CN110812479A - 没食子酸和egfr靶点抗体组合物及其在肺癌上应用 - Google Patents
没食子酸和egfr靶点抗体组合物及其在肺癌上应用 Download PDFInfo
- Publication number
- CN110812479A CN110812479A CN201911125335.5A CN201911125335A CN110812479A CN 110812479 A CN110812479 A CN 110812479A CN 201911125335 A CN201911125335 A CN 201911125335A CN 110812479 A CN110812479 A CN 110812479A
- Authority
- CN
- China
- Prior art keywords
- composition
- compound
- egfr
- gallic acid
- ethanol
- 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.)
- Pending
Links
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 235000004515 gallic acid Nutrition 0.000 title claims abstract description 50
- 229940074391 gallic acid Drugs 0.000 title claims abstract description 50
- 206010058467 Lung neoplasm malignant Diseases 0.000 title claims abstract description 21
- 201000005202 lung cancer Diseases 0.000 title claims abstract description 21
- 208000020816 lung neoplasm Diseases 0.000 title claims abstract description 21
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 title claims abstract 18
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 title claims abstract 18
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 title claims abstract 18
- 239000003381 stabilizer Substances 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 229960005395 cetuximab Drugs 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000000284 extract Substances 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 13
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 235000001674 Agaricus brunnescens Nutrition 0.000 claims description 9
- 239000000469 ethanolic extract Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000002034 butanolic fraction Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 240000007440 Agaricus campestris Species 0.000 claims description 7
- 235000004570 Agaricus campestris Nutrition 0.000 claims description 7
- VXOZCESVZIRHCJ-KGHQQZOUSA-N ergosterol peroxide Chemical compound O1O[C@@]2(C=C3)[C@@H]4CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]2[C@]2(C)[C@@]13C[C@@H](O)CC2 VXOZCESVZIRHCJ-KGHQQZOUSA-N 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 241000222519 Agaricus bisporus Species 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 230000008685 targeting Effects 0.000 claims description 6
- 238000009210 therapy by ultrasound Methods 0.000 claims description 6
- 238000002137 ultrasound extraction Methods 0.000 claims description 6
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- 229940126208 compound 22 Drugs 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 5
- 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 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000004898 kneading Methods 0.000 claims description 3
- 229950008001 matuzumab Drugs 0.000 claims description 3
- 229960001972 panitumumab Drugs 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 238000002791 soaking Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- UPJVQRZPXLZUET-UHFFFAOYSA-N (10R)-3c,5t,8t-Trihydroxy-10r,13c-dimethyl-17c-((1R:4R)-1,4,5-trimethyl-hexen-(2t)-yl)-(9tH,14tH)-Delta6-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products OC12C=CC3(O)CC(O)CCC3(C)C2CCC2(C)C1CCC2C(C)C=CC(C)C(C)C UPJVQRZPXLZUET-UHFFFAOYSA-N 0.000 claims 1
- VXOZCESVZIRHCJ-KYQKSOQPSA-N ergosterol peroxide Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@@H]2[C@]1(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@]45OO[C@@]23C=C5 VXOZCESVZIRHCJ-KYQKSOQPSA-N 0.000 claims 1
- LESGHGUKCRHTCP-UHFFFAOYSA-N ergosteryl peroxide Natural products C1C(OO)CCC2(C)C(CCC3(C(C(C)C=CC(C)C(C)C)CCC33)C)C3=CC=C21 LESGHGUKCRHTCP-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 20
- 238000011282 treatment Methods 0.000 abstract description 10
- 206010027476 Metastases Diseases 0.000 abstract description 6
- 230000009401 metastasis Effects 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000003902 lesion Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 31
- 239000000243 solution Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 102000001301 EGF receptor Human genes 0.000 description 19
- 108060006698 EGF receptor Proteins 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 241000222518 Agaricus Species 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 230000002147 killing effect Effects 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 8
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 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 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- 229940125758 compound 15 Drugs 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- 241001327634 Agaricus blazei Species 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 4
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 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 4
- RGZHEOWNTDJLAQ-UHFFFAOYSA-N 3,4,5-trihydroxybenzaldehyde Chemical compound OC1=CC(C=O)=CC(O)=C1O RGZHEOWNTDJLAQ-UHFFFAOYSA-N 0.000 description 4
- UWQZVUQKBWZNLN-UHFFFAOYSA-N 4-(Ethoxymethyl)phenol Chemical compound CCOCC1=CC=C(O)C=C1 UWQZVUQKBWZNLN-UHFFFAOYSA-N 0.000 description 4
- IGCQTZQTGKNFLX-UHFFFAOYSA-N 4-[2-[2-(4-hydroxyphenyl)ethoxy]ethyl]phenol Chemical compound C1=CC(O)=CC=C1CCOCCC1=CC=C(O)C=C1 IGCQTZQTGKNFLX-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 4
- NMLPABRPTHFKMQ-UHFFFAOYSA-N 8-methoxynaphthalen-1-ol Chemical compound C1=CC(O)=C2C(OC)=CC=CC2=C1 NMLPABRPTHFKMQ-UHFFFAOYSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 4
- 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 4
- 239000007853 buffer solution Substances 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- AHXXIALEMINDAW-UHFFFAOYSA-N p-hydroxybenzyl methyl ether Natural products COCC1=CC=C(O)C=C1 AHXXIALEMINDAW-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- 241000222501 Agaricaceae Species 0.000 description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229960005305 adenosine Drugs 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- JMFRWRFFLBVWSI-UHFFFAOYSA-N cis-coniferyl alcohol Natural products COC1=CC(C=CCO)=CC=C1O JMFRWRFFLBVWSI-UHFFFAOYSA-N 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- ZENOXNGFMSCLLL-UHFFFAOYSA-N vanillyl alcohol Chemical compound COC1=CC(CO)=CC=C1O ZENOXNGFMSCLLL-UHFFFAOYSA-N 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 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 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 240000001414 Eucalyptus viminalis Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OCOMKVVSXFCESC-UHFFFAOYSA-N bis-(4-hydroxybenzyl)ether Chemical compound C1=CC(O)=CC=C1COCC1=CC=C(O)C=C1 OCOMKVVSXFCESC-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- LSKFUSLVUZISST-UHFFFAOYSA-N guaiacylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC=C1O LSKFUSLVUZISST-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- FFWOKTFYGVYKIR-UHFFFAOYSA-N physcion Chemical compound C1=C(C)C=C2C(=O)C3=CC(OC)=CC(O)=C3C(=O)C2=C1O FFWOKTFYGVYKIR-UHFFFAOYSA-N 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- SQEBMLCQNJOCBG-HVHJFMEUSA-N (5s)-3-(hydroxymethyl)-5-methoxy-4-methyl-5-[(e)-2-phenylethenyl]furan-2-one Chemical compound C=1C=CC=CC=1/C=C/[C@]1(OC)OC(=O)C(CO)=C1C SQEBMLCQNJOCBG-HVHJFMEUSA-N 0.000 description 1
- KEQXNNJHMWSZHK-UHFFFAOYSA-L 1,3,2,4$l^{2}-dioxathiaplumbetane 2,2-dioxide Chemical compound [Pb+2].[O-]S([O-])(=O)=O KEQXNNJHMWSZHK-UHFFFAOYSA-L 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- SYYMNUFXRFAELA-BTQNPOSSSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol;hydrobromide Chemical compound Br.N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 SYYMNUFXRFAELA-BTQNPOSSSA-N 0.000 description 1
- FSZDTYBFTVKOOT-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1.OC1=CC=C(C=O)C=C1 FSZDTYBFTVKOOT-UHFFFAOYSA-N 0.000 description 1
- BOXYODYSHAHWPN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1.OC(=O)C1=CC=C(O)C=C1 BOXYODYSHAHWPN-UHFFFAOYSA-N 0.000 description 1
- 241000222485 Agaricales Species 0.000 description 1
- 241000777739 Agaricus gennadii Species 0.000 description 1
- 241000774330 Bacillus freudenreichii Species 0.000 description 1
- YKESCYBQWFUVGY-UHFFFAOYSA-N C(C1=CC=C(C=C1)OC)(=O)O.OC1=CC=C(C(=O)O)C=C1 Chemical compound C(C1=CC=C(C=C1)OC)(=O)O.OC1=CC=C(C(=O)O)C=C1 YKESCYBQWFUVGY-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- FBMORZZOJSDNRQ-UHFFFAOYSA-N Demethoxy,B,HCl-Adriamycin Natural products C1C2C(=C)CCCC2(C)CC2(O)C1=C(C)C(=O)O2 FBMORZZOJSDNRQ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- LSKFUSLVUZISST-WPRPVWTQSA-N Guaiacylglycerol Natural products COC1=CC([C@H](O)[C@@H](O)CO)=CC=C1O LSKFUSLVUZISST-WPRPVWTQSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- UGNZSMZSJYOGNX-UHFFFAOYSA-N Isoviocristine Natural products O=C1C=C(C)C(=O)C2=CC3=CC(OC)=CC(O)=C3C(O)=C21 UGNZSMZSJYOGNX-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 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 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- KRDUSXSFQFTEKC-UHFFFAOYSA-N OCCC1=CC=C(C(=O)O)C=C1.OC1=CC=C(C(=O)OCC)C=C1 Chemical compound OCCC1=CC=C(C(=O)O)C=C1.OC1=CC=C(C(=O)OCC)C=C1 KRDUSXSFQFTEKC-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 241000222350 Pleurotus Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 241000192023 Sarcina Species 0.000 description 1
- 241001085826 Sporotrichum Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000006468 Thea sinensis Nutrition 0.000 description 1
- 244000044283 Toxicodendron succedaneum Species 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- WLXGUTUUWXVZNM-UHFFFAOYSA-N anthraglycoside A Natural products C1=C(C)C=C2C(=O)C3=CC(OC)=CC(O)=C3C(=O)C2=C1OC1OC(CO)C(O)C(O)C1O WLXGUTUUWXVZNM-UHFFFAOYSA-N 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QXMNTPFFZFYQAI-IMDKZJJXSA-N beta-sitosterol 3-O-beta-D-glucopyranoside Natural products CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](CC[C@]4(C)[C@H]3CC[C@]12C)O[C@@H]5C[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)C(C)C QXMNTPFFZFYQAI-IMDKZJJXSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- NPJICTMALKLTFW-OFUAXYCQSA-N daucosterol Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CC[C@@H](CC)C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O NPJICTMALKLTFW-OFUAXYCQSA-N 0.000 description 1
- QDFKFNAHVGPRBL-UHFFFAOYSA-N daucosterol Natural products CCC(CCC(C)C1CCC2C1CCC3C2(C)CC=C4CC(CCC34C)OC5OC(CO)C(O)C(O)C5O)C(C)C QDFKFNAHVGPRBL-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000000312 effect on influenza Effects 0.000 description 1
- 208000026500 emaciation Diseases 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- JUTMAMXOAOYKHT-UHFFFAOYSA-N karrikinolide Natural products C1=COC=C2OC(=O)C(C)=C21 JUTMAMXOAOYKHT-UHFFFAOYSA-N 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PKUBGLYEOAJPEG-UHFFFAOYSA-N physcion Natural products C1=C(C)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O PKUBGLYEOAJPEG-UHFFFAOYSA-N 0.000 description 1
- 238000011202 physical detection method Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940045920 sodium pyrrolidone carboxylate Drugs 0.000 description 1
- HYRLWUFWDYFEES-UHFFFAOYSA-M sodium;2-oxopyrrolidine-1-carboxylate Chemical compound [Na+].[O-]C(=O)N1CCCC1=O HYRLWUFWDYFEES-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000003046 sporozoite Anatomy 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种EGFR靶点抗体的组合物,组合物为没食子酸和EGFR为靶点的单抗和/或双特异性抗体及稳定剂,并且公开了该组合物在肺癌上应用,该组合物可以抑制肺癌细胞NCI‑H1975转移及肿瘤病灶的形成;且组合物体系稳定;可以为临床治疗方案提供参考。
Description
技术领域:
本发明涉及天然产物的应用技术领域,从自然菌菇提取活性成分没食子酸及其应用,更具体涉及圆孢蘑菇中提取没食子酸及其没食子酸和EGFR靶点抗体的组合物在肺癌上应用。
背景技术:
蘑菇科(Agaricaceae)系真菌伞菌目的一科,种类多,分布广泛,大多数可以食用,全世界均有分布。蘑菇科有包括蘑菇属在内的28个属。蘑菇科蘑菇属(Agaricus)中常见种有圆孢蘑菇Agaricus gennadii(Chot.et Boud)P.D.Orton、双孢蘑菇Agaricus bisporus(Large)Sing.、姬松茸Agaricus blazei murrill、紫蘑菇Agaricus rubellus(Gill.)Sacc.、褐蘑菇Agaricus crocopeluspeck等。目前,该属的化学成分以及药理活性研究相关研究主要集中在双孢蘑菇和姬松茸两种。
蘑菇科(Agaricaceae)蘑菇属(Agaricus)的化学成分研究从上个世纪九十年代开始,发现本属真菌的化学成分主要有挥发油、Agariblazeispirol类、甾醇类、固醇类、A-1(吡咯烷酮羧酸钠)、黄酮等。可能含有神经酰胺类成分、胡萝卜苷、二萜类、三萜类、大黄素甲醚,洋芹素-7-4’-二甲醚和愈创木基丙三醇、丁烯羟酸内酯类等。
圆孢蘑菇Agaricus gennadii属伞菌目蘑菇科蘑菇属(Agaricus),别名“圆孢托柄蘑菇”。圆孢蘑菇呈伞形,有浓郁的蘑菇香味。菌褶幼时乳白色,后渐变为粉红色至黑褐色,单个重58-350g,最大可达2-5kg。夏秋季生长于灌丛沙地、湖边芦苇丛下20-70cm的土中,在地下能开伞,单生、散生或丛生,多生长在新疆西部及西南部地区。从上世纪九十年代以来,人们已经发现同属中姬松茸的活性成分以及它的多种活性。但同属中的圆孢蘑菇Agaricusgennadii的化学成分以及相关活性尚处在空白中。为开发利用这一资源,在青海省自然科学基金2018-ZL-919的资助下对圆孢蘑菇的小分子化学成分进行了较系统的研究。
没食子酸亦称五倍子酸或棓酸,是一种有机酸,可见于五倍子、漆树、茶等植物中。化学式C6H2(OH)3COOH。没食子酸易溶于水、醇和醚;具有酚(易被氧化和三氯化铁水溶液生成蓝黑色沉淀)及羧酸(加热时失去二氧化碳成焦性没食子酸)的性质。没食子酸可用作显影剂,它的碱性铋盐用作防腐剂,也用于制药工业上。
研究发现没食子酸具有抗菌,抗病毒,抗肿瘤作用。没食子酸在抗菌抗病毒方面:体外对金黄色葡萄球菌、八叠球菌、α-型键球菌、奈瑟氏球菌、绿脓杆菌、弗氏痢疾杆菌、伤寒杆菌Hd、副伤寒杆菌A等有抑制作用,其抑菌浓度为5mg/ml。体外在3%的浓度下对17种真菌有抑菌作用,对流感病毒亦有一定抑制作用。在抗肿瘤方面:对吗啉加亚硝钠所致的小鼠肺腺瘤有强抑制作用。
表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种跨膜蛋白。EGFR信号转导途径在调节肿瘤细胞的生长、损伤修复和生存、新生血管生成、侵袭和转移中具有更重要的作用,同时在相当一部分的人类肿瘤中都有表达。EGFR广泛存在于多种表皮来源的恶性肿瘤细胞当中:非小细胞肺癌、结直肠癌、胃癌、前列腺癌、卵巢癌、头颈部肿瘤。目前市场上以EGFR为靶点的药物主要有:a)作用于受体细胞内的小分子酪氨酸激酶抑制剂(TKI),如:吉非替尼、erlotinib、EKB-569、PKI-166、GW-2016及CI-1033;b)作用于受体胞外区的单克隆抗体(MAb)西妥昔单抗、ABX-EGF及EMD72000等。
在目前针对EGFR靶点临床治疗中,一般出现单一的化疗,化疗对HNSCC的治疗效果不够理想,仍有大约2/3的患者局部复发,5年生存率徘徊在30-40%。当化疗出现一定的耐药后,会有单一的单克隆抗体靶向治疗,单克隆抗体治疗HNSCC病人应答率可以达到13%(7-21%),疾病控制率为45%(36-56%)与中位总存活期为5.84月。后期综合治疗以单克隆抗体联合化疗,特别是对于复发或转移或耐药的HNSCC患者,当单克隆抗体同化疗联合治疗后,在临床中,表现出结果反应率有所提高,应答率可以达到16%(9-26%),疾病控制率为53%(43-63%)与中位总存活期为9.84月。但是无论哪种治疗手段,均达不到最好的治疗效果,想进一步取得好的治疗效果,化疗会带来皮疹、其他并发症或严重输液反应发生率。
发明内容
针对上述所述问题,本发明提出了一种没食子酸同EGFR靶点抗体形成的组合物,过没食子酸和EGFR靶点抗体的组合物在肺癌上应用,该组合物对肺癌具有良好效果。
为了实现上述目的,本发明采用以下的技术方案:
所述组合物为:没食子酸及以EGFR为靶点的单抗和/或双特异性抗体以及稳定剂。
其中所述稳定剂选用枸橼酸。
所述组合物的制备方法包括以下步骤:
(1)没食子酸的获得;
(2)步骤1中的没食子酸制备成10-200mg/ml溶液,将没食子酸溶液与以EGFR为靶点的单抗和/或双特异性抗体混合获得组合物。
其中组合物中以EGFR为靶点的单抗和/或双特异性抗体含量为10-1000μg/ml。
其中组合物中稳定剂百分比含量0.01-0.05%。
所述的抗体可以为:西妥昔单抗、ABX-EGF及EMD72000,以及其他的以EGFR为靶点的单抗和/或双特异性抗体一种或多种。
没食子酸溶液与以EGFR为靶点的单抗和/或双特异性抗体在无菌条件下混合,将抗体加入没食子酸溶液中,并在37℃水浴锅中孵育10-30Min,并通过常规方法混匀该组合物,后分装该组合物于容器中,4-8℃保存。
其中上述没食子酸的制备方法如下:
取新鲜、无毁坏的圆孢蘑菇子实体,以圆孢蘑菇为原料,切片先后经90-95%、60-65%乙醇浸泡浸提得浓缩液、浓缩液浓缩得浸膏、乙醇浸膏合并,最后合并后浸膏经有机溶剂萃取得萃取液,萃取液经色谱柱分离纯化即获得没食子酸及其他各活性成分其中,上述圆孢蘑菇子实体与乙醇比例为0.5-1:1-5,使乙醇完全浸泡圆孢蘑菇子实体。
作为本发明的一种优选的实施方式,本发明所述的圆孢蘑菇没食子酸具体通过以下方法制备获得:取新鲜、无毁坏的圆孢蘑菇子实体,切片后用90-95%乙醇浸泡一周圆孢蘑菇子实体,过滤得滤液,减压回收溶剂,滤渣加入90-95%乙醇超声提取3-5次,每次提取1-5h,减压浓缩得90-95%乙醇浸膏;用60-65%乙醇同法操作,减压浓缩得60-65%乙醇浸膏;醇提取后的圆孢蘑菇滤渣,加入蒸馏水超声提取三次,每次提取1-3h,减压浓缩得水提浸膏。
其中,上述减压回收条件为0.1-0.5MPA,温度25-40℃;上述超声提取条件为200-800HZ,超声30-45min,温度30-50℃。
将两部分醇提浸膏合并,将合并后的浸膏捏溶分散于纯水中,在分液漏斗中加入石油醚(水与石油醚比例为1:1-0.5),再将浸膏分散液加入分液漏斗中,萃取5次,萃取液合并浓缩,得石油醚部位。后再次向分液漏斗中加入乙酸乙酯(水与乙酸乙酯比例为0.5-1:1),萃取6次,萃取液合并浓缩,得乙酸乙酯部位;之后再向分液漏斗中加入正丁醇(水与正丁醇比例为0.4-1:1),萃取5次,萃取液合并浓缩,得正丁醇部位。
其中,上述萃取条件为:萃取压力为20MPa~40MPa,萃取温度30℃~50℃,萃取时间为0.8h~2.5h。
将上述获得的正丁醇部位加入乙醇,沉淀时在容器壁上析出结晶,反复多次操作,多次重结晶得化合物23。正丁醇部位经中压反相C18分离,用水-甲醇溶液(5%~100%)梯度洗脱,洗脱液按同一梯度合并,减压回收溶剂得到Z-Ⅰ~Z-Ⅵ共6个组分。Z-Ⅱ组分经由MCI树脂分离,用水-甲醇溶液(0%~100%)梯度洗脱,并用C18半制备柱分离纯化得化合物7、化合物8、化合物9、化合物10。Z-Ⅳ组分经C18半制备柱分离纯化后得化合物6。Z-Ⅰ组分即MCI树脂纯水洗脱部位,经Agilent Zorbax SB-CN全制备柱分离切段,用水-甲醇溶液(5%)等度洗脱,得Z-A~Z-D共4个组分。
其中,上述反相C18柱色谱分离的条件为:水-甲醇溶剂系统(5%~100%)梯度洗脱;流速:1.0-3.5ml/min,柱温:25-30℃。
其中,上述MCI树脂分离条件为水-甲醇溶剂系统(0%~100%)梯度洗脱;流速:1.0-3.5ml/min,柱温:25-30℃。
其中,上述C18半制备柱分离纯化条件为:流动相A:1ml/L磷酸水溶液(0.2%三乙胺,磷酸调PH2.0),流动相B:乙腈;流动相A、B均需抽滤,超声10min;流动相比例:流动相A:流动相B=90:10;流速:1.0-3.5ml/min,柱温:20-30℃。
Z-A组分经Agilent Zorbax SB-CN半制备柱分离纯化,得化合物13、化合物14、化合物16、化合物17、化合物19、化合物20和21。化合物14、16、17、20和21均为白色颗粒,化合物13为白色胶状物;化合物19为纯化后结晶所得,透明针状结晶。Z-B组分经AgilentZorbax SB-CN半制备柱分离纯化,得化合物11、12,化合物11、12为白色颗粒。Z-C组分经Agilent Zorbax SB-CN半制备柱分离纯化,得化合物18和化合物22,化合物18、22均为白色粉末。Z-D组分经Agilent Zorbax SB-CN半制备柱分离纯化,得化合物15,化合物15为白色粉末。
其中,上述Agilent Zorbax SB-CN半制备柱分离纯化条件为:流动相A:以10-30mM的Na2HPO4-NaH2PO4缓冲溶液或K2HPO4-KH2PO4缓冲溶液或Tris-HCl缓冲溶液作为洗脱液A(0.2%三乙胺,磷酸调PH2.0),流动相B:乙腈;流动相A、B均需抽滤,超声10min;流动相比例:流动相A:流动相B=90:10;流速:1.0-3.5ml/min,柱温:20-30℃。
采用上述的技术方案,本发明的有益效果是:
1、没食子酸同以EGFR为靶点的单抗和/或双特异性抗体混合后的组合物对肺癌细胞NCI-H1975杀伤作用强,且可以抑制肺癌细胞NCI-H1975转移及肿瘤病灶的形成;
2、稳定剂的加入可以调节抗体与组合物体系的稳定性,且没食子酸可促进抗体发挥作用;
3、组合物共同作用于受体,相较于单独疗法可大幅度降低治疗成本,获得有效的治疗效果,简化临床治疗过程;
4、组合物对EGFR靶点抗体产生耐药或者复发性和/或转移性头颈部鳞状细胞癌的患者有较好的效果,可以为临床治疗方案提供参考;
5、通过该分离提取方法,快速分离圆孢蘑菇各组分,分离提取工艺简单稳定、适合工业化连续生产、产品收率较高,对于各种活性成分可以高效、简便的分离。
具体实施方式:
下面结合具体的实施例,对本发明实施例中的技术方案进行清楚、完整地描述。应理解,所描述的实施例是本发明一部分实施例,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。
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例,进一步阐述本发明。
实施例1圆孢蘑菇中各活性组分粗提物制备
取新鲜、无毁坏的圆孢蘑菇子实体10kg,切片后用30L 95%乙醇浸泡7天(其中圆孢蘑菇子实体与乙醇比例为1:3,使乙醇完全浸泡圆孢蘑菇子实体),过滤得滤液,减压回收溶剂,滤渣加入30L 95%乙醇超声提取3次,每次提取2h。减压浓缩得95%乙醇浸膏。用65%乙醇同法操作,减压浓缩得65%乙醇浸膏。醇提取后的圆孢蘑菇滤渣,加入蒸馏水30L并1800HZ超声提取三次,每次提取2h。减压浓缩得水提浸膏538g。
其中,上述减压回收条件为0.25MPA,温度30℃;上述超声提取条件为800HZ,超声45min,温度30℃。
将两部分醇提浸膏合并得84.5g,将合并后的浸膏84.5g捏溶分散于500ml纯水中,在2000ml分液漏斗中加入石油醚(水与石油醚比例为1:1),再将浸膏分散液加入分液漏斗中,萃取5次,萃取液合并浓缩,得石油醚部位10.0g。再领取2000ml分液漏斗,向分液漏斗中加入乙酸乙酯(水与乙酸乙酯比例为1:1),再将浸膏分散液加入分液漏斗中,萃取6次,萃取液合并浓缩,得乙酸乙酯部位6.0g。再领取2000ml分液漏斗,向分液漏斗中加入正丁醇(水与正丁醇比例为1:1),再将浸膏分散液加入分液漏斗中萃取5次,萃取液合并浓缩,得正丁醇部位60.0g。
其中,上述萃取条件为:萃取压力为40MPa,萃取温度35℃,萃取时间为2h。
实施例2正丁醇部位组分分离纯化
将上述实施例1获得的正丁醇部位60.0g加入乙醇,沉淀时在容器壁上析出结晶,反复多次操作,多次重结晶得30mg的化合物23。正丁醇部位经中压反相C18分离用水-甲醇溶液(5%~100%)梯度洗脱,洗脱液按同一梯度合并,减压回收溶剂得到Z-Ⅰ~Z-Ⅵ共6个组分。Z-Ⅱ组分经由MCI树脂分离,用水-甲醇溶液(0%~100%)梯度洗脱,并用C18半制备柱分离纯化得4mg的化合物7、5mg的化合物8、4mg的化合物9、5mg的化合物10。Z-Ⅳ组分经C18半制备柱分离纯化后得5mg的化合物6。Z-Ⅰ组分即MCI树脂纯水洗脱部位,经Agilent ZorbaxSB-CN全制备柱分离切段,用水-甲醇溶液(5%)等度洗脱,得Z-A~Z-D共4个组分。
其中,上述反相C18柱色谱分离的条件为:水-甲醇溶剂系统(5%~100%)梯度洗脱;流速:1.5ml/min,柱温:30℃。
其中,上述MCI树脂分离条件为水-甲醇溶剂系统(0%~100%)梯度洗脱;流速:1.5ml/min,柱温:30℃。
其中,上述C18半制备柱分离纯化条件为:流动相A:1ml/L磷酸水溶液(0.2%三乙胺,磷酸调PH2.0),流动相B:乙腈;流动相A、B均需抽滤,超声10min;流动相比例:流动相A:流动相B=90:10;流速:1.5ml/min,柱温:30℃。
AA-A组分经Agilent Zorbax SB-CN半制备柱分离纯化,得化合物4mg的13、100mg的化合物14、5mg的化合物16、4mg的化合物17、15mg的化合物19、4mg的化合物20和3mg的21。化合物14、16、17、20和21均为白色颗粒,化合物13为白色胶状物;化合物19为纯化后结晶所得,透明针状结晶。Z-B组分经Agilent Zorbax SB-CN半制备柱分离纯化,得化合物4mg的11、5mg的12,化合物11、12为白色颗粒。Z-C组分经Agilent Zorbax SB-CN半制备柱分离纯化,得5mg的化合物18和4mg的化合物22,化合物18、22均为白色粉末。Z-D组分经AgilentZorbax SB-CN半制备柱分离纯化,得4mg的化合物15,化合物15为白色粉末。
其中,上述Agilent Zorbax SB-CN半制备柱分离纯化条件为:流动相A:以15mM的Na2HPO4-NaH2PO4缓冲溶液或K2HPO4-KH2PO4缓冲溶液或Tris-HCl缓冲溶液作为洗脱液A(0.2%三乙胺,磷酸调PH2.0),流动相B:乙腈;流动相A、B均需抽滤,超声10min;流动相比例:流动相A:流动相B=90:10;流速:1.5ml/min,柱温:30℃。
将分离纯化的化合物组分进行理化性质鉴定,通过常规物理检测方法:其检测方法有:EIS-MS、H-NMR、C-NMR。其检测方法同药典2015版检测方法。检测结果如下:
化合物6麦角甾醇(Ergosterol)
白色粉末;EI-MS m/z=428[M-H2O],410[M-2H20],382[M-2H2O-CO].1H-NMR(CD3OD,500MHz):5.21(2Hm,H-22,23),5.05(1H,brs,H-7),3.88(2H,m,H-3,6),1.05(3H,S,H-19),1.03(3H,d,J=6.7Hz,H-21),0.93(3H,d,J=6.9Hz,H-28),0.86(3H,d,J=6.8Hz,H-27),0.84(3H,d,J=6.8Hz,H-26),0.61(3H,S,H-18)。13C-NMR(DEPT)谱给出了28个碳的信号,分别为6个甲基、7个亚甲基、10个次甲基和5个季碳。其中四个碳信号在δc78.6,75.8,71.2,67.9,表明它们与氧连接。在δc143.3,137.0,133.3,122.0的四个碳信号表明有两个双键。以上数据与麦角甾醇的数据基本一致,故鉴定化合物6为麦角甾醇。
化合物7过氧麦角甾醇(peroxy-ergosterol)
白色粉末。1H-NMR(500MHz,CDCl3)δ:6.50(1H,d,J=8.5Hz,H-7),6.24(1H,d,J=8.5Hz,H-6),5.22(1H,dd,J=7.6,15.3Hz,H-23),5.14(1H,dd,J=8.3,15.5Hz,H-22),3.92(1H,m,H-3),1.25(3H,s,Me-19),1.00(3H,d,J=6.7,Me-21),0.91(3H,d,J=6.9Hz,Me-28),0.88(3H,s,Me-18),0.83(3H,d,J=6.8Hz,Me-26),0.82(3H,d,J=6.8Hz,Me-27)。13C-NMR(125MHz,CDCl3)δ:34.7(t,C-1),30.1(t,C-2),66.4(d,C-3),36.9(t,C-4),82.2(s,C-5),135.4(d,C-6),130.7(d,C-7),79.4(s,C-8),51.1(d,C-9),36.9(s,C-10),23.4(t,C-11),39.4(t,C-12),44.6(s,C-13),51.8(d,C-14),20.6(t,C-15),28.6(t,C-16),56.2(d,C-17),12.9(q,C-18),18.2(q,C-19),39.4(d,C-20),20.9(q,C-21),135.2(d,C-22),132.3(d,C-23),42.8(d,C-24),33.1(d,C-25),20.0(q,C-26),19.6(q,C-27),17.6(q,C-28);以上数据与过氧麦角甾醇的数据一致,故鉴定化合物7为过氧麦角甾醇。
化合物8Macrosphelide A
白色粉末,ESI-MS m/z:365.2[M+Na]+,341.2[M-H]-,由此推断相对分子质量为342,结合氢谱和碳谱,可以推得分子式为C16H22O8,1H-NMR(CDCl3):6.88(1H,dd,J=15.6,1.5Hz,H-7),6.83(1H,dd,J=15.6,1.5Hz,H-13),6.02(1H,dd,J=15.6,1.5Hz,H-12),6.01(1H,dd,J=15.6,1.5Hz,H-6),5.35(1H,m,H-3),4.93(1H,q,J=6.3Hz,H-9),4.82(1H,q,J=6.3Hz,H-15),4.18(1H,m,H-8),4.09(1H,m,H-14),3.57(2H,brs,8-OH,14-OH),2.58(2H,dd,J=7.2,2.4Hz,2-H2),1.40(3H,d,J=6.6Hz,9-CH3),1.33(3H,d,J=6.3Hz,15-CH3),1.29(3H,d,J=6.6Hz,3-CH3);13C-NMR(CDCl3),170.1(C-1),165.7(C-11),164.9(C-5),146.4(13-CH),145.6(7-CH),122.5(6-CH),122.1(12-CH),74.5(9-CH),74.4(8-CH),73.6(15-CH),72.8(14-CH),67.7(3-CH),40.9(2-CH2),19.6(3-CH3),17.8(9-CH3),17.7(15-CH3);以上数据与Macrosphelide A的数据一致,故鉴定化合物8为Macrosphelide A。
化合物9腺苷(a-denosine)
白色粉末,mp.230~232℃;1H-NMR(DMSO-d6,500MHz)δ:3.58(1H,d,J=10.8Hz,H-5′),3.67(1H,d,J=11.4Hz,H-5′),5.88(1H,d,J=9.6Hz,H-1′),7-33(2H,brs,J=1.0Hz,NH2),8.14(1H,s,H-8),8.34(1H,s,H-2);13CNMR(DMSO-d6,125MHz)δ:152.3(C-2),149.0(C-4),119.3(C-5),156.1(C-6),139.9(C-8),87.9(C-1′),73.4(C-2′),70.6(C-3′),85,8(C-4′),61.6(C-5′),156.1(C-6′),以上波谱数据及理化特征与腺苷一致,故鉴定该化合物9为腺苷(a-denosine)。
化合物10对羟基苯甲酸乙酯(4-hydroxy ethylbenzoate)
无色油状物;易溶于丙酮、氯仿和甲醇,难溶于水。ESIMS m/z=167[M+H]+;1H-NMR(Me2CO-d,6,500Hz)δ:7.87(2H,d,J=9.0Hz,H-2,6),6.90(2H,d,J=9.0Hz,H-3,5),4.22(2H,q,J=7.0Hz,H2-1′),1.31(3H,t,J=7.0Hz,H3-2′)。以上数据与对羟基苯甲酸乙酯的数据一致,故鉴定化合物10为对羟基苯甲酸乙酯。
化合物12对羟基苯甲醛(p-hydroxybenzaldehyde)
无色油状物;易溶于丙酮、氯仿和甲醇,难溶于水;ESIMS m/z=123[M+H]+;1H-NMR(Me2CO-d6,500Hz,)δ:9.84(1H,s,H-7),7.79(2H,d,J=9.0Hz,H-2,6),7.00(2H,d,J=8.5Hz,H-3,5)。以上数据与对羟基苯甲醛的数据一致,故鉴定化合物12为对羟基苯甲醛。
化合物134-羟基-3-甲氧基-苄醇(4-hydroxy-3-methoxy-benzyl alcohol)
白色固体。易溶于丙酮、氯仿和甲醇,不溶于水;ESIMS m/z=155[M+H]+;1H-NMR(Me2CO-,d,6,500Hz)δ:7.53(1H,s,4-OH),6.84(1H,d,J=1.5Hz,H-2),6.85(1H,d,J=8.0Hz,H-5),6.75(1H,dd,J=1.5,8.0Hz,H-6),4.47(2H,d,J=6.5Hz,H2-7),4.03(1H,t,J=6.5Hz,7-OH),3.80(3H,s,-OMe);13C-NMR(Me2CO-,d,6,125Hz)δ:136.1(C-1),112.2(C-2),147.3(C-或C-4),147.0(C-或C-4),114.7(C-5),118.5(C-6),64.4(C-7),56.3(-OMe)。以上数据与4-羟基-3-甲氧基-苄醇的数据一致,故鉴定化合物13为4-羟基-3-甲氧基-苄醇。
化合物14 5α,6α-Epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7α-diol
白色粉末;HRESIMS:m/z=451.3167[M+Na]+(calcdfor C28H44NaO3,451.3183);1H-NMR(600MHz,CDCl3)δ:5.21(2H,m,H-22,23),4.42(1H,d,J=6.3Hz,H-7),3.91(1H,m,H-3),3.14(1H,d,J=3.5Hz,H-6),1.02(3H,d,J=6.7Hz,H-21),0.92(3H,d,J=6.8Hz,H-28),0.87(6H,s,H-18,19),0.84(3H,d,J=6.8Hz,H-27),0.82(3H,d,J=6.8Hz,H-26);13C-NMR(150MHz,CDCl3)δ:152.75(C-14),135.41(C-22),132.44(C-23),125.38(C-8),68.87(C-3),67.92(C-5),65.25(C-7),61.49(C-6),57.02(C-17),43.15(C-13),43.01(C-24)39.78(C-20),39.39(C-4),38.92(C-9),36.78(C-12),36.01(C-10),33.27(C-25),32.38(C-1),31.31(C-2),27.31(C-16),25.13(C-15),21.40(C-21),19.82(C-27),19.17(C-26),18.24(C-11),17.77(C-18,28),16.70(C-19)。以上数据与5α,6α-Epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7α-diol的数据一致,故鉴定化合物14为5α,6α-Epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7α-diol。
化合物15对羟基苯甲醇(p-hydroxybenzyl alcohol)
白色针晶(甲醇);易溶于丙酮、氯仿和甲醇,不溶于水;(-)-ESIMS m/z=283[M-H]-;1H-NMR(500MHz,DMSO-d6)δ:9.31(1H,s,OH),7.25(2H,d,J=8.0Hz,H-2,6),6.89(2H,d,J=8.0Hz,H-3,5),4.76(1H,s,OH),4.36(2H,s,H-7)。以上数据与对羟基苯甲醇的数据对照基本一致,故鉴定化合物15为对羟基苯甲醇。
化合物16对羟基苯甲酸(p-hydroxybenzoic acid)
白色片状结晶(丙酮),易溶于氯仿和甲醇,不溶于水(-)-ESIMS m/z=137[M-H]-;1H-NMR(500MHz,Me2CO-d6)δ:7.68(2H,d,J=9.0Hz,H-2,6),6.79(2H,d,J=9.0Hz, H-3,5)。13C-NMR(125MHz,Me2CO-d6)δ:168.3(COOH),162.1(C-4),132.1(C-2,6),122.2(C-1),114.9(C-3,5)。以上数据与对羟基苯甲酸的数据一致,故鉴定化合物16为对羟基苯甲酸。
化合物17对羟基苄基甲基醚(p-hydroxybenzyl methyl ether)
白色片状结晶(丙酮),易溶于氯仿和甲醇,不溶于水。(-)-ESIMS m/z=137[M-H]-;1H-NMR(500MHz,DMSO-d6)δ:9.25(1H,OH),7.17(2H,d,J=8.0Hz,H-2,6),6.69(2H,d,J=8.0Hz,H-3,5),4.19(2H,s,H-7),3.18(3H,s,OMe)。以上数据与对羟基苄基甲基醚的数据一致,故鉴定化合物17为对羟基苄基甲基醚。
化合物18对羟基苄基乙基醚(p-hydroxybenzyl ethyl ether)
白色片状结晶(丙酮),易溶于氯仿和甲醇,不溶于水; (+)-ESIMS m/z=153[M+H]+;1H-NMR(300MHz,DMSO-d6)δ:9.29(1H,OH),7.09(2H,d,J=8.4Hz,H-2,6),6.80(2H,d,J=8.4Hz,H-3,5),4.31(2H,s,H-7),3.39(2H,q,J=6.9Hz,OCH2CH3),1.11(3H,t,J=6.9Hz,OCH2CH3)。以上数据与对羟基苄基乙基醚的数据一致,故鉴定化合物18为对羟基苄基乙基醚。
化合物19对甲氧基苯甲酸(p-hydroxybenzoic acid)
白色片状结晶(丙酮),易溶于氯仿和甲醇,难溶于水。(-)-ESIMS m/z=151[M-H]-;1H-NMR(500MHz,DMSO-d6)δ:7.87(2H,d,J=8.5Hz,H-2,6),6.77(2H,d,J=8.5Hz,H-3,5),3.74(3H,s,OMe)。以上数据与对甲氧基苯甲酸的数据一致,故鉴定化合物19为对甲氧基苯甲酸。
化合物208-甲氧基-1-萘酚(8-Methoxynaphthalene-1-ol)
白色粉末,ESI-MS m/z=175[M+H]+.1H-NMR(CDC13,500MHz)δ:9.31(1H,s,1-OH),7.41(1H,d,J=8.3Hz,H-4),7.36~7.28(3H,m,H-3,H-5,H-6)6.87(1H,d,J=7.5Hz,,H-7),6.78(1H,d,J=7.7Hz,H-2)4.06(3H,s,8-OCH3);13C-NMR(CDCl3,125MHz)δ:156.2(C-8)154.5(C-1)136.8(C-4a)127.7(C-3)125.6(C-6),121.9(C-5)118.8(C-4)115.1(C-8a)110.4(C-2)103.9(C-7),56.1(8-OCH3)。以上数据与8-甲氧基-1-萘酚基本一致,故鉴定化合物20为8-甲氧基-1-萘酚。
化合物22没食子酸(gallic acid)
白色针晶;EI-MS m/z(%):171[M+H]+;1H-NMR(500MHz,CDCl3):7.15(2H,s,H-2,6),7.60(2H,s,3,5-OH),7.28(1H,s,4-OH),12.10(1H,s,1-COOH);13C-NMR(100MHz,CDCl3):123.1(s,C-1),114.3(d,C-2,6),146.0(s,C-3,5),139.4(s,C-4),170.6(s,COOH)。数据与过氧麦角甾醇的基本一致,故鉴定化合物22为没食子酸。
化合物233,4,5-三羟基-苯甲醛(3,4,5-trihydroxybenzaldehyde)
白色无定型粉末(甲醇)。1H-NMR(CD3OD,500MHz)δ(ppm):9.55(1H,s,-CHO),7.27(2H,s,H-2,6);13C-NMR(CD3OD,100MHz)δ(ppm):192.8(-CHO),149.9(C-3,5),145.2(C-4),128.0(C-1),108.3(C-2,6)。以上数据与3,4,5-三羟基-苯甲醛一致,故鉴定化合物23为3,4,5-三羟基-苯甲醛。
实施例3组合物对肺癌细胞NCI-H1975的杀伤活性
细胞组合物的制备:将实施例2分离纯化提取的没食子酸制备成50mg/ml的溶液,后将以EGFR为靶点的单抗和/或双特异性抗体,优选西妥昔单抗溶液,缓慢加入没食子酸溶液中,无菌密封环境下将混合物在37℃水浴中孵育20min,同时混合物按照常规方法均匀混合,必须保证无菌操作。
其中西妥昔单抗溶液含有稳定剂枸橼酸,且使西妥昔单抗、枸橼酸混合于没食子酸溶液中的终浓度或含量分别为500μg/ml、0.02%。
实验组别:空白对照组:生理盐水;
组合物组:没食子酸与西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
单抗组:西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
过氧麦角甾醇组:50mg/ml的没食子酸溶液。
实验方法:
取对数生长期的肺癌细胞NCI-H1975,按照每孔100ul(6000-8000个细胞)接种96孔板中,待细胞贴壁后每孔分别加入空白对照组、组合物组、单抗组、没食子酸组各100ul进行试验,37℃孵育4h和8h后,加入1μg/ml的PI染料,CFSE+PI双阳性的细胞为死亡细胞,如表1所示。
表1肺癌细胞NCI-H1975的杀伤统计结果:
组别 | 空白对照 | 组合物组 | 单抗组 | 没食子酸组 |
杀伤率% | 0% | 80.6% | 34.7% | 2.6% |
除了对照组,实验各组均表现出抑制肿瘤细胞生长、杀伤细胞的作用,其中组合物组对癌细胞的抑制杀伤活性最强,可以达到近80%的杀伤率,单抗组次之,没食子酸组有抑制杀伤癌细胞的作用,但效果较次,但其同抗体组合后能够显著达到抑制杀伤癌细胞的效果,说明没食子酸可以促进抗体发挥作用,同抗体协同抑制杀伤癌细胞。
实施例4组合物抑制肺癌细胞NCI-H1975的迁移
实验材料:(1)Transwell chamber:24-well,8.0-μm pore membranes(Corning);
(2)细胞培养相关试剂:无血清培养基,10%血清培养基,PBS,0.02%EDTA;
(3)固定液:甲醇;
(4)染色液:Giemsa染液;
(5)封片剂:中性树胶;
(6)其他:小镊子,棉棒,载玻片,盖玻片;
实验组别:制备方法同实施例3组合物制备方法;
空白对照组:生理盐水;
组合物组:没食子酸与西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
单抗组:西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
没食子酸组:50mg/ml的没食子酸溶液。
实验过程:
(1)所有细胞培养试剂和Transwell chamber放在37℃温育;
(2)取培养至对数生长期的肺癌细胞NCI-H1975,消化细胞,用PBS和RMPI1640+50vt%X-vivo15的混合培养基先后洗涤一次,用无血清培养基悬浮细胞,计数,调整浓度为2×105/ml;
(3)在下室(即24孔板底部)加入600-800μl含10%自体血清的RMPI1640+50vt%X-vivo15的混合培养基,上室加入100-150μl细胞悬液,同时分别加入各实验组的物质,按照1:1进行,继续在孵箱培养24小时;
(4)用镊子小心取出chamber,吸干上室液体,移到预先加入约800μl甲醇的孔中,室温固定30分钟;
(5)取出chamber,吸干上室固定液,移到预先加入约800μl Giemsa染液的孔中,室温染色15-30分钟;
(6)轻轻用清水冲洗浸泡数次,取出chamber,吸去上室液体,用湿棉棒小心擦去上室底部膜表面上的细胞;
(7)用小镊子小心揭下膜,底面朝上晾干,移至载玻片上用中性树胶封片;
(8)显微镜下取9个随机视野计数,统计结果。统计结果见表1。
表2细胞迁移统计数目(个)
通过上述实验统计得到:在4组实验中,组合物组的肺癌细胞NCI-H1975迁移最少,当没食子酸同抗体联合作用于癌细胞后,可以有效阻止癌细胞的迁移及转移,肺癌细胞NCI-H1975有一部分凋亡,其余细胞迁移性降低,因此组合物抑制肺癌细胞NCI-H1975转移及成瘤有效,此种方法可以降低肺癌细胞NCI-H1975转移及成瘤风险。
实施例5组合物对体内肿瘤作用
组合物的制备:将实施例2分离纯化提取的没食子酸制备成50mg/ml的溶液,后将以EGFR为靶点的单抗和/或双特异性抗体,优选西妥昔单抗溶液,缓慢加入没食子酸溶液中,无菌密封环境下将混合物在37℃水浴中孵育20min,同时混合物按照常规方法均匀混合,必须保证无菌操作。
其中西妥昔单抗溶液含有稳定剂枸橼酸,且使西妥昔单抗、枸橼酸混合于没食子酸溶液中的终浓度或含量分别为500μg/ml、0.02%。
实验组别:制备方法同实施例3组合物制备方法;
空白对照组:生理盐水;
组合物组:没食子酸与西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
单抗组:西妥昔单抗及稳定剂(500μg/ml西妥昔单抗、0.02%稳定剂);
没食子酸组:50mg/ml的没食子酸溶液。
实验方法:
将处于对数生长期的肺癌细胞NCI-H1975制备成单细胞悬液,调整细胞浓度1*107/ml(共48只,每组12只),预备接种体积为0.2ml/只。将小鼠置于专用固定器中固定,用1ml一次性无菌注射器将细胞悬液在小鼠腹骨皮下缓慢注射进入小鼠体内。待小鼠身体状况趋于稳定后正常饲养,待肿瘤长至100mm3左右后,通过尾静脉注射给药,药物分为四组,见实验组别设计,之后每星期尾静脉注射药物1次,每次给药0.2ml,定期观察,当出现身体瘦弱、呼吸衰竭等症状时脱臼处死小鼠,未死亡小鼠在尾静脉注射给药2个月后脱臼处死解剖,观察小鼠体内肿瘤情况。具体统计结果见表2。
表3小鼠统计状况
其中抑瘤率计算公式如下:
抑瘤率=(空白对照组瘤重-给药组瘤重)/空白对照组瘤重*100%
由表2可以看出,组合物组对肺癌细胞NCI-H1975肿瘤具有强有效的敏感反应,可以有效抑制肿瘤生长,抑制率可以达到69%。且在注射药物期间,小鼠并没由出现其他并发症、身体其他不适等其他反应,其中单抗组和过氧麦角甾醇组也表现出抑制肿瘤作用,但其中没食子酸组抑制作用较小,从而从间接反映出没食子酸可以有效促进抗体发挥抑制肿瘤生长的作用。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种EGFR靶点抗体的组合物,其特征在于:组合物为没食子酸和EGFR为靶点的单抗和/或双特异性抗体及稳定剂。
2.根据权利要求1所述EGFR靶点抗体的组合物,其特征在于:其中所述稳定剂选用枸橼酸。
3.根据权利要求1所述EGFR靶点抗体的组合物,其特征在于:所述组合物的制备方法包括以下步骤:
(1)没食子酸的获得;
(2)步骤1中的没食子酸制备成10-200mg/ml溶液,将没食子酸溶液与以EGFR为靶点的单抗和/或双特异性抗体混合获得组合物。
4.根据权利要求1-3任一所述的EGFR靶点抗体的组合物,其特征在于:组合物中以EGFR为靶点的单抗和/或双特异性抗体含量为10-1000μg/ml;稳定剂百分比含量0.01-0.05%。
5.根据权利要求1-3任一所述的EGFR靶点抗体的组合物,其特征在于:抗体可以为:西妥昔单抗、ABX-EGF及EMD72000,以及其他的以EGFR为靶点的单抗和/或双特异性抗体一种或多种。
6.根据权利要求1-3任一所述的EGFR靶点抗体的组合物,其特征在于:上述没食子酸的制备方法如下:
取新鲜、无毁坏的圆孢蘑菇子实体,切片后用90-95%乙醇浸泡一周圆孢蘑菇子实体,过滤得滤液,减压回收溶剂,滤渣加入90-95%乙醇超声提取3-5次,每次提取1-5h,减压浓缩得90-95%乙醇浸膏;用60-65%乙醇同法操作,减压浓缩得60-65%乙醇浸膏;醇提取后的圆孢蘑菇滤渣,加入蒸馏水超声提取三次,每次提取1-3h,减压浓缩得水提浸膏;
将两部分醇提浸膏合并,将合并后的浸膏捏溶分散于纯水中,在分液漏斗中加入石油醚,再将浸膏分散液加入分液漏斗中,萃取5次,萃取液合并浓缩,得石油醚部位。后再次向分液漏斗中加入乙酸乙酯,萃取6次,萃取液合并浓缩,得乙酸乙酯部位;之后再向分液漏斗中加入正丁醇,萃取5次,萃取液合并浓缩,得正丁醇部位;
将上述获得的正丁醇部位加入乙醇,沉淀时在容器壁上析出结晶,反复多次操作,多次重结晶得化合物23,正丁醇部位经中压反相C18分离,用水-甲醇溶液(5%~100%)梯度洗脱,洗脱液按同一梯度合并,减压回收溶剂得到Z-Ⅰ~Z-Ⅵ共6个组分,Z-Ⅱ组分经由MCI树脂分离,用水-甲醇溶液(0%~100%)梯度洗脱,并用C18半制备柱分离纯化得化合物7、化合物8、化合物9、化合物10,化合物22即为过氧麦角甾醇。
7.根据权利要求6所述的EGFR靶点抗体的组合物,其特征在于:上述圆孢蘑菇子实体与乙醇比例为0.5-1:1-5,使乙醇完全浸泡圆孢蘑菇子实体。
8.根据权利要求6所述的EGFR靶点抗体的组合物,其特征在于:上述减压回收条件为0.1-0.5MPA,温度25-40℃;上述超声提取条件为200-800HZ,超声30-45min,温度30-50℃。
9.根据权利要求6所述的EGFR靶点抗体的组合物,其特征在于:上述浸膏萃取条件为:萃取压力为20MPa~40MPa,萃取温度30℃~50℃,萃取时间为0.8h~2.5h。
10.任一权利要求1-3的EGFR靶点抗体的组合物的应用,其特征在于:没食子酸和EGFR靶点抗体的组合物在肺癌上应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911125335.5A CN110812479A (zh) | 2019-11-18 | 2019-11-18 | 没食子酸和egfr靶点抗体组合物及其在肺癌上应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911125335.5A CN110812479A (zh) | 2019-11-18 | 2019-11-18 | 没食子酸和egfr靶点抗体组合物及其在肺癌上应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110812479A true CN110812479A (zh) | 2020-02-21 |
Family
ID=69556027
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911125335.5A Pending CN110812479A (zh) | 2019-11-18 | 2019-11-18 | 没食子酸和egfr靶点抗体组合物及其在肺癌上应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110812479A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110959851A (zh) * | 2019-11-18 | 2020-04-07 | 青海晨菲制药有限公司 | 圆孢蘑菇没食子酸在功能食品中的应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102247340A (zh) * | 2010-05-20 | 2011-11-23 | 上海亚盛医药科技有限公司 | 阿朴棉子酚酮在制备用于肿瘤治疗的药物中的应用 |
CN102397544A (zh) * | 2011-11-25 | 2012-04-04 | 百泰生物药业有限公司 | 一种单克隆抗体用于治疗非小细胞肺癌的用途 |
WO2012136829A1 (en) * | 2011-04-08 | 2012-10-11 | Lipotarg Gmbh | Novel combination treatment of cancer |
CN103298471A (zh) * | 2007-07-24 | 2013-09-11 | 诺瓦提斯公司 | 咪唑并喹啉类化合物在治疗egfr依赖性疾病或具有靶向egfr家族成员的活性剂的获得抗性的疾病中的应用 |
CN103781494A (zh) * | 2011-07-05 | 2014-05-07 | 梅里麦克制药股份有限公司 | 针对表皮生长因子受体(egfr)的抗体及其用途 |
CN109453212A (zh) * | 2019-01-06 | 2019-03-12 | 北京中医药大学 | 一种具有抗癌作用的毛诃子提取物及其有效部位制备方法 |
CN110227155A (zh) * | 2019-06-21 | 2019-09-13 | 安徽瑞达健康产业有限公司 | 一种nk细胞和egfr靶点抗体的组合物及在头颈部鳞状细胞癌上应用 |
CN110934877A (zh) * | 2019-11-18 | 2020-03-31 | 青海民族大学 | 过氧麦角甾醇和egfr靶点抗体组合物及其在头颈部鳞状细胞癌上应用 |
-
2019
- 2019-11-18 CN CN201911125335.5A patent/CN110812479A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103298471A (zh) * | 2007-07-24 | 2013-09-11 | 诺瓦提斯公司 | 咪唑并喹啉类化合物在治疗egfr依赖性疾病或具有靶向egfr家族成员的活性剂的获得抗性的疾病中的应用 |
CN102247340A (zh) * | 2010-05-20 | 2011-11-23 | 上海亚盛医药科技有限公司 | 阿朴棉子酚酮在制备用于肿瘤治疗的药物中的应用 |
WO2012136829A1 (en) * | 2011-04-08 | 2012-10-11 | Lipotarg Gmbh | Novel combination treatment of cancer |
CN103781494A (zh) * | 2011-07-05 | 2014-05-07 | 梅里麦克制药股份有限公司 | 针对表皮生长因子受体(egfr)的抗体及其用途 |
CN102397544A (zh) * | 2011-11-25 | 2012-04-04 | 百泰生物药业有限公司 | 一种单克隆抗体用于治疗非小细胞肺癌的用途 |
CN109453212A (zh) * | 2019-01-06 | 2019-03-12 | 北京中医药大学 | 一种具有抗癌作用的毛诃子提取物及其有效部位制备方法 |
CN110227155A (zh) * | 2019-06-21 | 2019-09-13 | 安徽瑞达健康产业有限公司 | 一种nk细胞和egfr靶点抗体的组合物及在头颈部鳞状细胞癌上应用 |
CN110934877A (zh) * | 2019-11-18 | 2020-03-31 | 青海民族大学 | 过氧麦角甾醇和egfr靶点抗体组合物及其在头颈部鳞状细胞癌上应用 |
Non-Patent Citations (5)
Title |
---|
PHILIPP STEINER,等: "Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor", 《CLINICAL CANCER RESEARCH》 * |
廖志明: "圆孢蘑菇化学成分及其活性的初步研究", 《万方数据》 * |
张庭秀等: "没食子酸诱导非小细胞肺癌A549细胞凋亡的机制研究", 《中国现代医学杂志》 * |
郗艳丽: "没食子酸诱导肺癌细胞凋亡机制及其应用的研究", 《中国优秀博硕士学位论文全文数据库(博士)医药卫生科技辑》 * |
黄倩等: "晚期非小细胞肺癌分子靶向单抗类药物治疗的研究进展", 《福建医药杂志》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110959851A (zh) * | 2019-11-18 | 2020-04-07 | 青海晨菲制药有限公司 | 圆孢蘑菇没食子酸在功能食品中的应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI648257B (zh) | 牛樟芝化合物、製備方法及其用途 | |
CN106834160B (zh) | 一种产角环素化合物的红灰链霉菌 | |
KR101670590B1 (ko) | Erk 신호활성 억제제를 유효성분으로 함유하는 암 줄기세포 성장 억제용 조성물 | |
CN103627772B (zh) | 一种雷公藤内酯醇衍生物的制备方法及其产物和应用 | |
TWI432420B (zh) | A compound isolated from the monascus, a process for its preparation and use | |
CN110812479A (zh) | 没食子酸和egfr靶点抗体组合物及其在肺癌上应用 | |
CN105524063A (zh) | 一种新的萜类吲哚生物碱化合物及其制备方法和医药用途 | |
CN110934877A (zh) | 过氧麦角甾醇和egfr靶点抗体组合物及其在头颈部鳞状细胞癌上应用 | |
CN103992333A (zh) | 色原酮二聚体衍生物及其制备方法和用途 | |
CN104523792B (zh) | 一种富含强心苷的马利筋乳汁提取物及其制备方法与应用 | |
CN101239964B (zh) | 15-氧代绣线菊内酯,其药物组合物和其制备方法及其应用 | |
CN107286123B (zh) | 一种二苯呋喃类化合物的制备方法与应用 | |
CN108250167B (zh) | 基于紫外诱导的桑叶中生物活性单体成分chalcomoracin及其制备方法和用途 | |
CN109180632B (zh) | 一种从雷公藤中分离出的化合物的制备方法 | |
CN103467479B (zh) | 螺环化合物、其组合物、其制备方法和用途 | |
TW202017578A (zh) | 牛樟芝萃取物、牛樟芝組合物的製備方法及醫藥組合物 | |
CN105418725B (zh) | 五环三萜类化合物及其应用 | |
CN105524135B (zh) | 毛酸浆内酯的制备方法及其在制备抗肿瘤药物中的应用 | |
CN109867657B (zh) | 二羟二苯并[b,f][1,5]二氧杂辛环类化合物、制备方法及其药用组合物和应用 | |
CN110959851A (zh) | 圆孢蘑菇没食子酸在功能食品中的应用 | |
US20090022827A1 (en) | Agent and method for eliminating malignance of cancer cells without harmful effect to normal cells | |
CN115894467B (zh) | 一种双环化二异戊烯基取代aspulvinone类化合物及其制备方法和应用 | |
CN109516970B (zh) | 一种新单萜环烯醚衍生物及其制备方法和应用 | |
KR101440853B1 (ko) | 솔잎 추출물로부터 분리된 공지 화합물을 함유하는 인체 파필로마바이러스(hpv)로 기인한 자궁경부암, 또는 후두암 예방 및 치료용 조성물 | |
CN117567438A (zh) | 一种新型生物碱aplysingoniopora A的制备方法及其应用 |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200221 |