CN117412772A - Compositions and methods for dual targeted treatment of neuroendocrine tumors - Google Patents
Compositions and methods for dual targeted treatment of neuroendocrine tumors Download PDFInfo
- Publication number
- CN117412772A CN117412772A CN202280039629.XA CN202280039629A CN117412772A CN 117412772 A CN117412772 A CN 117412772A CN 202280039629 A CN202280039629 A CN 202280039629A CN 117412772 A CN117412772 A CN 117412772A
- Authority
- CN
- China
- Prior art keywords
- composition
- compound
- group
- tumor
- thyroid
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 199
- 201000011519 neuroendocrine tumor Diseases 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000009977 dual effect Effects 0.000 title claims abstract description 13
- 238000011282 treatment Methods 0.000 title abstract description 52
- 210000001685 thyroid gland Anatomy 0.000 claims abstract description 59
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 claims abstract description 46
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 230000008685 targeting Effects 0.000 claims abstract description 20
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 claims abstract description 17
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 9
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 9
- PPJYSSNKSXAVDB-UHFFFAOYSA-N 3,3',5,5'-tetraiodothyroacetic acid Chemical compound IC1=CC(CC(=O)O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 PPJYSSNKSXAVDB-UHFFFAOYSA-N 0.000 claims description 36
- 229920001223 polyethylene glycol Polymers 0.000 claims description 27
- 239000002202 Polyethylene glycol Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 210000004881 tumor cell Anatomy 0.000 claims description 22
- 125000003277 amino group Chemical group 0.000 claims description 19
- 229920000642 polymer Polymers 0.000 claims description 19
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims description 14
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 12
- UOWZUVNAGUAEQC-UHFFFAOYSA-N tiratricol Chemical compound IC1=CC(CC(=O)O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 UOWZUVNAGUAEQC-UHFFFAOYSA-N 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 208000028591 pheochromocytoma Diseases 0.000 claims description 10
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000002560 nitrile group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- ABSNGNUGFQIDDO-UHFFFAOYSA-N 2-benzylguanidine Chemical compound NC(N)=NCC1=CC=CC=C1 ABSNGNUGFQIDDO-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 claims description 3
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 claims description 3
- 208000002458 carcinoid tumor Diseases 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- RGLHIDUSJZGWHY-UHFFFAOYSA-N 5-hydrazinyl-2H-triazol-4-amine Chemical compound N(N)C=1N=NNC1N RGLHIDUSJZGWHY-UHFFFAOYSA-N 0.000 claims 1
- 206010007275 Carcinoid tumour Diseases 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 42
- 150000003943 catecholamines Chemical class 0.000 abstract description 6
- 108010078791 Carrier Proteins Proteins 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000002059 diagnostic imaging Methods 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 91
- 210000004027 cell Anatomy 0.000 description 36
- 108010044426 integrins Proteins 0.000 description 36
- 102000006495 integrins Human genes 0.000 description 36
- 206010029260 Neuroblastoma Diseases 0.000 description 30
- 229940123038 Integrin antagonist Drugs 0.000 description 25
- 241000699670 Mus sp. Species 0.000 description 25
- 239000005557 antagonist Substances 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 21
- -1 MIBG Chemical class 0.000 description 18
- 125000005647 linker group Chemical group 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 150000003852 triazoles Chemical class 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 206010028851 Necrosis Diseases 0.000 description 10
- 230000017074 necrotic cell death Effects 0.000 description 10
- 230000037361 pathway Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 9
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 229940125758 compound 15 Drugs 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000007920 subcutaneous administration Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 208000017084 enterochromaffin cell serotonin-producing pancreatic neuroendocrine tumor Diseases 0.000 description 7
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- GZVHEAJQGPRDLQ-UHFFFAOYSA-N 6-phenyl-1,3,5-triazine-2,4-diamine Chemical class NC1=NC(N)=NC(C=2C=CC=CC=2)=N1 GZVHEAJQGPRDLQ-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 5
- 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 4
- RQJDUEKERVZLLU-UHFFFAOYSA-N 4-Hydroxybenzylamine Chemical class NCC1=CC=C(O)C=C1 RQJDUEKERVZLLU-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- 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
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 3
- 229940123712 Thyroid hormone receptor antagonist Drugs 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 230000001772 anti-angiogenic effect Effects 0.000 description 3
- 230000004700 cellular uptake Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000003032 molecular docking Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- 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 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- 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 3
- 125000006850 spacer group Chemical group 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000005495 thyroid hormone Substances 0.000 description 3
- 229940036555 thyroid hormone Drugs 0.000 description 3
- 125000005490 tosylate group Chemical group 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 229940127449 Integrin Receptor Antagonists Drugs 0.000 description 2
- 102000015927 Integrin beta-3 subunit Human genes 0.000 description 2
- 108050004177 Integrin beta-3 subunit Proteins 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 208000007660 Residual Neoplasm Diseases 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 230000004886 head movement Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- PDWUPXJEEYOOTR-IUAIQHPESA-N iobenguane (123I) Chemical compound NC(N)=NCC1=CC=CC([123I])=C1 PDWUPXJEEYOOTR-IUAIQHPESA-N 0.000 description 2
- PDWUPXJEEYOOTR-JRGAVVOBSA-N iobenguane (131I) Chemical compound NC(N)=NCC1=CC=CC([131I])=C1 PDWUPXJEEYOOTR-JRGAVVOBSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 150000002871 norepinephrines Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 208000007312 paraganglioma Diseases 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- PONJIMVVHPQAJL-UHFFFAOYSA-N tert-butyl n-[(4-hydroxyphenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(O)C=C1 PONJIMVVHPQAJL-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 108090000721 thyroid hormone receptors Proteins 0.000 description 2
- 102000004217 thyroid hormone receptors Human genes 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 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
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- 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 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- AAPRNHKWNGDTOT-DVRVPOOOSA-N 2-[(3s)-3-(aminomethyl)piperidine-1-carbonyl]-n-[1-(cyclononen-1-ylmethyl)piperidin-4-yl]-9h-xanthene-9-carboxamide Chemical compound C1[C@H](CN)CCCN1C(=O)C1=CC=C(OC=2C(=CC=CC=2)C2C(=O)NC3CCN(CC=4CCCCCCCC=4)CC3)C2=C1 AAPRNHKWNGDTOT-DVRVPOOOSA-N 0.000 description 1
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical class NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 1
- 102000019997 adhesion receptor Human genes 0.000 description 1
- 108010013985 adhesion receptor Proteins 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000003200 antithyroid agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- FZIZEIAMIREUTN-UHFFFAOYSA-N azane;cerium(3+) Chemical compound N.[Ce+3] FZIZEIAMIREUTN-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KFCUPNHUPHDVJC-UHFFFAOYSA-N bromine azide Chemical compound BrN=[N+]=[N-] KFCUPNHUPHDVJC-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 210000003737 chromaffin cell Anatomy 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229920000547 conjugated polymer Polymers 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FVODWHVTHJKQDH-UHFFFAOYSA-N tert-butyl 4-(3-methylsulfonyloxypropyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1 FVODWHVTHJKQDH-UHFFFAOYSA-N 0.000 description 1
- FWOBBEOKTITUHK-UHFFFAOYSA-N tert-butyl n-benzylcarbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC=C1 FWOBBEOKTITUHK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Disclosed are compound compositions and methods of synthesizing the same. The compositions disclosed and described herein are thyroid integrin αvβ3 receptor antagonists directed against targets that bind to the norepinephrine transporter (NET) or catecholamine transporter. The composition has dual targeting effects in the treatment and diagnostic imaging of neuroendocrine tumors and increases targeting efficiency.
Description
Technical Field
The present invention relates generally to compositions for targeting and treating neuroendocrine tumors. In particular, the compositions may include a thyroid hormone αvβ3 integrin receptor antagonist (referred to as a "thyroid integrin antagonist") and a compound targeting a norepinephrine transporter (NET) or catecholamine transporter (e.g., benzoguanidine ("BG") or a derivative thereof).
Background
Norepinephrine/catecholamine transporter ("norepinephrine transporter") is essential for uptake of norepinephrine at the synaptic terminals and on adrenal chromaffin cells. In neuroendocrine tumors, the norepinephrine transporter is highly active and imaging and/or therapy of localized radiotherapy can be targeted. One of the most widely used therapeutic agents targeting norepinephrine transporter is metaiodobenzoguanidine (migg), a guanidine analog of norepinephrine. Diagnostic therapeutics of 123I-MIBG/131I-MIBG have been used in the clinical assessment and management of neuroendocrine tumors, particularly in neuroblastomas, paragangliomas and pheochromocytomas. 123I-MIBG imaging has been used to evaluate neuroblastomas, while 131I-MIBG was used to treat recurrent Gao Weicheng neuroblastomas, however, the results remain poor. Positron Emission Tomography (PET) tracers targeting norepinephrine transporter and their targets present a better choice for imaging and evaluation following neuroblastoma, paraganglioma/pheochromocytoma and carcinoid treatment.
Integrins are a superfamily of cell surface adhesion receptors that control the adhesion of cells to the extracellular matrix (ECM) and other cells from a fixed extracellular environment. Adhesion is critical for cells; it provides signals for localization, migration pathways, and growth and differentiation. Integrins are directly involved in many normal and pathological conditions and are therefore the primary targets for therapeutic intervention. Integrins are integral transmembrane proteins, heterodimers, whose binding specificity depends on which of the 14 a-chains binds to which of the 8 β -chains. Integrins are divided into four overlapping subfamilies, comprising β1, β2, β3 or αv chains. The cells may express several different integrins from each subfamily. Over the past few decades, integrins have been shown to be the primary receptors involved in cell adhesion and thus may be suitable targets for therapeutic intervention. Integrin αvβ3 regulates cell growth and survival because this receptor attachment can induce tumor cell apoptosis in certain circumstances. Disruption of cell adhesion using anti- αvβ3 antibodies, RGD peptides, peptidomimetics or non-peptide derivatives, and other integrin antagonists has been shown to slow tumor growth.
Thyroid integrin antagonists have been shown to affect tumor angiogenesis by interacting with integrin αvβ3. The effects of thyroid integrin antagonists are described in U.S. patent publication No. 2017/0348425, entitled "non-cleavable Polymer conjugated to αvβ3 integrin thyroid antagonist," the contents of which are incorporated herein by reference.
A composition comprising a thyroid integrin antagonist compound and a norepinephrine transporter target compound would be welcomed in the art.
Disclosure of Invention
According to one aspect, the composition comprises a compound of the general formula:
or a salt thereof;
wherein R is 1 、R 2 、R 3 And R4 are each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, methoxy groups, nitro groups, amino groups, nitrile groups; wherein R is 5 、R 6 、R 7 And R is 8 Each independently selected from the group consisting of hydrogen, iodine, an alkane group; and n1 is more than or equal to 0; n2 is more than or equal to 1; and Y comprises an amino group.
According to another aspect, a method for dual targeting of tumor cells comprises administering a composition comprising a compound of formula (la):
or a salt thereof,
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, methoxy groups, nitro groups, amino groups, nitrile groups; wherein R is 5 、R 6 、R 7 And R is 8 Each independently selected from the group consisting of hydrogen, iodine, an alkane group; and n1 is more than or equal to 0; n2 is more than or equal to 1; and Y comprises an amino group.
According to another aspect, the composition comprises N-Gua and a thyroid integrin αvβ3 receptor antagonist, wherein the N-Gua and the thyroid integrin αvβ3 receptor antagonist are linked by a linker.
Drawings
This patent or this document contains at least one drawing in color. Copies of this patent or patent application publication with color drawings will be provided by the office upon request of the applicant and payment of the necessary fee.
Some embodiments will be described in detail with reference to the following drawings, wherein like designations denote like elements, and wherein:
FIG. 1 depicts a general formula of an exemplary composition for dual targeting neuroendocrine tumors;
FIG. 2a depicts another general formula of an exemplary composition having an amino linker;
FIG. 2b depicts another general formula of an exemplary composition having a diamino linker;
FIG. 2c depicts another general formula of an exemplary composition having a triazole linker;
FIG. 3 depicts one exemplary composition for dual targeting neuroendocrine tumors;
FIG. 4a depicts an outline of the synthetic pathway from composition 300 of FIG. 3;
FIG. 4b depicts a detailed schematic of the synthetic pathway of FIG. 4 a;
FIG. 4c depicts a summary of possible synthetic routes for producing two additional exemplary compositions, termed composition 201 (BG-PEG-MAT) and composition 202 (BG-PEG-DAT), wherein toluene sulfonate groups or acetaldehyde are used in the production;
FIG. 4d depicts an additional synthetic route overview for producing the composition shown in FIG. 4c, wherein the production uses tosylate groups or acetaldehyde;
FIG. 4e depicts a detailed schematic of the synthetic pathways of FIGS. 4c and 4d using acetaldehyde;
FIG. 4f depicts a detailed schematic of the synthetic pathways of FIGS. 4c and 4d using tosylate groups;
FIG. 5 depicts a graph showing that there is no significant change in body weight of mice when subcutaneously administered at different doses of 1-10mg/kg for 15 days during multiple day treatment of mice with control or composition 300;
FIG. 6 depicts a graph showing a dose-dependent decrease in tumor volume in mice over time (15 days) during multiple days of treatment at 1-10mg/kg of subcutaneously administered composition 300 as compared to an increase in tumor volume in the control group;
FIG. 7a shows an image of mice in a control group, mice with visible large subcutaneous tumors, and abnormal animal head movements with altered central behavior;
Fig. 7b shows an image of a mouse treated with composition 300 and shows that the visible subcutaneous tumor significantly reduced or disappeared in a dose-dependent manner (the tumor significantly contracted to disappeared), along with the observed abnormal animal head movements also disappeared;
FIG. 8 is a graph of tumor weight versus dose of composition 300 showing tumor shrinkage until tumor complete disappearance;
FIG. 9a is a photograph of a tumor showing relative tumor volume and blocking angiogenesis as a function of dose of composition 300;
FIG. 9b is a photograph of a tumor showing absolute tumor volume as a function of dose change for composition 300, demonstrating shrinkage from apparent tumor to disappearance at a dose level of 10 mg/kg;
FIG. 10 is a graph of neuroblastoma cancer cell activity as a function of dose change of composition 300, showing the loss of cancer cells from activity to complete loss at a dose level of 10 mg/kg;
FIG. 11 is a graph of cancer cell necrosis of neuroblastoma as a function of dose of composition 300, showing an increase in cancer cell necrosis of 80% -100% at dose levels of 3mg/kg and 10 mg/k;
FIG. 12a is a graph of tumor weight shrinkage as a function of treatment with various benzoguanamine derivatives including MIBG, BG and BG-conjugated polymers, showing comparable shrinkage compared to control (PBS vehicle) over 15 days of administration at 3mq/kg subcutaneously;
FIG. 12b is a graph of tumor weight shrinkage as a function of treatment with benzoguanamine, TAT derivative, or combination of BG-TAT derivatives versus BG-P-TAT (composition 300) administered subcutaneously 3mg/kg all daily for 15 days (data demonstrating 40-50% tumor shrinkage with BG, TAT, or combination of BG-TAT versus 80% tumor shrinkage with BG-P-TAT (composition 300) and maximum loss of cancer cells with BG-P-TAT);
FIG. 13a is a photograph of fluorescence images of various mice after 1 hour and 2 hours of administration of Cy 5-labeled TAT-coupled polymer (group 1), BG-coupled polymer (group 2), and BG-TAT-coupled polymer (composition 300, group 3);
FIG. 13b is a photograph of fluorescence images of the mice of FIG. 13a after 4 hours, 6 hours and 24 hours post-dose (data clearly indicate that there is a significant and highest intensity enrichment (circling and imaging) in neuroblastomas and coating with Cy 5-labeled BG-P-TAT coupled polymer (composition 300);
FIG. 14 depicts another exemplary composition for dual targeting neuroendocrine tumor, designated composition 7a or dI-BG-P-TAT;
FIG. 15 depicts another exemplary composition for dual targeting neuroendocrine tumor, designated as composition 7b or dM-BG-P-TAT;
FIG. 16 depicts another exemplary composition for dual targeting neuroendocrine tumor, referred to as composition 15 or BG-P-PAT;
FIG. 17 depicts an outline of the synthetic pathways from composition 7a and composition 7b in FIGS. 15 and 16;
FIG. 18 depicts a portion of the synthetic pathway overview from composition 15 of FIG. 16;
FIG. 19 depicts another partial synthetic pathway overview from composition 15 of FIG. 16;
FIG. 20 depicts binding affinities of various exemplary compositions;
FIG. 21A depicts cellular uptake of various exemplary compositions;
FIG. 21B depicts cellular uptake of various exemplary compositions;
FIG. 22 depicts a graph of the decrease in tumor volume over time in mice during multiple days (20 days) of treatment of 3mg/kg subcutaneous injection of composition 7a, composition 7b, and composition 15, as compared to the increase in tumor volume in the control group;
FIG. 23 depicts a graph of the decrease in tumor weight of mice over time during multiple days (20 days) of treatment of 3mg/kg subcutaneous injection of composition 7a, composition 7b, and composition 15, as compared to the increase in tumor weight of the control group;
fig. 24 depicts histological images showing the efficacy of compositions 7a, 7b, 15 compared to the control group.
Detailed Description
The details of the specific embodiments of the disclosed compositions and methods described above are given herein by way of example and not by way of limitation with reference to the accompanying drawings. While details of some embodiments are shown and described, it will be appreciated that various changes and modifications may be made without departing from the scope of the appended claims. The scope of the present invention is by no means limited to the number of constituent components, the materials thereof, the shapes thereof, the colors thereof, the relative arrangement thereof, and the like, and is disclosed only as an example of the embodiment of the present invention. A more complete understanding of the present embodiments and the advantages thereof may be acquired by referring to the following description taken in conjunction with the accompanying drawings, in which like reference numbers indicate like features.
In the introduction to the summary of the invention, it should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
SUMMARY
The examples of the present invention describe novel chemical compositions and methods of synthesizing the same. The compositions disclosed and described herein may be directed to anti-angiogenic agents, particularly thyroid integrin antagonists, which may interact with one or more cell surface receptors of the integrin αvβ3 receptor family. The compositions disclosed and described herein may also be directed against targets of norepinephrine transporter (also known as catecholamine transporter). The target of the norepinephrine transporter can be used as a neuroendocrine tumor cell targeting agent.
The compositions disclosed and described herein may be directed to compositions comprising a thyroid integrin and a norepinephrine transporter target. In addition, the shuffling composition can use polymers or other linkers to link the thyroid integrin to the norepinephrine transporter target.
Norepinephrine transporter is a regulator of catecholamine uptake in normal physiology, and is highly expressed and overactive in neuroendocrine tumors such as neuroblastoma. While the norepinephrine analog Metaiodobenzoguanidine (MIBG) is a given substrate for the norepinephrine transporter, analogs such as (123) I-MIBG/(131) I-MIBG or analogs containing fluoride (F18) instead of iodide (radioactivity) can also be used for diagnostic imaging of neuroblastomas and other neuroendocrine tumors.
Studies have shown that various neuroblastoma cell lines highly express the αvp3 integrin receptor (90-95%). However, the effect of high affinity αvβ3 integrin receptor antagonists on tumor growth rate and tumor activity inhibition is limited (40-50%). Similarly, benzoguanidine and its derivatives have demonstrated limited anticancer effects against neuroblastomas, although their uptake in neuroblastomas and other neuroblastoma tumors is greatest (90-100%). Furthermore, combination therapy of a norepinephrine transporter target (e.g., benzoguanidine or a derivative thereof) with a thyroid integrin antagonist (e.g., a triazole tetraiodothyroacetic acid derivative) does not inhibit the growth and activity of neuroblastoma by more than 50%.
Conversely and unexpectedly, coupling a norepinephrine transporter target (e.g., benzoguanidine derivative) and a thyroid integrin antagonist (e.g., triazol tetraiodothyroacetic acid derivative) via different polymer linkers (e.g., polyethylene glycol (PEG)) into a single novel chemical entity results in maximal uptake by neuroblastomas and other neuroendocrine tumors at different doses and maximal (80-100%) inhibition of tumor growth and activity. The thyroid integrin antagonists are coupled to norepinephrine/catecholamine transporter target compounds via linkers, which can provide compositions with dual targeting effects for neuroendocrine tumor targeting. For example, according to one embodiment of the invention, the composition may include an alpha-V-beta-3 (αvβ3) integrin-thyroid hormone receptor antagonist linked to benzoguanidine (or a benzoguanidine derivative).
The compositions described herein may be comprised of a compound, such as a thyroid integrin antagonist or a derivative thereof, covalently linked to a norepinephrine transporter target to form a single chemical entity. The thyroid integrin antagonist and the norepinephrine target may be linked by a linker.
Reference may be made to specific thyroid integrin compounds and norepinephrine compounds such as tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac) and benzoguanamine. These phrases include derivatives of such compounds in accordance with the full teachings of the present invention even if such derivatives are not specifically listed in the present invention.
Referring to the drawings, FIG. 1 depicts an embodiment of a formula 100, the formula 100 comprising a thyrointegrin antagonist 110 linked to a norepinephrine transporter target 120 by a linker 130. The composition may be referred to as a thyroid integrin antagonist derivative bound to a benzoguanidine derivative via linker 130, or a thyroid integrin antagonist derivative bound to a benzoguanidine derivative modified with linker 130. FIG. 1 depicts the carboxylic acid form of formula 100. It will be apparent to those skilled in the art that salts of formula 100 (e.g., sodium salts) may be used.
The linker 130 includes a spacer 132 and a polymer 131. The linker 130 is resistant to biodegradation such that the linker remains non-cleavable under physiological conditions. In one embodiment, the spacer 132 includes CH 2 Units and adjacent methylene groups (CH 2 ) The repeated attachment of units, which can be defined by n1 repeats, wherein n1 is an integer > 0. In other embodiments, n1 may be ≡1 2 or more than or equal to 3. The connector 130 also includes a portion "Y". In some cases, an example of moiety "Y" may be an amino group. For example, the moiety Y of the formula may be a divalent alkane having one amino group, or a divalent alkane having two amino groups, as shown in the examples of formulas 200a and 200b of fig. 2a and 2 b. In another embodiment, the Y moiety may be a triazole, as shown in the example of formula 200c shown in FIG. 2 c. The polymer 131 may include polyethers such as polyethylene glycol (PEG). Other polymers may be used including chitosan, alginic acid, hyaluronic acid and other polymers. In embodiments using PEG as polymer 131, the polymer may have a molecular weight of 200g/mol to 4000g/mol.
The term thyroid antagonist herein describes a compound having the ability to inhibit or combat one or more thyroid hormone receptors known to those skilled in the art, such as the integrin family of thyroid hormone receptors, like the thyroid hormone cell surface receptor αvβ3. The thyroid integrin antagonist 110 may be an anti-angiogenic thyroid hormone or thyroid hormone receptor antagonist. For example, the thyroid integrin antagonist 110 may be an alpha-V-beta-3 (αvβ3) integrin-thyroid hormone receptor antagonist.
Particular examples of thyroid integrin antagonists 110 may include tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac), derivatives thereof and variables thereof. In some embodiments, examples of one or more variables of a thyroid integrin antagonist comprising tetra c and triac may include diamino tetraiodo thyroacetic acid (DAT), or diamino triiodo thyroacetic acid (DATri) (hereinafter interchangeably referred to as "DAT"), monoamino tetraiodo thyroacetic acid (MAT), or monoamino triiodo thyroacetic acid (MATri) (hereinafter interchangeably referred to as "MAT"), triazole tetraiodo Thyroacetic Acid (TAT), or triazole triiodo thyroacetic acid (TATri) (hereinafter interchangeably referred to as "TAT"), and derivatives thereof or other thyroid antagonists known to those of skill in the art. The thyroid integrin antagonists may be of the type described in U.S. patent publication No. 2017/0348425, entitled "non-cleavable polymers conjugated to αvβ3 thyroid integrin antagonists," the contents of which are incorporated herein by reference.
Exemplary thyroid integrin antagonists based on general structure 100 of fig. 1 are shown in table 1 below.
TABLE 1
In some embodiments of the thyroid integrin antagonist 110, the variables described as R5, R6, R7, and R8 may each be independently substituted with a molecule such as hydrogen, iodine, and alkane. In some embodiments, the alkane has four or less carbons. For example, as shown in table 1, in some embodiments of thyroid integrin antagonist 110, it is described as R 5 、R 6 、R 7 And R is 8 The variables of (a) may each independently be substituted with molecules such as hydrogen, iodine and an alkane group such as isopropyl or isobutyl. In the examples of table 1, the alkane has four or less carbons.
The norepinephrine transporter target 120 may be a neuroendocrine tumor cell targeting agent. As one example, the norepinephrine transporter target 120 may be benzoguanidine or a benzoguanidine derivative. As another example, the norepinephrine transporter target 120 may be N-benzoguanidine or a derivative thereof.
Exemplary norepinephrine transporter targets 120 based on formula 100 from fig. 1 are shown in table 2 below.
TABLE 2
In some embodiments of the norepinephrine target 120, depicted as R 1 、R 2 、R 3 And R 4 The variables of (a) may each independently be substituted with molecules such as hydrogen, iodine, fluorine, bromine, methoxy groups, nitro groups, amino groups and nitrile groups. For example, in some embodiments of the norepinephrine transporter target 120, described as R 1 、R 2 、R 3 And R is 4 The variables of (a) may each independently be substituted with a molecule such as hydrogen, iodine, fluorine, bromine, methoxy groups, nitro groups, amino groups, and nitrile groups, as described in table 2. Other embodiments and substituents may also be used. In one embodiment, R 1 、R 2 、R 3 And R is 4 Is radiolabeled. Examples of suitable radiolabels include I (123), I (131) and F (18). The compounds may be administered to humans or animals.
Any of the exemplary thyroid integrin antagonists 110 (and any other thyroid integrin antagonist embodiments taught herein) can be linked to any of the exemplary norepinephrine transporter targets 120 (and any other norepinephrine transporter target embodiments taught herein) via the linker 130 to form a composition.
It is clear from tables 1 and 2 that there are many compounds in the composition that can be used as thyroid integrin antagonists 110 and many compounds that can be used as norepinephrine transporter targets 120. In addition, a variety of thyroid integrin antagonists 110 can bind to a variety of norepinephrine transporter targets 120, resulting in the compositions described herein having many possible chemical structures.
Embodiments of each of the compositions described herein may have multiple types of utility for treating several different diseases modulated by angiogenesis or inhibition thereof. Given the presence of the thyroid integrin antagonist 110 in the compositions, each of the compositions described herein may have a high degree of affinity for the targeted integrin receptor αvβ3 on numerous types of cells located throughout the human body and in various animal bodies.
Furthermore, embodiments of each of the compositions described herein may have utility in the treatment of a variety of different diseases characterized by the activity of the norepinephrine transporter. Given the presence of the norepinephrine transporter target 120 in the composition, each of the compositions described herein may each have an affinity to target numerous types of cells found throughout the human and various animal bodies utilizing the norepinephrine transporter. Each of the compositions described herein may have enhanced affinity for targeted cells that exhibit enhanced or higher than average activity of norepinephrine transporter, e.g., neuroendocrine tumor cells. As a more specific example, the composition may have enhanced affinity for targeting neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor cells.
Still further, because the composition uses the thyroid integrin antagonist 110 and the norepinephrine transporter target 120 together, the composition has enhanced utility and efficacy against certain diseases and/or conditions. For example, neuroendocrine tumors are sensitive to treatment with a thyroid integrin antagonist, while also indicating increased activity of the norepinephrine transporter. The compositions described herein use two compounds with dual targeting efficacy in the treatment of neuroendocrine tumor cells. Furthermore, the increased efficacy exceeds any increased efficacy expected or achieved by simultaneous monotherapy with a thyroid integrin antagonist and a norepinephrine transporter target. Further details regarding beneficial utility will be discussed in terms of experimental studies below.
As shown in the chemical structure of formula 100 of fig. 1, an embodiment of the chemical structure may include one or more variables that define additional features of the thyroid integrin antagonist 110 of formula 100. For example, in some embodiments of thyroid integrin antagonist 110, it is described as R 5 、R 6 、R 7 And R is 8 The variables of (a) may each independently be hydrogen, iodine and alkane as shown in table 1 above.
Thus, there are a wide variety of thyroid integrin antagonist compounds that are useful as thyroid integrin antagonist 110 of formula 100. For example, as shown in FIG. 2a, a thyroid integrin antagonist 110a may be included for R 5 -R 8 Resulting in the formation of tetraiodothyroacetic acid (tetra) derivatives having 3 carbon linkers and an amino group as the Y moiety. Formula 200a may be referred to as Monoaminotetraiodothyroacetic Acid (MAT) attached to benzoguanidine or a benzoguanidine derivative by PEG. Likewise, in fig. 2b, the tetraiodothyroacetic acid molecule further comprises a diamino Y moiety attached to the carbon linker. This formula 200b may be referred to as Diaminotetraiodothyroacetic Acid (DAT) conjugated to benzoguanidine or benzoguanidine derivatives by PEG. In another embodiment of fig. 2c, formula 200c may include a triazole moiety attached to a single carbon of the carbon linker. This formula 200c may be referred to as triazole Tetraiodothyroacetic Acid (TAT) attached to benzoguanidine or a benzoguanidine derivative by PEG.
Other thyroid integrin antagonist compounds may be used in the formation of the compositions described herein. For example, the general structure of thyroid integrin antagonists 110a, 110b and 110c may be used, wherein only R 5 -R 7 Iodine is included to provide a similar triiodothyroacetic acid derivative. In addition, as shown in Table 1 above, similar structures may be used wherein the thyroid integrin antagonists include substituents for other elements or functional groups for R 5 -R 8 Any and/or all of the following.
The norepinephrine transporter target 120 may include benzoguanidine or a benzoguanidine derivative. Embodiments of the chemical structure of the norepinephrine transporter target 120 may include one or more variables defining additional features of the norepinephrine transporter target 120 of the general formula 100 shown in fig. 1. For example, in some embodiments of the norepinephrine transporter target 120, described as R 1 、R 2 、R 3 And R is 4 The variables of (a) may each be independently substituted with hydrogen, iodine, fluorine, bromine, methoxy, nitro groups, amino groups, and nitrile group molecules as described in table 2 above.
FIG. 3 depicts an exemplary composition 300 of formula 100. Composition 300 includes triazole tetraiodothyroacetic acid conjugated to benzoguanide modified PEG. The composition 300 may also be referred to as BG-PEG-TAT or BG-P-TAT.
The synthesis of the compositions described herein will be demonstrated below with reference primarily to the exemplary composition shown in fig. 3, namely composition 300. The synthesis of similar compositions, namely composition 201 and composition 202 (see fig. 4c-4 f), is also provided as an example and is not limiting of the invention to such compositions.
Example 1a: synthesis of exemplary composition 300
This example provides a sampling method for preparing the composition 300 shown in fig. 3. Composition 300 is referred to as BG-PEG-TAT or BG-P-TAT. Composition 300 has the chemical name 2- (4- (4- (1- (20- (4- (guanidinomethyl) phenoxy) -3,6,9, 12,15, 18-hexaoxyeicosyl) -1H-1,2, 3-triazol-4-yl) methoxy) -3, 5-diiodophenoxy) -3, 5-diiodophenyl) acetic acid, or [4- {1- [2- (2- {2- [2- (2- {2- [2- (4-guanidinomethyl-phenoxy) -ethoxy ] -ethoxy } -ethoxy) -ethoxy ] -ethoxy) -ethyl ] -1H- [1,2,3] triazol-4-ylmethoxy } -3, 5-diiodo-phenoxy) -3, 5-diiodo-phenyl ] -acetic acid. The molecular weight of the composition 300 was 1284.44g/mol.
All commercial chemicals were used without further purification. All solvents were dried and activated molecular sieves (0.3 nm or 0.4nm, depending on the type of solvent) were used to obtain anhydrous solvents. All reactions, e.g. not particularly involving water as reactant, solvent or co-solvent, being in Ar or N 2 In an atmosphere in a baked glass vessel. All the novel compounds provide satisfactory results 1 H HMR and mass spectrometry results. Melting point is in electrothermal MEL-TEMPThe measurement was carried out on a melting point measuring instrument, followed by a Thomas HOOVER Uni-mel capillary melting point measuring instrument. Infrared spectra were recorded on a Thermo Electron Nicolet Avatar330FT-IR device. The UV spectrum was obtained from a SHIMADZU UV-1650P UV-visible spectrophotometer. All solution phase NMR experiments were performed at the Biotechnology interdisciplinary research center of the institute of Lensler engineering (RPI, troy, NY), fromBruker Advance II 800MHz spectrometer equipped with a z-axis gradient (Bruker Biospin, billerica, mass.) cryogenically cooled probe (TCI) was performed. All tubes used had an outer diameter of 5mm. NMR data will be referenced to chloroform (CDCl) 3 ;7.27ppm 1 H,77.20ppm 13 C) Or DMSO-d6 (=2.50 ppm,38.92 ppm) 13 C) As an internal standard. Chemical shift δ is in ppm; the weights are expressed as s (unimodal), d (bimodal), t (trimodal), q (tetramodal), m (multiplet), and br (broad); the coupling constant J is expressed in Hz. Thin layer chromatography was performed on silica gel plates with fluorescent indicators. Visualization is achieved by ultraviolet light (254 nm and/or 365 nm) and/or by staining in ammonium cerium molybdate or sulfuric acid solution. Following the procedure indicated in J.org.chem.43, 14, 1978, 2923-2925, flash column chromatography was performed with 230-400 mesh silica gel. High resolution mass spectrometry was performed on an applied biosystem API4000 LC/MS or an applied biosystem QSTAR XL mass spectrometer.
This example uses propynylated tetraiodothyroacetic acid (PGT). The preparation of PGT or derivatives thereof from tetraiodothyroacetic acid is described in U.S. patent publication No. 2017/0348425, entitled "non-cleavable Polymer binding to αvβ3 integrin thyroid antagonist," the contents of which are incorporated herein by reference.
Fig. 4a depicts an overview of the synthetic pathway of composition 300.
Fig. 4b depicts a detailed schematic of the synthesis path from fig. 4 a. Fig. 4a shows a scheme for synthesizing a composition 300, taking the attachment of tetraiodothyroacetic acid analogues to benzoguanidine-modified PEG by linking chemistry as an example. Other synthetic paths may be used.
The individual steps of the synthetic scheme of the composition 300 shown in fig. 4b will be described in more detail below, wherein the intermediates are represented by numbers shown in the linked chemistry scheme.
Synthesis of heterobifunctional PEG. Although heterobifunctional linkers are commercially available, for the purposes of this example, the following synthetic routes were used for preparation:
synthesis of product 2, namely tert-butyl [ (4-hydroxyphenyl) -methyl ] carbamate 2.
According to the previously disclosed protection method { 1) ACS Medicinal Chemistry Letters,8 (10), 1025-1030;2017.2 European Journal of Medicinal Chemistry,126, 384-407;2017.3 Tetrahedron Letters,47 (46), 8039-8042;3006 Synthesis of [ (4-hydroxyphenyl) -methyl ] ]Tert-butyl carbamate, the contents of which are incorporated herein by reference. The product 1, 4-hydroxyphenyl amine (0.62 g,5 mmol) was slowly added to a solution of di-tert-butyl dicarbonate (1.2 g,5.1 mmol) with stirring at room temperature. After stirring the reaction mixture for 8 hours, it was purified by column chromatography [ SiO 2 : etOAc/hexane (1:4)]The oily residue was purified to give 0.82g of N-Boc-4-hydroxybenzylamine as a colorless oil in 71% yield.
Synthesis of product 3 etherification of tert-Butoxyhydroxy-4-hydroxybenzylamine to bromo-azido modified PEG (400) 3
CsCO was added to the mixture at room temperature with stirring 3 (867 mg,2.67mmol,3 eq) was added to a solution of t-butoxycarbonyl-4-hydroxybenzylamine (300 mg,0.896mmol,1 eq) dissolved in CAN (25 mL). After stirring the reaction mixture for 30 minutes, bromo-azide modified PEG (400) (445 mg,1.05mmol,1.2 eq) was added to the mixture, which was then warmed until reflux for 24 hours. Filtration to remove excess CsCO 3 . The solvent was removed under reduced pressure, followed by column chromatography [ SiO ] 2 : etOAc/hexane (5:5)]The oily residue was purified to give product 3 as a yellow oil. Yield: 433mg,87%.
Synthesis of product 4. BOC deprotection
Product 3 (100 mg, 0.178 mmol,3 eq) was dissolved in 3ml of anhydrous 1, 4-dioxane at room temperature, 3ml of HCl (4N in dioxane) was added and stirred. After 24 hours, the solvent was removed under reduced pressure, and the oily residue was purified to quantitatively give product 4 (yield: 73g, 90%) as a yellow oil
Synthesis of product 5. Guanidination of product 4
Product 4 (85 mg,0.17mmol,1 eq) N, N' -bis-Boc-1H-pyrazole-1-carboxamidine (54 mg,17mg,1 eq) was dissolved in 3ml to 4ml anhydrous diethyl carbodiimide "DCM", and triethylamine "TEA" (48 μl,0.35mmol,2 eq) was then added to the solution. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (30 ml). Washed with% 5HCl (25 ml) and brine (25 ml), followed by drying (Mg 2 SO 4 ). The solvent was removed under reduced pressure to give product 5, which was purified by column chromatography [ SiO 2 : etOAc/hexane (2:8)]Purification, yield: 92mg,80%.
Synthesis of product 6
PGT of products 5 (100 mg,1 eq) and leq were dissolved in THF, stirred for 5 minutes, then 0.5eq sodium ascorbate and 0.5eq copper sulfate dissolved in 2ml water were added to the mixture, stirred at 65 ℃ for 24 hours. After 24 hours, the solvent was removed under reduced pressure, and the product 6 was purified in the yield: 65%.
Composition 300, synthesis of 2- (4- ((1- (20- (4- (guanidinomethyl) phenoxy) -3,6,9, 12,15, 18-hexacosyl) -1H-1,2, 3-triazol-4-yl) methoxy) -3, 5-diiodophenoxy) -3, 5-diiodophenyl) acetic acid)
Product 6 (50 mg) was dissolved in 3ml anhydrous 1, 4-dioxane, 3ml HCl (4N in dioxane) was added and stirred at 40 ℃. After 24 hours, the solvent was removed under reduced pressure, and the oily residue was purified to give composition 300 as a yellow powder.
Other synthetic methods may be used to obtain composition 300 or to obtain other compositions having general formula 100 shown in fig. 1.
Example 1b: synthesis of other exemplary compositions
Fig. 4c and 4d depict an outline of the synthetic pathways of other exemplary compositions, such as composition 201 following formula 200a, and composition 202 following formula 200b, using a tosylate group or acetaldehyde.
Composition 201 may be referred to as BG-P-MAT, BG-PEG-MAT, or benzoguanamine conjugated to monoamino tetraiodothyroacetic acid via PEG. Composition 202 may be referred to as BG-P-DAT, BG-PEG-DAT, or benzoguanamine conjugated to diaminotetraiodothyroacetic acid via PEG. As described herein, benzoguanidine derivatives or other norepinephrine transporter targets can be used. Tetraiodothyroacetic acid derivatives or other thyroid integrin antagonists, including but not limited to triiodothyroacetic acid and derivatives of triiodothyroacetic acid, may also be used as described herein.
Fig. 4e and 4f depict detailed schematic diagrams of the synthetic paths from fig. 4c and 4 d. Fig. 4e and 4f show the synthesis schemes of compositions 201 and 202 as another example of the incorporation of tetraiodothyroacetic acid to benzoguanidine modified PEG by linking chemistry. In addition, other synthetic paths may be used.
Application method
The compositions disclosed herein (including but not limited to exemplary compositions, such as composition 300, composition 201, and composition 202) exhibit novel dual targeting in the treatment of cancer cells and tumors, particularly neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, pancreatic neuroendocrine tumors, and carcinoid tumors. Furthermore, the compositions exhibit enhanced efficacy against neuroendocrine tumor cells when compared to thyroid integrin antagonists or norepinephrine transporter targets, either alone or administered alone, i.e., not combined into a single composition.
The compositions can also be used to image cancer cells/tumors. For example, neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor can be imaged using the compositions described herein. Imaging may be satisfactory for diagnostic and/or therapeutic monitoring. Furthermore, the composition may be used for both therapy and imaging. For example, the composition may exhibit increased retention in targeted cancer cells/tumors, enabling intensive treatment and more effective imaging.
Example 2: effects on subcutaneous transplantation tumor in female nude mice
Composition 300 (BG-P-TAT) was tested for efficacy using neuroblastoma SKNF2 cells transplanted into female nude mice.
Fifteen (15) female nude mice were transplanted twice, 10 per implantation 6 Individual cells. SKNF2 cell lines were used for subcutaneous xenografts.
Eight (8) days after implantation, mice were divided into four groups and received the following treatments for 15 days:
group of | Therapeutic compounds | Dosage of |
Group 1 | control-PBS | |
Group 2 | Composition 300 (BG-PEG-TAT) | 1mg/kg |
Group 3 | Composition 300 (BG-PEG-TAT) | 3mg/kg |
Group 4 | Composition 300 (BG-PEG-TAT) | 10mg/kg |
Fifteen (15) days of treatment, tumors were collected for evaluation of histopathology, and the following results were collected:
FIG. 5 shows the effect of control and treatment with composition 300 (BG-PEG-TAT) on body weight of mice transplanted with SKNF2 cell line. As shown, the body weights of all groups were uniform. The data indicate that daily treatment with different doses of composition 300 (BG-PEG-TAT) of 1mg/kg, 3mg/kg and 10mg/kg was continued for 15 days with no effect on animal body weight compared to control animals.
FIG. 6 shows the effect of composition 300 (BG-PEG-TAT) treatment and control on tumor volume of mice transplanted with SKNF2 cell line. As shown, the control group showed a tumor volume of from about 825mm after 15 days of treatment 3 To 1050mm 3 . All groups receiving treatment with composition 300 (BG-PEG-TAT) showed a decrease in tumor size. In addition, the group receiving treatment with composition 300 (BG-PEG-TAT) showed a dose-dependent decrease in tumor size, with the 10mg/kg group showing a tumor size of from about 825mm 3 Reduced to 100mm 3 。
Figures 7a-7b include photographs of mice from each treatment group in which subcutaneous tumors 70 can be visually compared. As shown in fig. 7a, the control group showed a large and clearly visible tumor 70. The control animals also showed abnormal convolutions (head rotations) 79, which were not found in all treatment groups. Abnormal convolutions are considered to be the effect of a tumor on the central nervous system.
As shown in fig. 7b, the treated group showed a significant dose-dependent decrease in tumor 70 size at the 10mg/kg dose until complete disappearance. As shown, there were no visible tumors located at tumor location 70' in the 10mg/kg treatment group.
FIG. 8 shows the effect of control and composition 300 (BG-PEG-TAT) treatment on tumor weight of mice transplanted with SKNF2 cell line. It can be seen that the treated group showed a dose dependent decrease in tumor weight compared to the control group. The data show that at doses of 1mg/kg, 3mg/kg and 10mg/kg, tumor shrinkage was 60%, 80% and 100%, respectively.
Figures 9a and 9b show the effect of control and composition 300 (BG-PEG-TAT) treatment on vasculature and tumor size in mice transplanted with SKNF2 cell lines. As shown, the control group showed a significant increase in tumor 70 size with increased angiogenesis. Vascularized areas 90 of the control tumor 70 are clearly visible. In contrast, the treated group showed a dose-dependent decrease in the size of tumor 70, including tumor shrinkage at a dose of 10 mg/kg. As shown, tumor vasculature is also clearly reduced. In fact, as shown in FIG. 9b, for the 10mg/kg group, only necrotic skin 75 at the site of implantation of tumor 70' (see FIG. 7 b) is needed for histopathological examination; treatment with this dose demonstrated tumor shrinkage.
FIG. 10 shows the effect of control and composition 300 (BG-PEG-TAT) treatment on tumor cell activity in mice transplanted with SKNF2 cell line. As shown, the treatment group showed a dose-dependent decrease in tumor cell activity. In the control, the cell activity was shown to be 70% -75% and the tumor center was shown to be 20% -30% necrotic. In contrast, daily treatment of composition 300 (BG-PEG-TAT) at different doses of 1mg/kg, 3mg/kg and 10mg/kg, respectively, showed loss of cell activity to 50%, 20% and 0.00%, respectively, for 15 days. After 15 days of treatment, the 10mg/kg dose group demonstrated that all tumor cells were not visible.
FIG. 11 shows the effect of control and composition 300 (BG-PEG-TAT) treatment on tumor necrosis in mice transplanted with SKNF2 cell line. It can be seen that the treated group showed a dose-dependent increase in tumor cell necrosis. The 10mg/kg group demonstrated a tumor cell necrosis rate of approximately 100%, the 3mg/kg group demonstrated a tumor cell necrosis rate of approximately 80%, and the 1mg/kg group demonstrated a tumor cell necrosis rate of approximately 50%.
Example 3: comparative example
Figures 12a and 12b show the effect of control and treatment with BG, BG derivatives, e.g., a thyrointegrin antagonist of TAT derivative, and compositions thereof (co-administration) on tumor cell necrosis in mice transplanted with SKNF2 cell line, compared to treatment with composition 300 (BG-PEG-TAT).
In summary, known thyroid integrin antagonists for treating tumor cells obtained substantially poorer results compared to composition 300 (BG-PEG-TAT). For example, subcutaneous administration of triazole tetraiodothyroacetic acid derivative at 3mg/kg daily for three (3) weeks showed a reduction in tumor growth of about 40% -50% and a reduction in tumor activity of about 40% -50%. Similarly, triazole tetraiodothyroacetic acid derivatives have been shown to reduce tumor growth by about 40% -50% and tumor activity by about 40% -50%. Furthermore, even if the combination therapy is administered subcutaneously at 3mg/kg of the combination of two triazole tetraiodothyroacetic acid derivatives daily, only 40% -50% reduction in tumor growth and tumor activity is achieved for three (3) weeks. Similar results were obtained with benzoguanidine and benzoguanidine derivative treatments. Furthermore, even combination therapy with benzoguanidine and thyroxine integrin antagonists does not show an increased efficacy over 40% -50% of the gates.
In contrast, treatment with composition 300 (BG-PEG-TAT) resulted in 80% reduction of tumors, with 80% reduction of residual tumor activity.
Comparative example 3a: effect of TAT derivatives on tumor weight:
in the case of neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, pancreatic neuroendocrine tumors and carcinoid tumors, αvβ3 integrin receptor antagonists (thyroid integrin antagonists) show limited efficacy (40% -50%) in terms of tumor growth rate and inhibition of cancerous activity. For example, the graph of fig. 12b includes the effect of triazole tetraiodothyroacetic acid derivative (referred to as TAT) on tumor body weight when compared to the control group (phosphate buffered saline "PBS"). The specific derivative tested was beta cyclodextrin triazole tetraiodothyroacetic acid. As shown, the 3mg/kg dose resulted in a reduction in tumor weight of approximately 40% -50%.
Comparative example 3b: effect of benzoguanidine and its derivatives on tumor weight
Similarly, in the case of neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, pancreatic neuroendocrine tumors and carcinoid tumors, benzoguanidine and its derivatives show limited efficacy (40% -50%) in terms of tumor growth rate and inhibition of cancer activity. For example, the graph in fig. 12a includes the effect of Benzoguanidine (BG) and benzoguanidine derivatives (e.g., migg and polymers that bind benzoguanidine (especially PLGA-PEG-BG, referred to as polymer-BG)) on tumor body weight when compared to control (PBS). Although the therapeutic compound is taken up in the maximum amount (90% -100%) into neuroblastomas and other neuroendocrine tumors, it exhibits limited anti-cancer efficacy of neuroblastomas.
Comparative example 3c: influence of Co-administration of separate norepinephrine transporter targets and thyroid integrin antagonists
Furthermore, combination therapy comprising co-administration of a norepinephrine transporter target, such as benzoguanidine or a derivative thereof, with a thyroid integrin antagonist, such as a triazole tetraiodothyroacetic acid derivative, does not inhibit neuroblastoma growth and activity by more than 40% -50%. For example, as shown in fig. 12b, treatment with either compound alone (bg+tat) showed no more than 40% -50% efficacy of co-administration of benzoguanamine in combination with tetraiodothyroacetic acid derivative (bg+tat). In addition, beta cyclodextrin triazole tetraiodothyroacetic acid is a tetraiodothyroacetic acid derivative that has been used.
Comparative example 3d: influence of composition 300 (BG-P-TAT) (Benzylguanidine conjugated to TAT by PEG)
In addition, treatment with composition 300 (BG-P-TAT) resulted in a significantly increased effect of tumor weight compared to the control group and other types of treatment shown in fig. 12 b. Composition 300 achieves a reduction in tumor of approximately 80%. In addition, the activity of the residual tumor was reduced by 80%. Indeed, composition 300 (TAT bound to BG) showed significantly increased efficacy, even over the combined administration of TAT and BG (bg+tat) administered separately.
The comparative examples from fig. 12a and 12b are summarized in table 3 below:
TABLE 3 Table 3
Example 4: imaging of subcutaneous engrafted tumors in thymus-free female mice
Female mice without thymus were transplanted twice, 10 each time 6 Individual cells/grafts. SKNF1 cell lines are used for subcutaneous xenografts.
Group 1 consisted of three mice treated with PEG-TAT-dye (Cy 5). Group 2 consisted of three mice treated with PEG-BG-dye (Cy 5). Group 3 consisted of three mice treated with TAT-PEG-BG-dye (Cy 5), wherein TAT and BG were covalently linked with a PEG linker as compound 300. The treatment groups are as follows:
fluorescence imaging (Cy 5) was performed 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after dosing. The imaging results are shown in fig. 13a and 13b, where the tumor location is circled with yellow, cy5 dye appears red. As shown in these figures, composition 300 shows a dramatic increase in fluorescence signal when TAT and BG are covalently linked, and a significant increase in uptake and retention time in SKNF1 neuroblastoma when compared to triazole tetraiodothyroacetic acid derivative alone or benzoguanidine derivative alone.
Neuroendocrine tumor-forming tumor cells are used in the treatment examples. It will be appreciated by those skilled in the art that these examples are effective models for treating other tumor types, particularly other neuroendocrine tumor types. In addition, any tumor or disease state that indicates an increase in the activity of the norepinephrine transporter can be treated by the disclosed compositions, wherein the thyroid integrin is expected to modulate anti-angiogenic activity.
According to these examples, the compositions described herein show increased efficacy against tumor cells, particularly neuroendocrine tumors. Such compositions can be used to treat neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, pancreatic neuroendocrine tumors, and carcinoid tumors, for example, by injection, topical, sublingual, oral, and other routes of administration.
Other exemplary Compounds
As described above, compositions based on general structure 100 may be included in R 1 -R 8 And/or variables in linker 130, such as in spacer 132, polymer 131, and/or the Y moiety. Exemplary embodiments including these variables are discussed in more detail below. These exemplary embodiments are not intended to limit the invention to any specifically set forth embodiments. Rather, various embodiments are described for purposes of illustration and are not intended to be exhaustive or to limit the various embodiments to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the embodiments.
FIG. 14 depicts an exemplary composition 7a of formula 100. Composition 7a included triazole tetraiodothyroacetic acid conjugated to a benzoguanidine-modified PEG, wherein an iodine group was selected as a substituent on the benzoguanidine aromatic ring. Composition 7a may also be referred to as dI-BG-PEG-TAT or dI-BG-P-TAT.
FIG. 15 depicts an exemplary composition 7b of formula 100. Composition 7b included triazole tetraiodothyroacetic acid conjugated to benzoguanidine-modified PEG, wherein a methoxy group was selected as a substituent on the benzoguanidine aromatic ring. Composition 7b may also be referred to as dM-BG-PEG-TAT or dM-BG-P-TAT.
FIG. 16 depicts an exemplary composition 15 of formula 100. Composition 15 includes tetraiodothyroacetic acid conjugated to benzoguanidine-modified PEG, wherein the amino group of the Y moiety is piperazine. Composition 15 may also be referred to as BG-PEG-PAT or BG-P-PAT, where PAT is referred to as piperazine tetraiodothyroacetic acid.
The synthesis of these compositions is demonstrated below.
Example 5: synthesis of composition 7a and composition 7b
The synthesis of dI-BG-P-TAT (composition 7 a) and dM-BG-P-TAT (composition 7 b) was completed as described in scheme 1. The amino groups of iodine and methoxy substituted 4-hydroxybenzylamine are protected with di-tert-butyl dicarbonate. For compound 2a and compound 2b 1 H-NMR was characterized. The peak observed at 1.49ppm was attributed to the tert-butoxycarbonyl (Boc) proton. In the following reaction, compound 2a and compound 2b are under reflux conditions, and K 2 CO 3 And ACN in the presence of a commercially available Br-PEG6-N 3 The reaction gave compound 3a and compound 3b in 90% and 85% yields, respectively. Compound 3a and compound 3b 1 H-NMR spectrum showed PEG proton peaks between 3.40-3.97 ppm. Next, the amino groups were deprotected in 4N HCl (in dioxane) by 4a and 4b 1 The disappearance of Boc proton signals at 1.48 and 1.49ppm for H NMR spectra confirmed the product. In the next step, N, N' -bis-Boc-1H-pyrazole-1-carboxamidine is reacted with compound 4a and compound 4b to afford Boc-protected guanidine compound 5a and guanidine compound 5b. Compound 5a and compound 5b 1 The H-NMR spectra clearly show peaks at 1.49-1.52ppm and 150-1.52ppm, respectively, which can be attributed to protons of two different Boc groups.
Scheme 1: synthetic patterns of compound 7a and compound 7 b. a) Boc 2 O,6h;b)K 2 CO 3 ,ACN,Br-PEG6-N 3 Refluxing for 24 hours; c) HCl (4N in dioxane), room temperature, 4h; d) DCM, TEA, N, N' -bis-Boc-1H-pyrazole-1-carboxamidine, room temperature, 12H; e) PGT, THF: water 4:1, sodium sulfate, sodium ascorbate, room temperature, 24 hours; f) HCl [ ]4N in dioxane), room temperature, 24h. Scheme 1 is shown in fig. 17.
Then, azide-containing compound 5a and compound 5b were combined with propynylated tetraiodothyroacetic acid (terminal alkyne-containing tetraiodothyroacetic acid, PGT) 36 ) In combination, triazole rings were formed by click reaction, resulting in compound 6a and compound 6b. The following were used in THF: cuSO in Water (4:1) 4 Sodium ascorbate (0.3 eq:0.6 eq) and cu+ was generated in situ at room temperature. Compound 6a and compound 6b 1 The H-NMR spectra showed characteristic single peaks of triazole ring protons at 8.59 and 8.60ppm, respectively. Finally, the Boc protecting group was removed with 4NHCl (in dioxane) with methanol: the product was purified by reverse phase column chromatography with water (70:30) to give compound 7a and compound 7b. Compound 7a and compound 7b 1 H-NMR (FIGS. S21 and S23), 13 C-NMR and Mass Spectrometry confirm the structure of these compounds.
Example 6: synthesis of composition 15
The synthesis of BG-P-PAT 15 was completed as described in scheme 2. First, the amino group of 4-hydroxybenzylamine is protected with a Boc group. Next, br-PEG7-OH at reflux temperature, and at K 2 CO 3 And ACN in the presence of a phenol hydroxyl group of 9 to give 10 and 1 it was characterized by H-NMR and PEG proton peaks at 3.6-3.8ppm were observed.
Scheme 2: synthetic pattern of compound 15. a) Boc 2 O,6h;b)K 2 CO 3 Refluxing ACN, br-PEG7-OH for 24h; c) P-toluenesulfonyl chloride (Tos-Cl), DCM, TEA,0 ℃ to room temperature for 2h; d) Compound 19 (see scheme 3), ACN, K 2 CO 3 60 ℃ for 18h; e) HCl (4N in dioxane), room temperature, 4h; f) DCM, TEA, N, N' -bis-Boc-1H-pyrazole-1-carboxamidine, room temperature, 12H; g) Dioxane: water; concentrated HCl, room temperature, 24h. Scheme 2 is shown in fig. 18.
The tetraiodothyroacetic acid units on PEG were introduced using different methods (scheme 3). First, tetraiodoCarboxylic acid groups of methylacetic acid 16 are found in MeOH and SOCl 2 Converted to methyl ester to afford 17. Then with tert-butyl 4- (3- (methylsulfonyloxy) propyl) piperazine-1-carboxylate hydrochloride 18 and Cs as base in ACN 2 CO 3 The reaction was then treated with HCl (4, N in dioxane) solution to deprotect the Boc group. The structure of the obtained compound 19 1 H-NMR was characterized. Aromatic protons of tetraiodothyroacetic acid were observed at 7.32 and 8.04ppm, piperazine protons were observed at 2.77 and 2.94 ppm.
Scheme 3. Synthesis of Compound 19. a) SoCl 2 ,MeOH;b)17,ACN,Cs 2 CO 3 60 ℃ for 18 hours; c) 4N HCl in dioxane for 2h. Scheme 3 is shown in fig. 19.
At K 2 CO 3 And in the presence of ACN, after tosylation of PEG-OH 10, compound 19 (scheme 2) was introduced into the PEG monomer to give compound 12. Compound 12 1 The H-NMR spectrum (FIG. S40) confirmed the structure, and aromatic proton peaks of tetraiodothyroacetic acid and N-Boc benzylamine were observed at 7.18-7.79 and 6.88-7.20, respectively. After N-Boc deprotection of compound 12, the free amine of compound 13 introduces a Boc-protected guanidino group with N, N' -bis-Boc-1H-pyrazole-1-carboxamidine in DCM and TEA as base to give compound 14. Finally, the solution is dissolved in dioxane: concentrated hydrochloric acid in water hydrolyzes the methyl ester and Boc protecting groups to give the desired compound 15. Compound 15 1 H-NMR (FIG. S46) and mass spectrometry confirmed the structure. The purity of the final synthesis products 7a, 7b and 15 was determined by HPLC and were all>95%。
Compounds dI-BG-P-TAT (7 a), dM-BG-P-TAT (7 b) and BG-P-PAT (15) show relatively high binding affinity to purified integrin αvβ3 receptor, but with IC 50 These compounds have lower IC than BG-P-TAT at 10.3nM a0 Values were 1.1nM, 0.5nM, 0.3nM, respectively. Thus, compound 15BG-P-PAT showed binding affinity relative to BG-P-TATAbout 30 times greater. Figure 20 shows the respective percent binding to purified integrin αvβ3 receptors.
In addition, the compound behaves similarly to BG-P-TAT in vitro cellular uptake (SK-N-F1 neuroblastoma cells). Ingestion is graphically shown in fig. 21A and 21B.
Molecular docking studies were also performed on compound 7a, compound 7b and compound 15. The molecular docking results show that the molecules are in a curved structure at the binding site. Interaction and docking analysis showed that compound 15 has the best interaction rate with integrin beta 3 subunit, has a high binding energy of-14.4 kcal/mol, and forms 9 hydrogen bonds; while the binding energies of compound 7a and compound 7b to integrin β3 subunit are-6.1 kcal/mol and-7.8 kcal/mol, respectively, compound 7a forms 6 hydrogen bonds (1 hydrogen bond with the αv domain, 5 hydrogen bonds with the β3 domain), and compound 7b forms 6 hydrogen bonds (1 hydrogen bond with the αv domain, 4 hydrogen bonds with the β3 domain, 1 hydrogen bond with the Mn atom). The energy values of compound 7a, compound 7b and compound 15, and the binding energy and residues involved in the interactions are listed in table 4. The binding affinity of compound 15 for αvβ3 was 30-fold higher than that of the close analog BG-P-TAT, probably due to the additional hydrogen bonding between the BG moiety of compound 15 and Asp-127 and Asp-126. This may be due to the longer linker chain in the BG-P-PAT, making the BG portion of the BG-P-PAT easier to enter the domain than the BG in the BG-P-TAT. The additional hydrogen bonding of piperazine nitrogen also increases the binding affinity of BG-P-PAT to αvβ3.
Table 4: binding energy of Compounds to integrin αvβ3
Application method
Example 7: effects on subcutaneous implantation of tumors in female nude mice
The efficacy of composition 7a (dI-BG-P-TAT), composition 7b (dM-BG-P-TAT) and composition 15 (BG-P-PAT) was tested by neuroblastoma SKNF1 cells implanted in female nude mice, similar to the examples of composition 300 (BG-P-TAT) described above.
Twenty (20) days after treatment at a dose of 3mg/kg (7 days of treatment with composition 7a due to skin irritation and physical discomfort), tumors were collected to evaluate histopathology, and the following results were collected:
FIG. 22 shows the efficacy of composition 7a (dI-BG-P-TAT), composition 7b (dM-BG-P-TAT), and composition 15 (BG-P-PAT) on tumor volumes of mice transplanted with SKNF1 cell line, as compared to the control. As shown, the tumor volumes of the two completed treatment groups (composition 7b (dM-BG-P-TAT) and composition 15 (BG-P-PAT)) were reduced compared to the control. The control group was from 175mm within 20 days 3 Up to 1000mm 3 Without a significant increase in tumor volume in the completed treatment group.
FIG. 23 shows the effect of composition 7a (dI-BG-P-TAT), composition 7b (dM-BG-P-TAT), and composition 15 (BG-P-PAT) on tumor weight of mice transplanted with SKNF1 cell line, as compared to the control. As shown, the completed treatment group showed a decrease in tumor weight compared to the control. The data shows a 90% decrease in tumor weight for composition 15 (BG-P-PAT); for composition 7b (dM-BG-P-TAT), tumor weight was reduced by 86%. For composition 7a (dI-BG-P-TAT), the treatment group stopped treatment also showed a 67% reduction in tumor weight.
In addition, to compare tumor histopathological changes in untreated and treated groups, tumors were resected, fixed, and stained with hematoxylin and eosin (H & E). As shown, necrosis of tumors in animals treated with compound 7a, compound 7b and compound 15 was clearly seen under a low power microscope compared to the control. Staining showed large area necrosis, fibrosis and cell debris, approximately 98% (composition 15 BG-P-PAT), 85% (composition 7b dM-BG-P-TAT) and 70% (composition 7a dI-BG-P-TAT). On the other hand, tumors from the untreated group are mostly living tumor cells. Tumors treated with composition 15BG-P-PAT showed large area necrosis replaced by normal tissue under high magnification (40 fold). (likewise, compound 7a dI-BG-P-TAT was administered for only 7 days, while the other two regimens were administered for 20 days).
Neuroblastomas are used in the treatment example in question. Those skilled in the art will appreciate that these examples are effective models for treating other tumor types, particularly other neuroendocrine tumors. In addition, any tumor or disease state that exhibits increased norepinephrine transporter activity can be treated by the disclosed compositions, wherein a thyroid integrin can be expected to modulate anti-angiogenic activity.
According to these examples, the compositions described herein show enhanced efficacy against tumor cells, in particular neuroendocrine tumors. These compositions are useful for the treatment of neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, pancreatic neuroendocrine tumors, and carcinoid tumors, for example, by injection, topical administration, sublingual administration, oral and other routes of administration.
Various embodiments of the invention have been described for purposes of illustration, but are not intended to be exhaustive or to limit the various embodiments to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or to surpass the technical improvements in the market that are found in relation to technology, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Claims (20)
1. A composition comprising:
compounds of the general formula
Or a salt thereof,
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from hydrogen, iodine, fluorine, bromine, and methoxyA group consisting of a nitro group, an amino group, and a nitrile group;
Wherein R is 5 、R 6 、R 7 And R is 8 Each independently selected from the group consisting of hydrogen, iodine, and an alkane group;
n1≥0;
n2 is more than or equal to 1; and
y comprises an amino group.
2. The composition of claim 1, wherein R 5 、R 6 、R 7 And R is 8 Independently selected from the group consisting of isopropyl groups and t-butyl groups.
3. The composition of claim 1 wherein Y is selected from the group consisting of mono-amino, di-amino, triazole, and piperazine.
4. The composition of claim 1, wherein R 1 、R 2 、R 3 And R is 4 At least two of which are iodine.
5. The composition of claim 1, wherein R 1 、R 2 、R 3 And R is 4 At least two of which are methoxy groups.
6. The composition of claim 1, wherein the compound has the formula:
7. the composition of claim 1, wherein the compound has the formula:
8. the composition of claim 1, wherein the compound has the formula:
9. a method for dual targeting of tumor cells, comprising:
use of a composition comprising a compound of formula (la):
or a salt thereof,
wherein R is 1 、R 2 、R 3 And R is 4 Each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, methoxy groups, nitro groups, amino groups, and nitrile groups;
Wherein R is 5 、R 6 、R 7 And R is 8 Each independently selected from the group consisting of hydrogen, iodine, and an alkane group;
n1≥0;
n2 is more than or equal to 1; and
y comprises an amino group.
10. The method of claim 9, wherein the compound comprises one of N-benzoguanidine and an N-benzoguanidine derivative.
11. The method of claim 9, wherein the composition comprises a thyroid integrin αvβ3 receptor antagonist selected from the group consisting of triiodothyroacetic acid, a triiodothyroacetic acid derivative, tetraiodothyroacetic acid, a tetraiodothyroacetic acid derivative.
12. A compound, comprising:
n-benzoguanamine;
thyroid integrin αvβ3 receptor antagonists;
wherein the N-benzoguanidine and the thyroid integrin αvβ3 receptor antagonist are linked by a linker.
13. The compound of claim 12, wherein the linker comprises a polymer.
14. The compound of claim 12, wherein the polymer is polyethylene glycol, PEG.
15. The compound of claim 12, wherein the polyethylene glycol PEG has a molecular weight of 200g/mol to 4,000g/mol.
16. The compound of claim 12, wherein the thyroid integrin αvβ3 receptor antagonist is selected from the group consisting of triiodothyroacetic acid, a triiodothyroacetic acid derivative, tetraiodothyroacetic acid, and a tetraiodothyroacetic acid derivative.
17. The compound of claim 12, wherein the composition has therapeutic efficacy for neuroendocrine tumors.
18. The compound of claim 12, wherein the neuroendocrine tumor is one of a neuroendocrine tumor, a pheochromocytoma, a pancreatic neuroendocrine tumor, and a carcinoid tumor.
19. The compound of claim 12, wherein the therapeutic efficacy of neuroendocrine tumor is provided by both N-benzoguanidine and a thyroid integrin αvβ3 receptor antagonist.
20. The compound of claim 12, wherein the composition targets neuroendocrine tumors via a norepinephrine transporter.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/340,843 | 2021-06-07 | ||
US17/340,843 US11351137B2 (en) | 2018-04-11 | 2021-06-07 | Composition and method for dual targeting in treatment of neuroendocrine tumors |
PCT/US2022/031876 WO2022260918A1 (en) | 2021-06-07 | 2022-06-02 | Composition and method for dual targeting in treatment of neuroendocrine tumors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117412772A true CN117412772A (en) | 2024-01-16 |
Family
ID=84425339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280039629.XA Pending CN117412772A (en) | 2021-06-07 | 2022-06-02 | Compositions and methods for dual targeted treatment of neuroendocrine tumors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP4351650A1 (en) |
CN (1) | CN117412772A (en) |
AU (1) | AU2022287943A1 (en) |
CA (1) | CA3220332A1 (en) |
WO (1) | WO2022260918A1 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207665B1 (en) * | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
NO20220050A1 (en) * | 2005-11-21 | 2008-08-12 | Novartis Ag | Neuroendocrine tumor treatment |
EP2268317B1 (en) * | 2008-03-14 | 2020-02-26 | VisEn Medical, Inc. | Integrin targeting agents and in vivo and in vitro imaging methods using the same |
US10328043B1 (en) * | 2018-04-11 | 2019-06-25 | Nanopharmaceuticals, Llc. | Composition and method for dual targeting in treatment of neuroendocrine tumors |
US10961204B1 (en) * | 2020-04-29 | 2021-03-30 | Nanopharmaceuticals Llc | Composition of scalable thyrointegrin antagonists with improved blood brain barrier penetration and retention into brain tumors |
-
2022
- 2022-06-02 AU AU2022287943A patent/AU2022287943A1/en active Pending
- 2022-06-02 WO PCT/US2022/031876 patent/WO2022260918A1/en active Application Filing
- 2022-06-02 EP EP22820793.2A patent/EP4351650A1/en active Pending
- 2022-06-02 CN CN202280039629.XA patent/CN117412772A/en active Pending
- 2022-06-02 CA CA3220332A patent/CA3220332A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP4351650A1 (en) | 2024-04-17 |
CA3220332A1 (en) | 2022-12-15 |
WO2022260918A1 (en) | 2022-12-15 |
AU2022287943A1 (en) | 2023-12-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111971038B (en) | Compositions and methods for dual targeted treatment of neuroendocrine tumors | |
Choe et al. | Anticancer drug delivery systems: multi-loaded N4-acyl poly (ethylene glycol) prodrugs of ara-C.: II. Efficacy in ascites and solid tumors | |
JP5008783B2 (en) | Prodrugs based on high molecular weight polymers | |
JP2002512265A (en) | Terminally branched polymer linker and polymer conjugate containing same | |
JP4663233B2 (en) | Polymeric thiol-linked prodrugs utilizing benzyl elimination systems | |
JP2020508985A5 (en) | ||
US11186551B2 (en) | Composition of scalable thyrointegrin antagonists with improved retention in tumors | |
JP2005513006A6 (en) | Polymeric thiol-linked prodrugs utilizing benzyl elimination systems | |
EP2780041B1 (en) | Multimodal contrast and radiopharmaceutical agent for an imaging and a targeted therapy guided by imaging | |
US9364570B2 (en) | Functionalisation of cage amine ligands for metallo-radiopharmaceuticals | |
CN117412772A (en) | Compositions and methods for dual targeted treatment of neuroendocrine tumors | |
US11351137B2 (en) | Composition and method for dual targeting in treatment of neuroendocrine tumors | |
JP2004520261A (en) | Positively charged peptide nucleic acid analogs with improved properties | |
RU2789198C2 (en) | Composition and method for double targeting in treatment of neuro-endocrine tumors | |
JP2024520888A (en) | Compositions and methods for dual targeting in the treatment of neuroendocrine tumors - Patents.com | |
Yao et al. | Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer | |
US20230181747A1 (en) | Drug loaded peptide brush polymers | |
WO2010083154A2 (en) | Heterofunctional segment-poly(ethylene glycol) polymers as delivery vehicles | |
EP4055020A1 (en) | Radiolabelled targeting ligands | |
WO2018175595A1 (en) | Modified histone deacetylase inhibitors and uses thereof | |
WO2021002481A1 (en) | Renal targeting-type drug delivery carrier having excellent biodegrability |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
CB02 | Change of applicant information |
Country or region after: U.S.A. Address after: Troy, New York, USA Applicant after: NANOPHARMACEUTICALS, LLC Address before: New York, NY, USA Applicant before: NANOPHARMACEUTICALS, LLC Country or region before: U.S.A. |
|
CB02 | Change of applicant information |