁数据1H-NMR和13C-NMR用Bruker-500测定;高分辨质谱(HRMS-ESI)由Agilent Technologies 6230 Accurate Mass TOF LC/MS测定。GCMS-EI由ThermoScienticific ISQ QD测定。
功能性双乙烯磺酰胺连接子与还原后Oxytocin上两个-SH成环的通用步骤B:在微孔板(330ul LABTIDE 96 Round Well)的五个不同的孔中分别均加入12ul的oxytocin(大连美仑生物,MB1177,1mM的水溶液)、20ul的TCEP(1mM的水溶液,用NaOH/H3PO4调节PH为7.0)、120ul PBS缓冲液(商品号Cat.NO.SH30256.0)以及80ul的CH3CN,然后放在微孔板振荡器上室温反应1.5小时。再依次往上述五个孔中分别加入12ul不同的双乙烯磺酰胺连接子溶液(1mM的CH3CN或DMF溶液),微孔板振荡器上室温反应2小时后用HPLC(型号Waters1525,固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,0~10分钟)分析,用HRMS-ESI判断产物峰。
基于双乙烯磺酰胺连接子往Oxytoein上引入炔基后的进一步应用的通用步骤C:在微孔板(330ul LABTIDE 96 Round Well)的三个不同的孔中分别均加入炔基修饰后的oxytocin,即化合物35(1mg)、抗坏血酸钠(0.15mg)、硫酸铜(0.12mg)和tBuOH/H2O/DMF(1/1/1)(300ul)。再依次往上述三个孔中分别加入不同的功能性叠氮化物,微孔板振荡器上室温反应2小时后用HPLC(型号Waters 1525,固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,0~10分钟)分析,用HRMS-ESI判断产物峰。
双乙烯磺酰胺连接子与还原后sCT上两个-SH成环的通用步骤D:在微孔板(330ulLABTIDE 96Round Well)的三个不同的孔中分别均加入12ul的sCT(1mM的水溶液)、20ul的TCEP(1mM的水溶液,用NaOH/H3PO4调节PH为7.0)、120ul PBS缓冲液(商品号Cat.NO.SH30256.0)以及80ul的CH3CN,然后放在微孔板振荡器上室温反应1.5小时。再依次往上述三个孔中分别加入12ul不同的双乙烯磺酰胺连接子溶液(1mM的CH3CN或DMF溶液),微孔板振荡器上室温反应2小时后用HPLC(型号Waters 1525,固定相为C.18硅胶柱,流动相为CH3CN/H2O=10~100%,0~10分钟)分析,用HRMS-ESI判断产物峰。
实施例1
双乙烯磺酰胺连接子1的制备
使用通用步骤A,加入原料对乙酰基苯胺675.8mg,其它按当量加入,0℃下反应10分钟。其中通用步骤A中加入3ml CH2Cl2和3g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物770mg。
1H NMR(500MHz,CDCl3)δ8.01(d,J=8.5Hz,2H),7.38(d,J=8.5Hz,2H),7.07(dd,J=16.5,9.9Hz,2H),6.30(d,J=16.6Hz,2H),6.18(d,J=9.8Hz,2H),2.62(s,3H)ppm.13CNMR(126MHz,CDCl3)δ196.95,138.48,137.71,136.07,131.33,130.30,129.62,26.94ppm.ESI-HRMS calcd for C12H14NO5S2[(M+H)+]:316.0313,found:316.0296
实施例2
双乙烯磺酰胺连接子2的制备
使用通用步骤A,加入原料对硝基苯胺552.5mg,其它按当量加入,0℃下反应1小时。其中通用步骤A中加入3ml CH2Cl2和2.5g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物100mg。
1H NMR(500MHz,CDCl3)δ8.33-8.24(m,2H),7.49-7.42(m,2H),7.07(dd,J=16.5,9.8Hz,2H),6.31(dd,J=16.5,0.9Hz,2H),6.22(dd,J=9.9,0.9Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ148.85,139.24,135.86,132.19,130.80,124.90ppm.EI-GCMS calcd forC10H11N2O6S2(M):317.9980,found:218.20
实施例3
双乙烯磺酰胺连接子3的制备
使用通用步骤A,加入原料对甲氧基苯胺1.23g,其它按当量加入,0℃下反应10分钟。其中通用步骤A中加入10ml CH2Cl2和5g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物1.93g。
1H NMR(500MHz,CDCl3)δ7.22-7.14(m,2H),7.04(dd,J=16.6,9.9Hz,2H),6.94-6.88(m,2H),6.28(d,J=16.6Hz,2H),6.13(d,J=9.8Hz,2H),3.82(s,3H)ppm.13C NMR(126MHz,CDCl3)δ161.17,136.21,132.19,129.70,125.97,114.91,55.67ppm.ESI-HRMScalcd for C11H14NO5S2[(M+H)+]:304.0313,found:304.0298
实施例4
双乙烯磺酰胺连接子4的制备
使用通用步骤A,加入原料对乙炔基苯胺234.3mg,其它按当量加入,加热回流1小时。其中通用步骤A中加入5ml CH2Cl2和1.5g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物251mg。
1H NMR(500MHz,CDCl3)δ7.56(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),7.07(dd,J=16.5,9.9Hz,2H),6.32(d,J=16.6Hz,2H),6.18(d,J=9.8Hz,2H),3.20(s,1H)ppm.13CNMR(126MHz,CDCl3)δ136.11,133.83,133.40,131.05,130.13,124.89,82.34,79.89ppm.ESI-HRMS calcd for C12H12NO4S2[(M+H)+]:298.0208,found:298.0239.
实施例5
双乙烯磺酰胺连接子5的制备
使用通用步骤A,加入原料苯胺372.5mg,其它按当量加入,常温下反应1小时。其中通用步骤A中加入5ml CH2Cl2和2g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/10作为洗脱剂,过柱得到产物339mg。
1H NMR(500MHz,CDCl3)δ7.48-7.39(m,3H),7.27-7.23(m,2H),7.04(dd,J=16.6,9.9Hz,2H),6.27(d,J=16.6Hz,2H),6.13(d,J=9.8Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ136.22,133.79,131.02,130.69,129.84,129.72ppm.ESI-HRMS calcd for C10H12NO4S2[(M+H)+]:274.0208,found:274.0208
实施例6
双乙烯磺酰胺连接子6的制备
使用通用步骤A,加入原料3-氨基吡啶470.5mg,其它按当量加入,0℃下反应30分钟。其中通用步骤A中加入8ml CH2Cl2和3g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/3作为洗脱剂,过柱得到产物82mg。
1H NMR(500MHz,CDCl3)δ8.69(dd,J=4.8,1.4Hz,1H),8.52(d,J=2.4Hz,1H),7.64(ddd,J=8.1,2.3,1.6Hz,1H),7.42(dd,J=8.1,4.8Hz,1H),7.06(dd,J=16.5,9.9Hz,2H),6.30(dd,J=16.5,0.7Hz,2H),6.19(dd,J=9.8,0.7Hz,2H)ppm.13CNMR(126MHz,CDCl3)δ151.16,150.95,138.68,135.86,131.12,130.67,124.47ppm.ESI-HRMS:m/z=275.0117[M+H]+,296.9929[M+Na]+,312.9662[M+K]+(calcd.exact mass:275.0160[M+H]+,296.9980[M+Na]+,312.9719[M+K]+,formula:C9H10N2O4S2).
实施例7
双乙烯磺酰胺连接子7的制备
使用通用步骤A,加入原料对3-氨基-2-氯吡啶642.8mg,其它按当量加入,0℃下反应30分钟。其中通用步骤A中加入10ml CH2Cl2和4g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物300mg。
1H NMR(500MHz,CDCl3)δ8.48(d,J=4.7Hz,1H),7.66(d,J=7.8Hz,1H),7.33(dd,J=7.8,4.8Hz,1H),7.10(dd,J=16.5,9.8Hz,2H),6.37(d,J=16.5Hz,2H),6.22(d,J=9.8Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ153.36,151.07,141.37,136.49,130.70,129.29,123.33ppm.ESI-HRMS:m/z=308.9771[M+H]+,330.9589[M+Na]+,346.9333[M+K]+(calcd.exact mass:308.9770[M+H]+,330.9590[M+Na]+,346.9329[M+K]+,formula:C9H9ClN2O4S2).
实施例8
双乙烯磺酰胺连接子8的制备
使用通用步骤A,加入原料3-氨基-4-氯吡啶642.8mg,其它按当量加入,0℃下反应10分钟。其中通用步骤A中加入10ml CH2Cl2和4g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物562mg。
1H NMR(500MHz,CDCl3)δ8.56(d,J=5.3Hz,1H),8.48(s,1H),7.50(d,J=5.3Hz,1H),7.11(dd,J=16.5,9.8Hz,2H),6.37(d,J=16.5Hz,2H),6.22(d,J=9.8Hz,2H)ppm.13CNMR(126MHz,CDCl3)δ152.92,152.09,145.99,136.37,130.75,129.56,125.91ppm.ESI-HRMS:m/z=308.9772[M+H]+,330.9589[M+Na]+(calcd.exact mass:308.9770[M+H]+,330.9590[M+Na]+,formula:C9H9ClN2O4S2).
实施例9
双乙烯磺酰胺连接子9的制备
使用通用步骤A,加入原料5-氨基-2-氯吡啶642.8mg,其它按当量加入,0℃下反应1小时。其中通用步骤A中加入10ml CH2Cl2和4g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作为洗脱剂,过柱得到产物369mg。
1H NMR(500MHz,CDCl3)δ8.29(d,J=2.6Hz,1H),7.55(dd,J=8.4,2.6Hz,1H),7.41(d,J=8.4Hz,1H),7.04(dd,J=16.5,9.8Hz,2H),6.31(d,J=16.5Hz,2H),6.20(d,J=9.8Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ153.33,151.28,140.70,135.76,130.91,129.93,125.31ppm.ESI-HRMS:m/z=308.9785[M+H]+,330.9605[M+Na]+,(calcd.exact mass:308.9770[M+H]+,330.9590[M+Na]+,formula:C9H9ClN2O4S2).
实施例10
双乙烯磺酰胺连接子10的制备
使用通用步骤A,加入原料赖氨酸甲酯306mg,其它按当量加入,0℃下反应3小时。其中通用步骤A中加入5ml CH2Cl2和3g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/4作为洗脱剂,过柱得到产物242mg。
1H NMR(500MHz,MeOD)δ6.63(ddd,J=16.5,10.0,2.1Hz,2H),6.13(dd,J=16.5,6.6Hz,2H),5.95(dd,J=22.2,10.0Hz,2H),3.86(dd,J=8.7,5.2Hz,1H),3.72(s,3H),2.94(t,J=6.9Hz,2H),1.88-1.73(m,1H),1.67(dt,J=9.4,4.3Hz,1H),1.61-1.36(m,4H)ppm.13C NMR(126MHz,MeOD)δ174.02,138.19,137.63,126.45,126.27,56.85,52.74,43.49,33.20,30.19,23.59ppm.
实施例11
双乙烯磺酰胺连接子11的制备
将哌嗪(1mmol,86.1mg.)溶于CH2Cl2(15ml)中,冰浴下加入Et3N(6mmol,0.83ml.),充分冷却后缓慢滴加2-氯乙烷磺酰氯(2.4mmol,0.25ml)到上述体系中。自然升至室温搅拌2h,TLC说明反应完全(展开剂为乙酸乙酯/石油醚=1∶1)。加入水淬灭反应。加入CH2Cl2萃取3次。有机层合并后,用饱和氯化钠洗2次后,无水硫酸钠干燥,过滤,减压旋蒸除去溶剂,加入5ml CH2Cl2和1g60-100目硅胶,拌匀旋干。采用纯乙酸乙酯作洗脱剂,快速柱层析得到产物。
1H NMR(500MHz,CDCl3)δ6.42(dd,J=16.6,9.9Hz,2H),6.28(d,J=16.6Hz,2H),6.11(d,J=9.9Hz,2H),3.27(s,8H)ppm.13C NMR(126MHz,CDCl3)δ132.14,129.97,45.41ppm.ESI-HRMS:m/z=267.0478[M+H]+,289.0300[M+Na]+,(calcd.exact mass:267.0473[M+H]+,289.0293[M+Na]+,formula:C8H14N2O4S2).
实施例12
功能性双乙烯磺酰胺连接子16的制备,路线如图2所示:
将4-氨基苯酚(2.0g,18.3mmol)、Boc酸酐(5ml,22mmol)和Et3N(36.6mmol,5ml.)溶于THF(50ml)中,室温反应过夜。减压旋蒸除去溶剂,加入30ml CH2Cl2和8g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/10作洗脱剂,快速柱层析,得到产物13(白色固体,产率96%)。
1H NMR(500MHz,DMSO)δ9.04(s,1H),8.99(br,1H),7.22(d,J=7.1Hz,2H),6.71-6.58(m,2H),1.45(s,9H).13C NMR(126MHz,DMSO)δ153.06,152.56,131.08,119.99,115.07,78.45,28.24ppm.
将化合物13(1.7g,8.1mmol)、3-溴丙炔(0.84ml,9.7mmol)和K2CO3(3.3g,24.3mmol)溶于DMF(30ml)中,室温下反应过夜。然后用水(600ml)和乙酸乙酯(3X 50ml)萃取产物,合并后的有机相依次用饱和NaHCO3(20ml)、NH4Cl(20ml)和NaCl(20ml)洗,再用无水Na2SO4干燥。减压旋蒸除去溶剂后得到的化合物14的粗产物用DCM(30ml)溶解,在冰浴下冷却至0℃后加入三氟乙酸(12ml),冰浴下反应1h后减压旋蒸除去溶剂,加入20ml CH2Cl2和3g60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/8作洗脱剂,快速柱层析,得到产物15(红色油状物,两步总产率84%)。
1H NMR(500MHz,CDCl3)δ6.80(dd,J=8.7,1.6Hz,2H),6.60(dd,J=8.8,3.1Hz,2H),4.58(t,J=2.4Hz,2H),3.49(s,2H),2.51(d,J=2.3Hz,1H)ppm.13C NMR(126MHz,CDCl3)δ150.38,140.99,116.23,116.09,79.15,75.27,56.57ppm.ESI-HRMS calcd forC9H10NO[(M+H)+]:148.0762,found:148.0815
化合物15(1.0g,6.8mmol)和Et3N(40.8mmol,5.66ml.)溶于DCM(50ml)中,冰浴下冷却至0℃后缓慢加入2-氯乙烷磺酰氯(1.6ml,15.0mmol),反应液45℃下冷凝回流2h。冷却至室温后加入水(10ml),产物用DCM(3X 50ml)萃取,合并后的有机相用饱和NaCl(20ml)洗后用无水Na2SO4干燥。减压旋蒸除去溶剂,加入15ml CH2Cl2和4g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/6作洗脱剂,快速柱层析得到双乙烯磺酰胺连接子16(淡黄色固体,产率35%)。
1H NMR(500MHz,CDCl3)δ7.23-7.17(m,2H),7.09-6.96(m,4H),6.28(d,J=16.6Hz,2H),6.14(d,J=9.9Hz,2H),4.70(d,J=2.4Hz,2H),2.56(t,J=2.4Hz,1H)ppm.13C NMR(126MHz,CDCl3)δ159.16,136.18,132.24,129.79,126.81,115.76,77.97,76.37,56.17ppm.ESI-HRMS calcd for C13H14NO5S2[(M+H)+]:328.0313,found:328.1552
实施例13
功能性双乙烯磺酰胺连接子19的制备,制备路线如图3所示:
将Biotin(100mg,0.41mmol)、2-叠氮乙胺(70mg,0.82mmol)、HATU(171mg,0.45mmol)和HOBt(69mg,0.45mmol)溶于DMF(2ml)中,然后加入DIPEA(0.35ml)。室温下反应4h后用湿法上样过柱,用CH3OH/DCM=1/20作洗脱剂,快速柱层析得到化合物18(白色固体,产率36%)。
1H NMR(500MHz,DMSO)δ8.07(t,J=5.4Hz,1H),6.44(s,1H),6.38(s,1H),4.30(dd,J=7.5,5.3Hz,1H),4.15-4.08(m,1H),3.33(t,J=5.8Hz,2H),3.22(dd,J=11.5,5.7Hz,2H),3.11-3.05(m,1H),2.81(dd,J=12.5,5.1Hz,1H),2.57(d,J=12.4Hz,1H),2.07(t,J=7.4Hz,2H),1.30-1.20(m,6H)ppm.13C NMR(126MHz,DMSO)δ172.42,162.73,61.02,59.19,55.43,53.42,49.99,38.15,35.14,28.21,28.05,25.17ppm.ESI-HRMS calcd forC12H21N6O2S[(M+H)+]:313.1447,found:313.1473
化合物18(46mg,0.147mmol)、化合物16(58mg,0.177mmol)、抗坏血酸钠(29.2mg,0.147mmol)和硫酸铜(23.5mg,0.147mmol)溶于tBuOH/H2O(1/1)(2ml)中。室温下反应过夜后用制备HPLC分离(固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,21分钟),得到双乙烯磺酰胺连接子19(淡黄色固体,产率33%)。
1H NMR(500MHz,MeOD)δ8.07(s,1H),7.22(d,J=8.8Hz,2H),7.14-7.03(m,4H),6.23(d,J=4.1Hz,2H),6.21(d,J=1.9Hz,2H),5.18(s,2H),4.53(t,J=5.6Hz,2H),4.42(dd,J=7.7,4.8Hz,1H),4.25(dd,J=7.8,4.4Hz,1H),3.65(d,J=3.2Hz,2H),3.34(s,1H),3.19-3.11(m,1H),2.86(dd,J=12.7,4.9Hz,1H),2.64(d,J=12.7Hz,1H),2.14(td,J=7.1,2.0Hz,2H),1.68(dt,J=13.4,7.2Hz,1H),1.62-1.47(m,4H),1.34(dt,J=15.0,7.5Hz,3H)ppm.13C NMR(126MHz,MeOD)δ176.46,166.05,161.11,144.49,137.52,133.61,130.76,128.13,125.88,116.42,63.25,62.68,61.56,56.89,50.61,41.07,40.36,36.57,29.60,29.42,26.69ppm.ESI-HRMS calcd for C25H34N7O7S3[(M+H)+]:640.1682,found:640.1714
实施例14
功能性双乙烯磺酰胺连接子22的制备,制备路线如图4所示:
将3-羧酸香豆素(380.3mg,2mmol)、2-叠氮乙胺(206mg,2.4mmol)、Et3N(6mmol,0.83ml.)、EDC(1.15g,6mmol)和HOBt(810.7mg,6mmol)溶于DMF(30ml)中,室温下反应3h后加入水(10ml),用DCM(3X 30ml)萃取产物,合并后的有机相依次用饱和NaHCO3(20ml)、NH4Cl(20ml)和NaCl(20ml)洗,再用无水Na2SO4干燥。减压旋蒸除去溶剂,加入10ml CH2Cl2和2g60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/4作洗脱剂,快速柱层析得到化合物21(白色固体,产率65%)。
1H NMR(500MHz,CDCl3)δ9.07(s,1H),8.91(s,1H),7.69(ddd,J=15.8,8.2,1.3Hz,2H),7.40(dd,J=16.4,8.0Hz,2H),3.66(dd,J=11.7,5.8Hz,2H),3.55(t,J=5.8Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ162.15,161.57,154.65,148.86,134.45,130.05,125.55,118.71,118.22,116.88,50.68,39.38ppm.ESI-HRMS calcd for C12H11N4O3[(M+H)+]:259.0831,found:259.0451
化合物21(45mg,0.174mmol)、化合物16(68.5mg,0.2mmol)、抗坏血酸钠(34.6mg,0.174mmol)和硫酸铜(27.8mg,0.174mmol)溶于tBuOH/H2O/DMF(1/1/1)(6ml)中。室温下反应3h后用制备HPLC(固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,21分钟)分离得到双乙烯磺酰胺连接子22(白色固体,产率29%)。
1H NMR(500MHz,CDCl3)δ9.03(s,1H),8.89(s,1H),7.73-7.69(m,2H),7.68(s,1H),7.40(t,J=8.6Hz,2H),7.17(d,J=8.8Hz,2H),7.08-6.94(m,4H),6.27(d,J=16.6Hz,2H),6.13(d,J=9.8Hz,2H),5.21(s,2H),4.65(t,J=6.0Hz,2H),3.97(dd,J=11.9,5.9Hz,2H)ppm.13C NMR(126MHz,CDCl3)δ162.48,161.48,159.84,154.67,149.07,143.86,136.19,134.68,132.28,130.12,129.78,126.49,125.64,123.60,118.62,117.92,116.92,115.73,62.36,49.55,40.13ppm.ESI-HRMS calcd for C25H24N5O8S2[(M+H)+]:586.1066,found:586.0504
实施例15
功能性双乙烯磺酰胺连接子26的制备,制备路线如图4所示:
将3-羧酸香豆素(0.762g,4mmol),HOBt(1.62g,12mmol),EDC·HCl(2.30g,12mmol)混合后,加入DCM(40ml)充分溶解后加入单Boc-乙二胺(0.769g,4.8mmol),最后加入Et3N(1.21g,12mmol),室温持续搅拌24h。加入适量的水淬灭反应,用DCM和水萃取,除去水溶性盐,分出有机相,无水Na2SO4干燥。减压旋蒸除去溶剂后,加入10ml CH2Cl2和3g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/4作洗脱剂,快速柱层析得到化合物23(白色固体,产率38%)。
1H NMR(500MHz,CDCl3)δ8.91(s,1H),7.68(ddd,J=8.8,8.2,1.5Hz,2H),7.45-7.34(m,2H),3.59(dd,J=11.9,6.0Hz,2H),3.38(d,J=5.3Hz,2H),1.64(s,2H),1.44(s,9H)ppm.13C NMR(126MHz,DMSO)δ162.01,160.10,153.92,147.75,137.34,134.28,130.36,128.89,128.20,125.23,118.70,118.36,116.16,99.53,38.48,37.11,21.03ppm.ESI-HRMS:m/z=333.1444[M+H]+,355.1266[M+Na]+,371.0996[M+K]+(calcd.exact mass:333.1450[M+H]+,355.1270[M+Na]+,371.1009[M+K]+,formula:C17H20N2O5).
化合物23用DCM(30ml)溶解,冰浴下加入三氟乙酸(7.7g,67mmol),1h后反应完全,直接减压旋蒸掉低沸点的副产物及过量的三氟乙酸,即得到了化合物24(白色固体,产率100%)。
1H NMR(500MHz,DMSO)δ8.97-8.87(m,2H),8.02(dd,J=7.8,1.3Hz,1H),7.54(d,J=8.3Hz,1H),7.47(t,J=7.5Hz,1H),3.58(q,J=6.1Hz,2H),3.01(dd,J=11.8,6.0Hz,2H)ppm.ESI-HRMS:m/z=233.0940[M+H]+,255.0759[M+Na]+,(calcd.exact mass:233.0926[M+H]+,255.0746[M+Na]+,formula:C12H12N2O3).
3-氨基吡啶-2-羧酸(0.53g,3.85mmol),HOBt(1.42g,10.5mmol),EDC.HCl(2.01g,10.5mmol)与化合物24混合后,加入DCM(40ml)充分溶解后加入Et3N(1.41g,14mmol),室温持续搅拌24h。加入适量的水淬灭反应,用DCM和水萃取,除去水溶性盐,分出有机相,无水Na2SO4干燥。减压旋蒸除去溶剂后,加入10ml CH2Cl2和3g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/4作洗脱剂,快速柱层析得到化合物25(白色固体,产率28%)。
1H NMR(500MHz,DMSO)δ8.90-8.80(m,2H),8.76(t,J=5.7Hz,1H),7.98(dd,J=7.8,1.3Hz,1H),7.79(dd,J=4.2,1.3Hz,1H),7.77-7.72(m,1H),7.50(d,J=8.3Hz,1H),7.46-7.40(m,1H),7.23(dd,J=8.4,4.2Hz,1H),7.14(dd,J=8.4,1.3Hz,1H),6.83(s,2H),3.53(dd,J=11.7,5.8Hz,2H),3.46(dd,J=11.7,5.7Hz,2H)ppm.13C NMR(126MHz,DMSO)δ167.90,161.47,160.19,153.88,147.43,146.30,135.47,134.08,130.27,128.79,127.24,125.13,124.45,120.11,119.03,118.45,116.13,38.22ppm.ESI-HRMS:m/z=353.1240[M+H]+,375.1055[M+Na]+,(calcd.exact mass:353.1250[M+H]+,375.1070[M+Na]+,formula:C18H16N4O4).
化合物25(35mg,0.1mmol)用DCM(20ml)溶解后,冰浴下加入Et3N(31mg,0.3mmol),充分冷却后缓慢滴加2-氯乙烷磺酰氯(36mg,0.22mmol)到上述体系中,冰浴下反应30min。加入适量的水淬灭反应,用DCM和水萃取,除去水溶性盐,分出有机相,无水Na2SO4干燥。减压旋蒸除去溶剂后,加入5ml CH2Cl2和2g 60-100目硅胶,拌匀旋干。采用乙酸乙酯/石油醚=1/2作洗脱剂,快速柱层析得到双乙烯磺酰胺连接子26(淡黄色固体,产率56%)。
1H NMR(500MHz,DMSO)δ8.92(t,J=5.6Hz,1H),8.86(s,1H),8.84(t,J=5.7Hz,1H),8.72(dd,J=4.6,1.4Hz,1H),7.98(dd,J=7.8,1.3Hz,1H),7.86(dd,J=8.1,1.4Hz,1H),7.77-7.71(m,1H),7.70(dd,J=8.1,4.7Hz,1H),7.49(d,J=8.3Hz,1H),7.43(dd,J=11.5,4.3Hz,1H),7.23(dd,J=16.5,9.9Hz,2H),6.32(d,J=9.4Hz,2H),6.17(d,J=16.4Hz,2H),3.53(dd,J=11.6,5.8Hz,2H),3.46(dd,J=11.5,5.6Hz,2H)ppm.13C NMR(126MHz,DMSO)δ172.12,163.93,161.53,160.15,153.88,150.52,149.86,147.43,143.00,141.97,135.97,134.06,130.73,130.26,128.86,127.65,126.63,125.11,119.06,118.46,116.11,38.87,38.75ppm.ESI-HRMS:m/z=533.0831[M+H]+,555.0657[M+Na]+,571.0394[M+K]+(calcd.exact mass:533.0801[M+H]+,555.0621[M+Na]+,571.0360[M+K]+,formula:C22H20N4O8S2).
实施例16
功能性双乙烯磺酰胺连接子30的制备,制备路线如图5所示:
将喜树碱(174.2mg,0.5mmol)和丁二酸酐(150mg,1.5mmol)溶于DCM(15ml)中,冰浴下冷却至0℃后缓慢加入DBU(0.23ml,1.5mmol),反应液室温反应过夜后加入水(10ml),用DCM(3X 20ml)萃取产物,合并后的有机相用饱和NaCl(10ml)洗后用无水Na2SO4干燥。减压旋蒸浓缩后得到化合物28的粗产物溶液,然后加入2-叠氮乙胺(51.6mg,0.6mmol)、Et3N(1.5mmol,0.21ml.)、EDC(287.6mg,1.5mmol)和HOBt(202.7mg,1.5mmol),室温下反应5h后加入水(10ml),用DCM(3X 15ml)萃取产物,合并后的有机相依次用饱和NaHCO3(10ml)、NH4Cl(10ml)和NaCl(10ml)洗,再用无水Na2SO4干燥。减压旋蒸除去溶剂,加入10ml CH2Cl2和2g60-100目硅胶,拌匀旋干。采用CH3OH/DCM=1/40作洗脱剂,快速柱层析得到化合物29(淡黄色固体,两步总产率81%)。
1H NMR(500MHz,CDCl3)δ8.44(s,1H),8.26(d,J=8.3Hz,1H),7.95(d,J=8.1Hz,1H),7.85(t,J=7.5Hz,1H),7.68(t,J=7.4Hz,1H),7.35(s,1H),6.38(s,1H),5.66(d,J=17.0Hz,1H),5.36(d,J=17.0Hz,1H),5.33-5.19(m,2H),3.31(s,4H),2.98-2.88(m,1H),2.87-2.76(m,1H),2.61-2.46(m,2H),2.22(td,J=14.4,7.2Hz,1H),2.11(dq,J=14.4,7.1Hz,1H),0.99(t,J=7.3Hz,3H)ppm.13C NMR(126MHz,CDCl3)δ172.09,167.75,157.52,151.88,148.25,146.72,145.87,132.16,131.34,129.05,128.71,128.50,128.44,128.38,119.98,97.43,77.40,76.50,66.97,50.62,50.29,39.20,31.66,30.85,29.53,7.74ppm.ESI-HRMS calcd for C26H25N6O6[(M+H)+]:517.1836,found:517.1914
化合物29(176mg,0.34mmol)、化合物16(133.8mg,0.4mmol)、抗坏血酸钠(67.4mg,0.34mmol)和硫酸铜(54.3mg,0.34mmol)溶于tBuOH/H2O/DMF(1/1/1)(9ml)中。室温下反应2h后用制备HPLC(固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,21.5分钟)分离得到双乙烯磺酰胺连接子30(淡黄色固体,产率49%)。
1H NMR(500MHz,CDCl3)δ8.38(s,1H),8.22(d,J=7.8Hz,1H),7.91(d,J=7.9Hz,1H),7.82(t,J=7.1Hz,1H),7.65(t,J=7.2Hz,1H),7.53(s,1H),7.30(s,1H),7.11(d,J=8.1Hz,2H),6.98(dd,J=16.2,9.9Hz,2H),6.91(d,J=7.9Hz,2H),6.64(s,1H),6.23(d,J=16.5Hz,2H),6.10(d,J=9.7Hz,2H),5.58(d,J=16.9Hz,1H),5.31(d,J=16.9Hz,1H),5.17(dd,J=37.5,18.8Hz,2H),5.04(s,2H),4.27(s,2H),3.56(d,J=30.6Hz,2H),2.95-2.70(m,2H),2.43(s,2H),2.14(ddd,J=49.5,13.7,7.1Hz,2H),0.97(t,J=6.9Hz,3H)ppm.13CNMR(126MHz,CDCl3)δ172.20,172.14,167.67,159.49,157.27,151.91,148.35,146.47,146.00,135.95,132.10,131.83,131.03,129.81,129.73,129.13,128.61,128.37,128.26,128.22,126.39,124.29,119.61,115.64,96.70,76.47,66.80,61.70,50.07,49.22,39.76,31.42,30.43,29.24,7.66ppm.ESI-HRMS calcd for C39H38N7O11S2[(M+H)+]:844.2071,found:844.2049
实施例17
双乙烯磺酰胺连接子3对-SH和N-NH2的选择性研究,如图6所示:
在微孔板(330ul LABTIDE 96 Round Well)的一个孔中加入12ul的四肽,即化合物31(1mM的水溶液)、12ul双乙烯磺酰胺连接子3(1mM的CH3CN溶液)、120ul PBS缓冲液(商品号Cat.NO.SH30256.0)以及80ul的CH3CN,然后放在微孔板振荡器上室温反应2小时后用HPLC(型号Waters 1525,固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,0~10分钟)分析知还是原料,没有发生反应。用HRMS-ESI(型号Agilent Technologies 6230,流动相为CH3OH/H2O=7∶3)分析也是得到相同的结果。
在微孔板(330ul LABTIDE 96 Round Well)的一个孔中加入12ul的四肽,即化合物32(1mM的水溶液)、12ul双乙烯磺酰胺连接子3(1mM的CH3CN溶液)、120ul PBS缓冲液(商品号Cat.NO.SH30256.0)以及80ul的CH3CN,然后放在微孔板振荡器上室温反应2小时后用HPLC(型号Waters 1525,固定相为C-18硅胶柱,流动相为CH3CN/H2O=10~100%,0~10分钟)分析得知发生反应得到了化合物33。ESI-HRMS calcd for C32H47N6O11S3[(M+H)+]:787.2465,found:787.2420。
实施例18
功能性双乙烯磺酰胺连接子与还原后Oxytocin上两个-SH成环,如图7所示:
化合物34的制备:使用通用步骤B,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子3溶液(1mM的CH3CN溶液)。HPLC产率74%,ESI-HRMS calcd for C54H82N13O17S4[(M+H)+]:1312.4834,found:1312.4793。化合物35的制备:使用通用步骤B,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子16溶液(1mM的CH3CN溶液)。HPLC产率76%,ESI-HRMS calcd forC56H82N13O17S4[(M+H)+]:1336.4834.found:1336.4791。
化合物36的制备:使用通用步骤B,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子19溶液(1mM的DMF溶液)。HPLC产率79%,ESI-HRMS calcd for (C68H103N19O19S5)/2[(M/2+H)+]:824.8140,found:824.8125。
化合物37的制备:使用通用步骤B,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子22溶液(1mM的DMF溶液)。HPLC产率54%,ESI-HRMS calcd for (C68H93N17O20S4)/2[(M/2+H)+]:797.7833,found:797.7820。双乙烯磺酰胺连接子同时偶联踪荧光物质香豆素和多肽Oxytocin的荧光测定结果如图9所示。
化合物38的制备:使用通用步骤B,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子30溶液(1mM的DMF溶液)。HPLC产率70%,ESI-HRMS calcd for (C82H107N19O23S4)/2[(M/2+H)+]:926.8335,found:927.3335。
实施例19
基于双乙烯磺酰胺连接子往Oxytocin上引入炔基的进一步应用,如图8所示:
化合物37的制备:使用通用步骤C,功能性叠氮化物为香豆素-N3,即化合物21(2.8mg)。HPLC产率56%,ESI-HRMS calcd for(C68H93N17O20S4)/2[(M/2+H)+]:797.7833,found:797.7820。
化合物38的制备:使用通用步骤C,功能性叠氮化物为喜树碱-N3,即化合物29(2.8mg)。HPLC产率62%,ESI-HRMS calcd for(C82H107N19O23S4)/2[(M/2+H)+]:926.8335,found:927.3335。
化合物40的制备:使用通用步骤C,功能性叠氮化物为罗丹明-N3,即化合物39(2.8mg)。HPLC产率42%,ESI-HRMS calcd for(C85H117N19O23S6)/2[(M/2+H)+]:981.8447,found:982.1964。
实施例20
双乙烯磺酰胺连接子与还原后sCT上两个-SH成环,如图10所示:
化合物42的制备:使用通用步骤D,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子3溶液(1mM的CH3CN溶液)。HPLC产率81%,ESI-HRMS calcd for (C156H259N45O53S4)/4[(M/4+H)+]:934.6960,found:935.1928。
化合物43的制备:使用通用步骤D,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子16溶液(1mM的CH3CN溶液)。HPLC产率83%,ESI-HRMS calcd for(C158H259N45O53S4)/4[(M/4+H)+]:940.6960,found:941.1922。
化合物44的制备:使用通用步骤D,双乙烯磺酰胺连接子溶液为双乙烯磺酰胺连接子19溶液(1mM的DMF溶液)。HPLC产率60%,ESI-HRMS calcd for(C170H279N51O55S5)/4[(M/4+H)+]:1018.7302,found:1019.2246。
Claims (10)
1.一种双乙烯磺酰胺连接子,其结构式为式I或者式II:
式I中,X选自C或者N;R选自氢,硝基,羟基,烷基羟基,芳香基羟基,胺基,烷基胺基,芳香基胺基,巯基,烷基巯基,芳香基巯基,羧酸,烷基羧酸,芳香基羧酸,炔基,烷基炔基,芳香基炔基,叠氮,烷基叠氮,芳香基叠氮,羰基,烷基羰基,芳香基羰基,醛基,烷基醛基,芳香基醛基,或其中任意组合;式II中W选自直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合;R1选自氢,直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合;R2选自氢,直链、支链或环状烷烃,苄基或其它芳香苄基,苯基或其它芳香基,或其中任意组合。
2.权利要求1所述的双乙烯磺酰胺连接子的制备方法,其特征在于,包括:以胺基化合物为起始物,在氯乙烷基磺酰氯和碱的作用下,反应得到乙烯磺酰胺连接子。
3.如权利要求2所述的双乙烯磺酰胺连接子的制备方法,其特征在于,所述的胺基化合物包括直链、支链或环状烷基胺,苄基或其它芳香苄基胺,苯基或其它芳香基胺,或其中任意组合。
4.如权利要求2所述的双乙烯磺酰胺连接子的制备方法,其特征在于,所述的碱包括三乙胺或其它有机碱,氢氧化钠或其它无机碱。
5.如权利要求2所述的双乙烯磺酰胺连接子的制备方法,其特征在于,具体步骤包括:将胺基化合物溶于溶剂中,冰浴下加入碱,充分冷却后加入氯乙烷基磺酰氯,在一定温度下进行反应一段时间,得到双乙烯磺酰胺连接子。
6.如权利要求5所述的双乙烯磺酰胺连接子的制备方法,其特征在于,所述的反应温度为0℃-45℃。
7.权利要求1所述的双乙烯磺酰胺连接子的应用方法,其特征在于,包括:先在双乙烯磺酰胺连接子的所需官能团上接入Tag,再与多肽或蛋白偶联;或者,先将双乙烯磺酰胺连接子同多肽或蛋白偶联,然后再连接Tag;其中,所述的双乙烯磺酰胺连接子由在带有反应基团的胺基化合物引入所需官能团形成。
8.如权利要求7所述的双乙烯磺酰胺连接子的应用方法,其特征在于,所述的所需官能团包括羟基,烷基羟基,芳香基羟基,胺基,烷基胺基,芳香基胺基,巯基,烷基巯基,芳香基巯基,羧酸,烷基羧酸,芳香基羧酸,炔基,烷基炔基,芳香基炔基,叠氮,烷基叠氮,芳香基叠氮,羰基,烷基羰基,芳香基羰基,醛基,烷基醛基,芳香基醛基,或其中任意组合。
9.如权利要求7所述的双乙烯磺酰胺连接子的应用方法,其特征在于,所述的Tag包括亲和标记物、示踪荧光物质以及活性药物中的至少一种。
10.一种化合物,其特征在于,其结构式为式III:
P-(D-S)n
III
其中,P是多肽或者蛋白;D是上述的双乙烯磺酰胺连接子;S是亲和标记物或示踪荧光物质或活性药物;n是一个范围在0-4的整数。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710529954.5A CN107400072B (zh) | 2017-06-30 | 2017-06-30 | 一种双乙烯磺酰胺连接子及其制备和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710529954.5A CN107400072B (zh) | 2017-06-30 | 2017-06-30 | 一种双乙烯磺酰胺连接子及其制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107400072A true CN107400072A (zh) | 2017-11-28 |
CN107400072B CN107400072B (zh) | 2021-02-05 |
Family
ID=60404757
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710529954.5A Active CN107400072B (zh) | 2017-06-30 | 2017-06-30 | 一种双乙烯磺酰胺连接子及其制备和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107400072B (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108530512A (zh) * | 2018-03-28 | 2018-09-14 | 上海科技大学 | 乙烯磺酰胺链接子及其应用 |
CN110251680A (zh) * | 2019-07-03 | 2019-09-20 | 上海科技大学 | 一种哌嗪类二乙烯基磺酰胺类链接子及其制备方法与应用 |
CN110269943A (zh) * | 2019-07-29 | 2019-09-24 | 上海科技大学 | 一种靶向于egfr的抗体-药物偶联物及其制备方法与应用 |
WO2020125546A1 (zh) * | 2018-12-17 | 2020-06-25 | 荣昌生物制药(烟台)有限公司 | 一种用于抗体药物偶联物的连接子及其应用 |
CN111349058A (zh) * | 2018-12-21 | 2020-06-30 | 石家庄圣泰化工有限公司 | 1,4-双(甲基磺酰基)哌嗪的合成方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009009434A1 (en) * | 2007-07-06 | 2009-01-15 | University Of Chicago | Polymers and uses thereof |
-
2017
- 2017-06-30 CN CN201710529954.5A patent/CN107400072B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009009434A1 (en) * | 2007-07-06 | 2009-01-15 | University Of Chicago | Polymers and uses thereof |
Non-Patent Citations (2)
Title |
---|
W. G. DAVIES ET AL.: "The Addition of Alcohols to Vinyl Sulphones and Sulphonamides", 《JOURNAL OF THE CHEMICAL SOCIETY. [SECTION] B: PHYSICAL ORGANIC CHEMISTRY》 * |
孙立春等: "多肽药物研究进展", 《药物研发》 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108530512A (zh) * | 2018-03-28 | 2018-09-14 | 上海科技大学 | 乙烯磺酰胺链接子及其应用 |
WO2020125546A1 (zh) * | 2018-12-17 | 2020-06-25 | 荣昌生物制药(烟台)有限公司 | 一种用于抗体药物偶联物的连接子及其应用 |
CN111433188A (zh) * | 2018-12-17 | 2020-07-17 | 荣昌生物制药(烟台)股份有限公司 | 一种用于抗体药物偶联物的连接子及其应用 |
JP2022512057A (ja) * | 2018-12-17 | 2022-02-02 | 栄昌生物制薬(烟台)股▲分▼有限公司 | 抗体薬物複合体のためのリンカーおよびその使用 |
CN111433188B (zh) * | 2018-12-17 | 2023-08-01 | 荣昌生物制药(烟台)股份有限公司 | 一种用于抗体药物偶联物的连接子及其应用 |
CN111349058A (zh) * | 2018-12-21 | 2020-06-30 | 石家庄圣泰化工有限公司 | 1,4-双(甲基磺酰基)哌嗪的合成方法 |
CN110251680A (zh) * | 2019-07-03 | 2019-09-20 | 上海科技大学 | 一种哌嗪类二乙烯基磺酰胺类链接子及其制备方法与应用 |
CN110251680B (zh) * | 2019-07-03 | 2022-10-18 | 上海科技大学 | 一种哌嗪类二乙烯基磺酰胺类链接子及其制备方法与应用 |
CN110269943A (zh) * | 2019-07-29 | 2019-09-24 | 上海科技大学 | 一种靶向于egfr的抗体-药物偶联物及其制备方法与应用 |
CN110269943B (zh) * | 2019-07-29 | 2023-03-24 | 上海科技大学 | 一种靶向于egfr的抗体-药物偶联物及其制备方法与应用 |
Also Published As
Publication number | Publication date |
---|---|
CN107400072B (zh) | 2021-02-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107400072A (zh) | 一种双乙烯磺酰胺连接子及其制备和应用 | |
CN104844578B (zh) | 5元杂环酰胺及相关的化合物 | |
CN105899490B (zh) | 嘧啶fgfr4抑制剂 | |
CN105189515B (zh) | 作为溴结构域抑制剂的呋喃并吡啶类 | |
CN105669657B (zh) | 一类苯并吡喃-4-酮取代的萘酰亚胺-多胺缀合物及其制备方法和用途 | |
CN110372598A (zh) | 一种合成氘代酰胺及氘代磺酰胺的新方法 | |
CN109311813A (zh) | 钯催化的间位-c-h官能化的通用型配体 | |
CN109796439B (zh) | 一种羟脯氨酸类肽衍生物及其制备方法和应用 | |
CN109384715B (zh) | 前列腺特异性膜抗原的小分子抑制剂的制备方法 | |
CN102627615A (zh) | 一种新化合物l-4-四嗪-苯丙氨酸及其制备方法和应用 | |
CN104341396A (zh) | 二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用 | |
Ma et al. | Design, synthesis, and structure–activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists | |
CN111704648A (zh) | 以氧桥双环庚烯类化合物为雌激素受体配体的蛋白水解靶向嵌合体化合物及制备方法与应用 | |
CN104072493A (zh) | 一类含2-巯基苯并噻唑和三唑杂环的萘酰亚胺化合物,其制备方法及其应用 | |
CN106478505B (zh) | 一种双光子gsh探针及其制备与应用 | |
CN110078708A (zh) | Smo抑制剂及其合成方法和应用 | |
CN102558172B (zh) | 5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物,其制备方法和用途 | |
CN105916857B (zh) | 吡咯并吡咯酮衍生物及其作为bet抑制剂的用途 | |
CN109665987A (zh) | 萘内酰亚胺-多胺缀合物及其制备方法和用途 | |
CN107033043B (zh) | N-取代苯磺酰基-取代苯甲酰胺类化合物及其制备药物的用途 | |
CN109983014A (zh) | 突变型异柠檬酸脱氢酶抑制剂、组合物及其方法 | |
CN105669532B (zh) | 尼莫地平水溶性衍生物及其制备方法和应用 | |
CN104587487B (zh) | 一种应用于靶向给药系统的新的支链连接体 | |
CN105712992B (zh) | 作为cMet抑制剂的化合物及其制备方法和用途 | |
Banerjee et al. | Bifunctional chelates with aliphatic amine donors for labeling of biomolecules with the {Tc (CO) 3}+ and {Re (CO) 3}+ cores: the crystal and molecular structure of [Re (CO) 3 {(H2NCH2CH2) 2 N (CH2) 4CO2Me}] Br |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |