CN113563293A - 基于n-氧化物的前药复合物及其制备方法和应用 - Google Patents
基于n-氧化物的前药复合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN113563293A CN113563293A CN202110977165.4A CN202110977165A CN113563293A CN 113563293 A CN113563293 A CN 113563293A CN 202110977165 A CN202110977165 A CN 202110977165A CN 113563293 A CN113563293 A CN 113563293A
- Authority
- CN
- China
- Prior art keywords
- prodrug
- therapeutic drug
- compound
- prodrug complex
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940002612 prodrug Drugs 0.000 title claims abstract description 54
- 239000000651 prodrug Substances 0.000 title claims abstract description 54
- 150000001204 N-oxides Chemical class 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940126585 therapeutic drug Drugs 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052796 boron Inorganic materials 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 28
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 16
- 229940124597 therapeutic agent Drugs 0.000 claims description 16
- -1 cyano, hydroxy, amino, difluoromethyl Chemical group 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- GLNDAGDHSLMOKX-UHFFFAOYSA-N coumarin 120 Chemical compound C1=C(N)C=CC2=C1OC(=O)C=C2C GLNDAGDHSLMOKX-UHFFFAOYSA-N 0.000 claims description 7
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000003379 elimination reaction Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 229960002707 bendamustine Drugs 0.000 claims description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 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
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 229940009456 adriamycin Drugs 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000012650 click reaction Methods 0.000 abstract description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 230000008859 change Effects 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 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 4
- 238000003384 imaging method Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 2
- 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 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GUJMUFSJFDQBJC-UHFFFAOYSA-N bis(trichloromethyl) carbonate;carbonyl dichloride Chemical compound ClC(Cl)=O.ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl GUJMUFSJFDQBJC-UHFFFAOYSA-N 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000276 dose-dependent cytotoxicity Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种基于N‑氧化物的前药复合物，由N‑氧化物与含有羟基、氨基或羧基的治疗药物组成，N‑氧化物与治疗药物通过N‑氧化物上的羟基与治疗药物上的羟基、氨基或羧基连接，该前药复合物可与硼试剂发生点击反应释放出治疗药物，治疗药物进入肿瘤细胞中杀伤肿瘤细胞，实现肿瘤治疗效果。本发明的前药复合物能够可控且高效地释放出治疗药物，在制备肿瘤治疗药物方面具有潜在的应用前景。
Description
技术领域
本发明涉及生物医药技术领域，尤其涉及一种基于N-氧化物的前药复合物及其制备方法和应用。
背景技术
生物正交化学领域致力于满足对可促进生物过程分子分析的方法的需求。它的基础应用包括在培养的细胞和活生物体中用探针和亲和试剂对生物分子进行化学靶向，以及构建用于治疗应用的修饰后的生物分子。目前化学家已经发展出一批有效的方法，其中包括施陶丁格连接法，铜介导的和无金属叠氮化物-炔烃环加成反应和四嗪连接法。生物正交反应的应用主要就是通过这一类反应方法实现小分子开关的作用下来调节靶分子的活性。目前现有的生物正交成键反应已经被发展了很多可以应用的方法，但更多的也只是在作为探针成像的应用上，显然想让生物正交反应更好地与药物分子相结合，断键释放更为合适，虽然断键释放的生物正交反应也有很多类型，但真正能做到可以简单、快速和更具耐受性的断键反应还是比较局限的。因此发展一种新的触发手段来实现断键释放反应目前来说显得尤为重要，它可以通过结合一种通用的成键方式，最终达到触发断键释放出所需的目标化合物的目的。
发明内容
为解决上述技术问题，本发明提供了一种基于N-氧化物的前药复合物，能够与硼试剂发生点击反应释放出治疗药物，并在体内杀伤肿瘤细胞，抑制肿瘤生长，延长生存期。
本发明的第一个目的是提供一种基于N-氧化物的前药复合物，前药复合物为通式I所示化合物或其对映体、非对映体、外消旋混合物或其药学上可接受的盐：
其中，R1和R2为甲基；
R3、R4、R5和R6分别独立地选自氢、卤素、氰基、羟基、氨基、二氟甲基、三氟甲基、氨甲基、甲基卤素、苯基、烷基、烷氧基、异丙基、叔丁基、环丙基、羰基或醛基；
R7和R8分别独立地选自氢或卤素；
Payload为含有羟基、氨基或羧基的治疗药物；
L选自
其中，当L为
时，Payload为含有羟基的治疗药物；当L为
时，Payload为含有氨基的治疗药物；当L为
时，Payload为含有羧基的治疗药物。
进一步地，含有羟基的治疗药物为7-乙基-10-羟基喜树碱、康普瑞汀、喜树碱或7-羟基香豆素，含有氨基的治疗药物为苯胺氮芥、阿霉素或7-氨基-4-甲基香豆素，含有羧基的治疗药物为苯丁酸氮芥、甲氨蝶呤或苯达莫斯汀。
本发明的前药复合物由N-氧化物和治疗药物分子连接而成，避免了N-氧化物在生物环境下缓慢的分解释放，保证前药的稳定性，通过1,6消除反应在细胞外释放出治疗药物，而后治疗药物主动进入细胞杀伤肿瘤细胞。
进一步地，当治疗药物为含有羟基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
进一步地，当治疗药物为含有羧基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
本发明的上述前药复合物的制备方法包括以下步骤：将治疗药物和三苯基膦加入有机溶剂中，加入N-氧化物，在保护气氛下，放置在冰浴中，加入偶氮化合物混合搅拌，得到上述前药复合物；有机溶剂选自二氯甲烷、氯仿、乙腈、甲醇、N,N-二甲基甲酰胺和四氢呋喃中的一种或几种，偶氮化合物选自偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯和偶氮二甲酸二叔丁酯中的一种或几种。
进一步地，治疗药物、三苯基膦和N-氧化物的摩尔比为1:2:2。
进一步地，反应时间为3-12h。
进一步地，反应温度为20-30℃。
进一步地，前药复合物通过薄层色谱法以体积比为3-7:1的二氯甲烷和甲醇混合溶液分离得到。
进一步地，当治疗药物为含有氨基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
本发明的上述前药复合物的制备方法包括以下步骤：向苄醇类化合物中加入有机溶剂，随后加入N,N-二异丙基乙胺，使反应体系处于保护气氛中，搅拌30-60min后，向其中缓慢滴加三光气的有机溶液，继续搅拌30-60min，接着缓慢滴加治疗药物的有机溶液，滴加完成后搅拌3-4h得到上述前药复合物；有机溶剂选自二氯甲烷、氯仿、乙腈、甲醇、N,N-二甲基甲酰胺和四氢呋喃中的一种或几种。
进一步地，反应完成后加入二氯甲烷和甲醇的混合溶液，二氯甲烷和甲醇的体积比为5:1，有助于更好地溶解化合物。
本发明还要求保护上述前药复合物在制备肿瘤治疗药物中的应用。
进一步地，前药复合物与硼试剂通过1,6-消除反应释放出治疗药物进行肿瘤治疗。
治疗药物为含有活性羟基、氨基或羧基的荧光分子时，可通过荧光变化观察肿瘤部位药物富集的程度，从而实现肿瘤的可视化。当硼试剂与前药复合物反应后，L与Payload之间的化学键断裂，释放出治疗药物，进入肿瘤细胞，实现肿瘤治疗的效果。
进一步地，硼试剂选自联硼酸频那醇酯、苯硼酸和苯硼酸酯中的一种或几种。
进一步地，上述前药复合物可用于治疗结肠癌、黑色素瘤、乳腺癌、肺癌、胃癌、肝癌、急性白血病(淋巴细胞性和粒细胞性)、恶性淋巴瘤、卵巢癌、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、母细胞瘤、神经母细胞瘤、膀胱癌、甲状腺癌、前列腺癌、头颈部鳞癌、睾丸癌等。
借由上述方案，本发明至少具有以下优点：
本发明提供了一种基于N-氧化物的前药复合物，其生物相容性好，可以在活体内与硼试剂发生点击和释放反应，快速且高效地释放出治疗药物，实现治疗药物的可控释放，治疗药物主动进入癌细胞内可实现肿瘤治疗。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合详细附图说明如后。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明。
图1为实施例1制备的前药复合物与联硼酸频那醇酯在0.2％DMSO/PBS中的荧光强度增强的荧光曲线；
图2为实施例2制备的前药复合物与联硼酸频那醇酯在0.2％DMSO/PBS中的荧光强度变化的荧光曲线；
图3为实施例3制备的前药复合物3c与联硼酸频那醇酯在1％DMSO/PBS中的荧光比例变化的荧光曲线及对应的液相色谱图；
图4为1％DMSO、SN-38、3c、联硼酸频那醇酯及3c与联硼酸频那醇酯在A549细胞中孵育1小时后的细胞成像结果；
图5为前药复合物3c与联硼酸频那醇酯发生点击反应后不同浓度下的细胞毒性对照以及3c在A549细胞中24小时内的稳定性结果；
图6为前药复合物3c与联硼酸频那醇酯发生点击反应后在A549异种移植瘤小鼠模型中的肿瘤内成像结果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1
合成路线：
将7-羟基香豆素(1.0equiv)和三苯基膦PPh3(2.0equiv)加入到无水二氯甲烷中，随后加入I2’(1.0equiv)，并用氮气保护，放置在冰浴中，接下来将偶氮二甲酸二乙酯DEAD(2.0equiv)缓慢加入到悬浊反应液中，该反应在室温下混合搅拌3小时。反应液直接用大板以DCM：MeOH＝10:1的极性分离。最终得到白色固体产物3a，产率51％。1H NMR(400MHz,DMSO):δ7.98(d,J＝8.0Hz,2H),7.63(d,J＝12.0Hz,1H),7.51(d,J＝12.0Hz,2H),7.38(d,J＝8.0Hz,1H),6.89(dd,J＝4.0Hz,1H),6.83(d,J＝4Hz,1H),6.24(d,J＝8.0Hz,1H),5.14(s,2H),3.57(s,6H)；13C NMR(100MHz,DMSO):δ161.8,160.7,155.8,144.8,137.0,130.1,128.5,121.1,120.8,113.4,113.2,113.1,102.1,69.6,63.6ppm；LCMS(ESI)m/z 311.3。
实施例2
合成路线：
将I2’(15.2mg,0.1mmol,1eq.)加入到反应瓶中，向其中加入无水二氯甲烷溶剂，随后加入N,N-二异丙基乙胺DIEA(12.9mg,0.1mmol,1eq.)。在反应瓶上接入一个N2气球，使反应体系处于N2氛围中。反应在室温下搅拌半小时后，用注射器向其中缓慢滴加三光气Triphosgene(17.8mg,0.06mmol,0.6eq.)的无水二氯甲烷溶液，反应继续在室温下搅拌半小时。接着用注射器向反应体系中缓慢加入7-氨基-4-甲基香豆素(17.5mg,0.1mmol,1eq.)和DIEA(15.5mg,0.12mmol,1.2eq.)的无水二氯甲烷溶液，滴加完成后使反应在室温下搅拌3小时。反应完成后将反应液浓缩，加入二氯甲烷和甲醇的混合溶液，利用TLC大板分离(DCM:MeOH＝100:1)。由于分离出的中间体稳定性较差，因此直接将分离出的中间体(7.1mg,0.02mmol,1eq.)溶于无水二氯甲烷中，再向其中加入间氯过氧苯甲酸mCPBA(38.0mg,0.22mmol,1.1eq.)，反应在室温下搅拌3小时。反应完成后将反应液浓缩，加入二氯甲烷和甲醇的混合溶液溶解，通过制备薄层色谱分离(DCM:MeOH＝5:1,Rf＝0.1)。最终得到化合物3b，产率23％。1H NMR(400MHz,CDCl3):δ7.86(d,J＝8Hz,2H),7.41(d,J＝8Hz,2H),7.34(d,J＝8Hz,1H),6.59(d,J＝8Hz,1H),6.36(s,1H),5.96(s,1H),4.44(d,J＝8Hz,2H),3.59(s,6H),2.32(s,3H)；13C NMR(100MHz,CDCl3):δ162.1,155.8,153.3,153.1,151.5,140.0,127.8,125.6,120.2,110.7,110.6,109.2,98.3,63.0,50.1,46.5,18.6ppm；MS(ES+)m/z＝369.2；HRMS(ESI,m/z)calculated for C20H20N2O5[M+H]+:369.1376；found:369.1372；Melting point:253.3-256.4℃。
实施例3
合成路线：
将7-乙基-10-羟基喜树碱SN-38(39.2mg,0.1mmol,1.0eq.)和三苯基膦PPh3(52.5mg,0.2mmol,2.0eq.)加入到无水二氯甲烷中，随后加入化合物I2’(16.8mg,0.1mmol,1.0eq.)，并用氮气保护，放置在冰浴中，接下来将偶氮二甲酸二乙酯DEAD(34.8mg,0.2mmol,2.0eq.)缓慢加入到悬浊反应液中，该反应在室温下混合搅拌12小时。反应液直接通过制备薄层色谱以DCM：MeOH＝5:1(Rf＝0.2)的极性分离，最终得到黄色固体产物3c，产率22.3％。1H NMR(400MHz,CDCl3):δ8.12(d,J＝8Hz,2H),7.64(d,J＝8Hz,2H),7.57(s,1H),7.36(d,J＝8Hz,2H),7.28(s,1H),6.60(s,1H),5.41(d,J＝8Hz,4H),5.28(s,2H),3.42(s,6H),3.17(m,2H),1.87(m,2H),1.16(m,3H),0.88(m,3H)；13C NMR(100MHz,DMSO-d6):δ172.6,157.0,156.9,154.7,150.1,149.7,146.2,144.5,143.9,143.7,131.5,129.7,128.1,126.5,122.6,120.6,118.3,103.8,96.1,72.4,65.3,62.8,60.8,48.6,29.8,22.1,13.4,7.8ppm；MS(EI+)m/z＝311.3；HRMS(ESI,m/z)calculated for C18H17NO4[M+H]+:542.2213；found:542.2218；Melting point:241.2-244.1℃。
实施例4
监测6分钟内一定浓度下的荧光强度变化并收集相应的光谱数据。荧光分光光度计设定激发波长为366nm，发射波长为450nm，测定浓度为2.0μM的化合物3a与联硼酸频那醇酯反应后的荧光强度随时间变化的数据，并通过拟合得出荧光强度增强的曲线。结果如图1所示，在10μM联硼酸频那醇酯存在下，荧光强度在450nm处显著增加，表明7-羟基香豆素的释放。
实施例5
将实施例3合成得到的化合物3b作为模板验证7-氨基-4-甲基香豆素的释放。将化合物3b配置成10mM的DMSO母液，以PBS作为反应溶剂，配制成50μM的化合物3b的PBS标准溶液，往其中加入10当量的联硼酸频那醇酯，分别使反应在37℃下反应10,30和60分钟，用荧光分光光度计监测对应时间下7-氨基-4-甲基香豆素的释放情况。结果如图2所示。3b在PBS中释放出强烈的蓝色荧光，当加入联硼酸频那醇酯时荧光快速消失，随后经过1,6-消除过程释放出7-氨基-4-甲基香豆素，显示强烈的蓝色荧光。我们推测最初荧光强度的降低是由于中间体4的形成，然后中间体4经过缓慢的1,6消除，释放出具有强烈蓝色荧光的7-氨基-4-甲基香豆素。
实施例6
配制5μM的前药复合物3c的PBS标准溶液，同样测定了其在0秒时的最大发射波长为431nm，随后加入10当量的联硼酸频那醇酯，分别在室温下测定了10、30、60、120秒和6小时的荧光曲线。图3表明在该反应浓度下可以明显观察到前药复合物3c荧光强度降低的变化趋势。为了确定在延长反应时间后7-乙基-10-羟基喜树碱的荧光强度是否变化，对此继续反应6小时后进行监测，发现荧光强度略有增强。此外通过HPLC监测5μM的前药复合物3c的PBS标准溶液与10当量的联硼酸频那醇酯反应2min后，可以观察到化合物1以及SN-38的释放。因此可以推测该反应在2分钟后基本反应完全，且能顺利释放出相应的药物SN-38。6小时后荧光强度的变化可能是由于前药复合物3c在体系中缓慢分解释放7-乙基-10-羟基喜树碱所导致。
实施例7
所用的药物母液除联硼酸频那醇酯之外都是10mM。使用玻璃底材质的24孔板，提前12小时将细胞铺好。吸掉培养基，将相应的药物配置成需要的浓度的稀释液以1mL/孔的方式加入到铺有细胞的孔里，随后培养箱中孵育1小时。吸掉培养基，PBS洗三次，再加入200μL的PBS，随后可以拿去做激光共聚焦成像。结果如图4所示。进行各组分的共聚焦荧光成像对照实验，可以观察到SN-38呈现出明显的黄色荧光，而前药复合物3c呈现出明显的蓝色荧光，反应组则呈现出SN-38被释放后的黄色荧光。通过荧光成像实验可以实时的观察细胞内前药复合物3c的释放情况，并通过荧光颜色的变化监测前药的释放，验证了细胞内的时间可控释放和监测的可行性。
实施例8
10mM浓度的3c的DMSO母液先稀释成10μM的1640培养基溶液，并在该基础上分别配制0.005、0.015、0.045、0.135μM浓度的溶液。100mM浓度的B2pin2的DMSO母液分别稀释成100/200μM的1640培养基溶液。培养好的细胞将其中的培养基吸掉，分别加入SN-38、3c、3c与联硼酸频那醇酯(100μM)及3c与联硼酸频那醇酯(200μM)四组药液，每个浓度3个孔。将96孔板放置于在恒温培养箱(37℃，5％CO2)中孵育72小时。结果如图5所示。与母药SN-38相比，前药复合物3c的细胞毒性明显减弱，而联硼酸频那醇酯(100和200μM)的添加可产生与阳性对照SN-38相当的抗增殖活性，并在选定浓度内观察到剂量依赖性的细胞毒性。因此，3c与联硼酸频那醇酯共同作用产生的细胞毒性主要是由于3c与联硼酸频那醇酯的click反应释放了SN-38。值得注意的是，前药复合物3c也表现出一定的抗增殖活性，可能是由于药物释放的轻微非特异性所致。确实，细胞成像实验表明3c在A549细胞中孵育24h后开始出现淡黄色荧光
实施例9
将A549癌细胞以1×107/小鼠的量皮下植入裸鼠。当肿瘤体积达到75mm3时，分别以5mg/kg，5mg/kg，50mg/kg的剂量将包含SN-38、3c和B2pin2的化合物静脉内注射到患有A549肿瘤的小鼠中。经过1小时后，处死小鼠，将肿瘤切成5μm切片，然后用Reddots染色剂将细胞核染色，并用PBS冲洗数次。最后，用CLSM(LSM 710)观察肿瘤切片。结果如图6所示。分别接受3c(5mg/kg)和联硼酸频那醇酯(50mg/kg)的小鼠肿瘤切片均呈现强烈的黄色荧光染色，没有出现蓝色荧光，说明点击反应时药物释放迅速、完全，而仅接受3c的对照组没有出现黄色荧光染色。综上所述，这些结果有力地证实了体内3c与联硼酸频那醇酯之间的click反应具有特异性的前药激活。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种基于N-氧化物的前药复合物，其特征在于，所述前药复合物为通式I所示化合物或其对映体、非对映体、外消旋混合物或其药学上可接受的盐：
其中，R1和R2为甲基；
R3、R4、R5和R6分别独立地选自氢、卤素、氰基、羟基、氨基、二氟甲基、三氟甲基、氨甲基、甲基卤素、苯基、烷基、烷氧基、异丙基、叔丁基、环丙基、羰基或醛基；
R7和R8分别独立地选自氢或卤素；
Payload为含有羟基、氨基或羧基的治疗药物；
L选自
其中，当L为
时，Payload为含有羟基的治疗药物；当L为
时，Payload为含有氨基的治疗药物；当L为
时，Payload为含有羧基的治疗药物。
2.根据权利要求1所述的前药复合物，其特征在于：所述含有羟基的治疗药物为7-乙基-10-羟基喜树碱、康普瑞汀、喜树碱或7-羟基香豆素，含有氨基的治疗药物为苯胺氮芥、阿霉素或7-氨基-4-甲基香豆素，含有羧基的治疗药物为苯丁酸氮芥、甲氨蝶呤或苯达莫斯汀。
3.根据权利要求1所述的前药复合物，其特征在于，当治疗药物为含有羟基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
4.根据权利要求1所述的前药复合物，其特征在于，当治疗药物为含有氨基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
5.根据权利要求1所述的前药复合物，其特征在于，当治疗药物为含有羧基的治疗药物时，前药复合物中除Payload以外的部分选自如下结构式所示的基团之一：
6.一种权利要求3或5所述的前药复合物的制备方法，其特征在于，包括以下步骤：
将治疗药物和三苯基膦加入有机溶剂中，加入N-氧化物，在保护气氛下，放置在冰浴中，加入偶氮化合物混合搅拌，得到所述前药复合物；
所述有机溶剂选自二氯甲烷、氯仿、乙腈、甲醇、N,N-二甲基甲酰胺和四氢呋喃中的一种或几种，所述偶氮化合物选自偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯和偶氮二甲酸二叔丁酯中的一种或几种。
7.一种权利要求4所述的前药复合物的制备方法，其特征在于，包括以下步骤：
向苄醇类化合物中加入有机溶剂，随后加入N,N-二异丙基乙胺，使反应体系处于保护气氛中，搅拌30-60min后，向其中缓慢滴加三光气的有机溶液，继续搅拌30-60min，接着缓慢滴加治疗药物的有机溶液，滴加完成后搅拌3-4h得到所述前药复合物；
所述有机溶剂选自二氯甲烷、氯仿、乙腈、甲醇、N,N-二甲基甲酰胺和四氢呋喃中的一种或几种。
8.权利要求1-5任一项所述的前药复合物在制备肿瘤治疗药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述前药复合物与硼试剂通过1,6-消除反应释放出治疗药物进行肿瘤治疗。
10.根据权利要求9所述的应用，其特征在于：所述硼试剂选自联硼酸频那醇酯、苯硼酸和苯硼酸酯中的一种或几种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110977165.4A CN113563293B (zh) | 2021-08-24 | 2021-08-24 | 基于n-氧化物的前药复合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110977165.4A CN113563293B (zh) | 2021-08-24 | 2021-08-24 | 基于n-氧化物的前药复合物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113563293A true CN113563293A (zh) | 2021-10-29 |
| CN113563293B CN113563293B (zh) | 2022-12-30 |
Family
ID=78172551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110977165.4A Active CN113563293B (zh) | 2021-08-24 | 2021-08-24 | 基于n-氧化物的前药复合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113563293B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114939162A (zh) * | 2022-03-24 | 2022-08-26 | 上海大学 | 一种超声介导生物正交反应的多功能纳米催化剂及其制备方法和应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020086996A1 (en) * | 1999-03-15 | 2002-07-04 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as protease inhibitors |
| WO2007095383A2 (en) * | 2006-02-15 | 2007-08-23 | Myriad Genetics, Inc. | Prodrugs |
| US20140193334A1 (en) * | 2011-09-02 | 2014-07-10 | Ulrich Bierbach | Targeted Delivery and Prodrug Designs for Platinum-Acridine Anti-Cancer Compounds and Methods Thereof |
| CN107709320A (zh) * | 2015-05-21 | 2018-02-16 | 中国科学院上海药物研究所 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
| CN112239469A (zh) * | 2020-10-20 | 2021-01-19 | 苏州大学 | 靶向蛋白降解c-Met降解剂及其制备方法与应用 |
-
2021
- 2021-08-24 CN CN202110977165.4A patent/CN113563293B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020086996A1 (en) * | 1999-03-15 | 2002-07-04 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as protease inhibitors |
| WO2007095383A2 (en) * | 2006-02-15 | 2007-08-23 | Myriad Genetics, Inc. | Prodrugs |
| US20140193334A1 (en) * | 2011-09-02 | 2014-07-10 | Ulrich Bierbach | Targeted Delivery and Prodrug Designs for Platinum-Acridine Anti-Cancer Compounds and Methods Thereof |
| CN107709320A (zh) * | 2015-05-21 | 2018-02-16 | 中国科学院上海药物研究所 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
| CN112239469A (zh) * | 2020-10-20 | 2021-01-19 | 苏州大学 | 靶向蛋白降解c-Met降解剂及其制备方法与应用 |
Non-Patent Citations (1)
| Title |
|---|
| 孔娇 等: "蛋白酪氨酸磷酸酶SHP2及其抑制剂的研究进展", 《药学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114939162A (zh) * | 2022-03-24 | 2022-08-26 | 上海大学 | 一种超声介导生物正交反应的多功能纳米催化剂及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113563293B (zh) | 2022-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chadwick et al. | Scalable synthesis of strained cyclooctyne derivatives | |
| Sun et al. | Metal-free visible-light-initiated direct C3 alkylation of quinoxalin-2 (1 H)-ones and coumarins with unactivated alkyl iodides | |
| JP7400005B2 (ja) | 細胞傷害性ベンゾジアゼピン誘導体の調製方法 | |
| Zhang et al. | Pyrrolo-imidazo [1, 2-a] pyridine scaffolds through a sequential coupling of N-tosylhydrazones with imidazopyridines and reductive cadogan annulation, synthetic scope, and application | |
| Li et al. | Synthesis of 8-Alkoxy-5 H-isochromeno [3, 4-c] isoquinolines and 1-Alkoxy-4-arylisoquinolin-3-ols through Rh (III)-Catalyzed C–H Functionalization of Benzimidates with 4-Diazoisochroman-3-imines and 4-Diazoisoquinolin-3-ones | |
| CN113563293B (zh) | 基于n-氧化物的前药复合物及其制备方法和应用 | |
| Curti et al. | Exploring the Remote Reactivity of π-Extended Carbonyl Compounds: The Vinylogous Alkylidene Malononitrile Activation Strategy | |
| EP4001285A1 (en) | Near-infrared (nir) absorbing photosensitizers | |
| Praveen et al. | Triflic acid promoted tandem ring-closure-aryl-migration of 2′-amino chalcone epoxide: A new synthetic route to azaisoflavones | |
| Adhikari et al. | Perspective on acridine: A versatile heterocyclic biologically imperative framework | |
| Tietze et al. | SiFA azide: A new building block for PET imaging using click chemistry | |
| CA3142717A1 (en) | Ruthenium (ii) complexes and conjugates thereof for use as photosensitizer agent in photodynamic therapy | |
| Jiang et al. | Oxidative Cyclization of Kynuramine and Ynones Enabling Collective Syntheses of Pyridoacridine Alkaloids | |
| KR20240035820A (ko) | Ikzf2를 조절하는 아릴 화합물 및 약학 조성물 | |
| Butler et al. | Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1 H, 3′ H]-3-Aryl-2, 2′-diindol-3′-ones | |
| Tolstikov et al. | One-Pot Synthesis of Novel Cyclopentene-Fused Octahydropyridoquinolines and Octahydrophenanthrolines | |
| KR101825024B1 (ko) | 미토콘드리아 표지를 위한 화합물 및 이의 제조방법 | |
| WO2024131790A1 (en) | A bioorthogonal cycloaddition reaction and use thereof | |
| WO2024130526A1 (en) | A bioorthogonal cycloaddition reaction and use thereof | |
| Alizadeh et al. | Molecular Iodine-Mediated Synthesis of 2-Azaanthraquinones from [3.3. 3] Propellanes via a Metal-Free Rearrangement | |
| Angelini | New Synthetic Strategies Involving Dearomatization | |
| Banert et al. | Reactions of Unsaturated Azides; Part 27: Synthesis of 1, 4-Diazidobuta-1, 3-dienes | |
| Lim et al. | Microwave-assisted synthesis and evaluation of chalcone-ligated molybdenum carbonyl complexes as cytotoxic agents and DNA binders | |
| Dong et al. | Synthesis of Spiro Polycyclic N-Heterocycles and Indolecarbazoles via Merging Oxidative Coupling and Cascade Palladium-Catalyzed Intramolecular Oxidative Cyclization | |
| Heilmann | Molecular recognition in aqueous media within modularly constructed molecular tweezers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |