CN112480140A - C5-位取代汉防己甲素衍生物及其制备方法和应用 - Google Patents
C5-位取代汉防己甲素衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN112480140A CN112480140A CN202011584843.2A CN202011584843A CN112480140A CN 112480140 A CN112480140 A CN 112480140A CN 202011584843 A CN202011584843 A CN 202011584843A CN 112480140 A CN112480140 A CN 112480140A
- Authority
- CN
- China
- Prior art keywords
- tetrandrine
- cancer
- substituted
- derivative
- preparation
- 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
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical class C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 14
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 9
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- ANJMFZGRGHQXMA-VMPREFPWSA-N C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=C(Br)C(OC)=C(OC)C1=C23 Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=C(Br)C(OC)=C(OC)C1=C23 ANJMFZGRGHQXMA-VMPREFPWSA-N 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 206010018338 Glioma Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 4
- 229930182821 L-proline Natural products 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 229960002429 proline Drugs 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- VBCYHQYCGGUMFM-UHFFFAOYSA-N BrC=1C(=[N+](C=CC=1)Br)Br Chemical class BrC=1C(=[N+](C=CC=1)Br)Br VBCYHQYCGGUMFM-UHFFFAOYSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000005251 aryl acyl group Chemical group 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 208000018026 neoplasm of middle ear Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 206010023825 Laryngeal cancer Diseases 0.000 claims 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 206010023841 laryngeal neoplasm Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 11
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000001446 anti-myeloma Effects 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000030833 cell death Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000006277 sulfonation reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000004113 cell culture Methods 0.000 description 12
- -1 isoquinoline compound Chemical class 0.000 description 10
- TVHXQQJDMHKGGK-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 TVHXQQJDMHKGGK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000003954 Autophagy-Related Proteins Human genes 0.000 description 1
- 108010082399 Autophagy-Related Proteins Proteins 0.000 description 1
- DFOCUWZXJBAUSQ-UHFFFAOYSA-N Berbamine Natural products O1C(C(=CC=2)O)=CC=2CC(C=23)N(C)CCC3=CC(OC)=C(OC)C=2OC(=CC=23)C(OC)=CC=2CCN(C)C3CC2=CC=C1C=C2 DFOCUWZXJBAUSQ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 201000005264 laryngeal carcinoma Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- C07D491/12—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 three hetero rings
- C07D491/18—Bridged systems
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了氨基磺化通式为(I)的C5‑位取代汉防己甲素衍生物及其制备方法和制备抗肿瘤药物的应用。用本发明的C5‑位取代汉防己甲素衍生物作用于不同的肿瘤细胞，采用MTT法检测药物处理后不同肿瘤细胞的活性，结果发现本发明的C5‑位取代汉防己甲素衍生物能有效的诱导多发性骨髓瘤细胞死亡，与汉防己甲素本身比较，本发明的C5‑位取代汉防己甲素衍生物具有明显的抗细胞株活性，其抗骨髓瘤RPMI‑8226细胞株活性提高近2倍，具有良好的生物活性。
Description
技术领域
本发明涉及天然药物及药物化学领域，具体涉及C5-位取代汉防己甲素衍生物的制备方法。
背景技术
汉防已甲素(Tetrandrine简写为Tet)又叫粉防己碱，为防已科植物粉防已干燥根的主要生物碱，属异喹啉化合物，分子式为C38H42N2O6，化学式(6,6’,7,12-四甲氧基-2,2’二甲基小檗胺)，分子量为622.73g/mol，其结构如下所示：
防已科植物粉防已干燥根，这种草药的根在中国药典中被广泛引用治疗结核病、痢疾、哮喘、高血糖等疾病，以及对心肌、疟疾、癌症和发烧的负离子性和变时性影响。汉防已甲素是一种具有广泛生物活性的分子，能与Ca2+非竞争性对抗，具有钙通道阻断作用，属慢通道阻滞剂。几十年来，作为我国临床用药，汉防已甲素主要用于治疗矽肺患者，自身免疫性疾病，炎症性肺部疾病，心血管疾病和高血压等疾病。近些年来，越来越多的研究发现，汉防已甲素在癌症治疗中具有药理作用的潜力，例如在人白血病U937，人肝癌HepG2，人肺癌A549以及人结肠癌HCT-116细胞的研究中发现汉防已甲素能抑制肿瘤细胞增殖。因为汉防已甲素是高脂溶性的，具有低分子量的疏水分子，它可能可以穿过血脑屏障，Chen等的研究发现，一定剂量的汉防已甲素(150毫克/千克/天)可通过抑制胶质瘤中VEGF的表达，从而对皮下RT-2胶质瘤的血管生成产生抑制作用[Chen Y,Chen JC and TsengSH.Tetrandrine suppressestumor growth and angiogenesis of gliomas inrats.International journal of cancer Journal.2009；124:2260-2269.]。汉防已甲素还能影响脑内肿瘤，对ECV304人脐带静脉内皮细胞有细胞毒性，并能抑制体内血管生成[Chen Y,Tseng SH.The Potential of Tetrandrine against Gliomas.AnticancerAgents Med Chem.2010；10:534-542.]。汉防已甲素在分子水平的癌症化疗作用也有相关研究报道，主要包括其在不同癌症中对细胞增殖、细胞凋亡、血管生成、转移、自噬和多药耐药等的影响[T.Liu,X.Liu,W.Li,Tetrandrine,a Chinese plant-derived alkaloid,is apotentialcandidate for cancer chemotherapy,Oncotarget 7(2016)40800–40815.]。汉防已甲素可调节多种信号分子，如细胞周期激酶、RAS通路[J.Kaur,J.Debnath,Autophagyat the crossroads of catabolism and anabolism,Nat.Rev.Mol.Cell Biol.16(2015)461–472.]、抑癌基因、自噬相关的蛋白质、β-catenins、caspase以及死亡受体等[T.Chen,B.Ji,Y.Chen,Tetrandrine triggers apoptosis and cell cycle arrest in humanrenal cell carcinoma cells,J.Nat.Med.68(2014)46–52.]。此外亦有报道表明，汉防已甲素在不同的肿瘤中，可通过调节P-Glyco蛋白(P-gp)的表达水平从而表现出对耐药性的逆转[C.Holohan,S.V.Schaeybroeck,D.B.Longley,P.G.Johnston,Cancer drugresistance:an evolving paradigm,Nat.Rev.Cancer 13(2013)714–726.L.Fu,Y.Liang,L.Deng,Y.Ding,L.Chen,Y.Ye,X.Yang,Q.Pan,Characterization of tetrandrine,apotent inhibitor of P-glycoprotein-mediated multidrug resistance,CancerChemother.Pharmacol.53(2004)349–356.]。
汉防已甲素作为一种具有广泛生物活性的药物，其在临床上有着极大的应用前景。虽然目前有研究者在动物体内的抗癌活性模型试验中发现汉防已甲素的药代动力学参数改变不大，但其生物利用度仍是一个限制因素，因此，研发具有良好生物活性和药动学特性的新型汉防已甲素衍生物仍是当今市场所需。
发明内容
本发明的目的之一是提供通式为(I)的新型C5-位取代汉防己甲素衍生物及其制备方法和应用或其药学上可接受的加成物、复合物，盐、分解产物和代谢产物。
C5-位取代汉防己甲素衍生物，为式(I)结构：
其中，
X选自氮、氰基或醛基；
当X为氰基或醛基，n＝0；当X为氮时，n＝1或2；
X为氮，R独立地选自氢、烷基酰基、取代芳基酰基、取代芳基磺酰基。
进一步，所述的C5-位取代汉防己甲素衍生物为以下结构的化合物：
本发明的目的之二是提供制备本发明氨基磺化通式为(I)的新型C5-位取代汉防己甲素衍生物、制备方法和应用的方法，其按以下工艺路线进行：
通式为(I)的新型C5-位取代汉防己甲素衍生物、制备方法和应用C5-位取代汉防己甲素衍生物、制备方法和应用的合成流程分为以下三个步骤：
一、汉防己甲素用三溴吡啶鎓盐进行溴代，得到5-溴汉防己甲素；
二、5-溴汉防己甲素在L-脯氨酸、碘化亚铜和叠氮化钠的作用下转化为5-氨基汉防己甲素；
三、5-氨基汉防己甲素在碱的作用下进行一步与含X-(R)n基的化合物(即含X-(R)n基的取代物，具体如苄氯、酰氯和磺酰氯)反应转化为目标衍生物，即式(I)结构的C5-位取代汉防己甲素衍生物。
具体地，先由汉防已甲素与三溴吡啶鎓盐在TLC监控下，室温反应4h，生成产物5-溴汉防己甲素；该产物溶于二甲基亚砜再与L-脯氨酸、叠氮化钠、碘化亚铜在130℃温度下反应4h生成产物5-胺基汉防己甲素；将5-胺基汉防己甲素与吡啶、三乙胺和4-三氟甲基苯磺酰氯，35℃搅拌反应6h后获得R基为芳基磺酰基(TET-13)的新型C5-位取代汉防己甲素衍生物。
本发明的目的之三是提供本发明化合物在制备抗肿瘤药物的制药用途。所述肿瘤特别选自白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、神经胶质瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤、前列腺癌等。
制备反应的原料是汉防已甲素(TET)。该原料是由天然产物提取分离而得到，可以在市场上购买获得。制备反应的有机酸、有机酸酐或有机酰氯等试剂全部可以在市场上购买获得。常规的化学转换可用于实施本发明。本领域的技术人员可以决定用于这些化学转换的适当的化学试剂、溶剂、保护基和反应条件。
与现有技术相比，本发明具有如下优点：
用本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物作用于不同的肿瘤细胞，采用MTT法检测药物处理后不同肿瘤细胞的活性，结果发现本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物能有效的诱导多发性骨髓瘤细胞死亡，与汉防己甲素本身比较，本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物具有明显的抗细胞株活性，其抗骨髓瘤RPMI-8226细胞株活性提高近2倍，具有良好的生物活性。
附图说明
图1为5-(4-三氟甲基苯磺酰胺基)-汉防己甲素的结构图。
图2为TET-13作用于不同肿瘤细胞后用MTT法检测细胞的活力的变化图。
具体实施方式
本实验采用已知的文献方法制备汉防己甲素衍生物，用TLC法对反应过程进行控制，用HPLC法对衍生物进行纯度分析，具体操作如下。
实施例：
5-溴汉防己甲素的制备：汉防己甲素溶解于冰醋酸，加入三溴吡啶鎓盐，室温下反应一定时间，反应液调碱后用二氯甲烷萃，合并有机层，用盐水洗涤，无水硫酸钠干燥，蒸干，得到5-溴汉防己甲素。1H NMR(400MHz,CDC13),δ7.34(dd,J＝8.2,2.2Hz,1H),7.14(dd,J＝8.1,2.5Hz,1H),6.87(s,2H),6.79(dd,J＝8.3,2.5Hz,1H),6.52(s,1H),6.50(s,1H),6.29(dd,J＝8.3,2.1Hz,1H),6.01(s,1H),3.93(s,3H),3.79(d,J＝10.1Hz,1H),3.74(s,3H),3.55-3.40(m,3H),3.37(s,3H),3.26(dd,J＝12.5,5.6Hz,1H),3.22(s,3H),3.02-2.95(m,2H),2.91-2.87(m,1H),2.82-2.67(m,5H),2.64(s,3H),2.49(d,J＝8.4Hz,1H),2.29(s,3H)；ESI-MS m/z:701.4[M+H]+.
5-氰基汉防己甲素(TET-01)的制备：取适量5-溴汉防己甲素溶解于二乙基甲酰胺溶液中，加入氰化亚铜，让其在140-150℃下保温反应一定时间，用二氯甲烷稀释，加入浓氨水滤除不溶物，分层，有机层用盐水洗涤，无水硫酸钠干燥，得到5-氰基汉防己甲素。1H NMR(400MHz，CDC13)，δ7.35(dd,J＝8.2,2.2Hz,1H),7.16(dd,J＝8.1,2.2Hz,1H),6.89(s,2H),6.80(dd,J＝8.3,2.2Hz,1H),6.54(s,1H),6.53(s,1H),6.30(dd,J＝8.3,2.1Hz,1H),6.03(s,1H),3.94(s,3H),3.79(d,J＝10.1Hz,1H),3.74(s,3H),3.56-3.42(m,3H),3.38(s,3H),3.25(dd,J＝12.5,5.6Hz,1H),3.21(s,3H),3.00-2.87(m,3H),2.82-2.65(m,5H),2.64(s,3H),2.47(d,J＝8.3Hz,1H),2.24(s,3H)；ESI-MS m/z:648.31[M+H]+.
5-胺基汉防己甲素(TET-07)的制备：取适量5-溴汉防己甲素，加入L-脯氨酸，叠氮化钠和二甲基亚砜，用氮气置换，加入碘化亚酮，在130℃下反应一定时间，加入乙酸乙酯稀释，滤除不溶解物，滤液依次用水和盐水洗涤，无水硫酸钠干燥，得5-胺基汉防己甲素。1HNMR(400MHz，CDC13)，δ7.32(dd,J＝8.2,2.2Hz,1H),7.15(dd,J＝8.1,2.3Hz,1H),6.86(s,2H),6.80(dd,J＝8.0,2.5Hz,1H),6.55(s,1H),6.53(s,1H),6.29(dd,J＝8.3,2.0Hz,1H),6.00(s,1H),3.92(s,3H),3.78(d,J＝10.0Hz,1H),3.73(s,3H),3.54-3.40(m,3H),3.35(s,3H),3.24(dd,J＝12.4,5.2Hz,1H),3.11(s,3H),3.01-2.65(m,8H),2.61(s,3H),2.45(d,J＝8.5Hz,1H),2.35(s,3H)；ESI-MS m/z:638.30[M+H]+.
5-(4-三氟甲基苯磺酰胺基)-汉防己甲素(TET-13)的制备：取适量5-胺基汉防己甲素加入吡啶、三乙胺和4-三氟甲基苯磺酰氯，35℃搅拌反应一定时间，无水硫酸钠干燥，蒸干，得5-(4-三氟甲基苯磺酰胺基)-汉防己甲素。1H NMR(400MHz,CDC13),δ8.06(d,J＝8.2Hz,2H),7.73(d,J＝8.2Hz,2H),7.34(dd,J＝8.2,2.2Hz,1H),7.18(dd,J＝8.1,2.5Hz,1H),6.89(s,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.54(s,1H),6.53(s,1H),6.30(dd,J＝8.3,2.1Hz,1H),6.03(s,1H),3.93(s,3H),3.79(d,J＝10.2Hz,1H),3.74(s,3H),3.54-3.40(m,3H),3.35(s,3H),3.26(dd,J＝12.4,5.2Hz,1H),3.13(s,3H),3.01-2.86(m,3H),2.84-2.64(m,5H),2.59(s,3H),2.47(d,J＝8.2Hz,1H),2.31(s,3H)；ESI-MS m/z:846.32[M+H]+.
以上反应一般在有碱和缩合试剂存在下进行。这里碱可以为有机碱或无机碱。
用于酰化反应的酰化试剂可以是相应的有机酸、有机酰卤或有机酸酐。用于磺酰化反应的磺酰化试剂可以是相应的有机磺酰卤。
酰化反应一般在溶剂中进行。溶剂的选择取决于原料的极性和溶解性。使用的溶剂包括但不限于有机极性溶剂。例如：二氯甲烷(DCM)，四氢呋喃(THF)，N，N-二甲基甲酰胺(DMF)，二甲亚砜(DMSO)。
应用例：本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物抗肿瘤细胞的活性测定。
(1)实验材料
白血病细胞株：H9(急性淋巴细胞白血病，ALL)，购自中国典型培养物保藏中心；骨髓瘤细胞株：RPMI-8226(多发性骨髓瘤)均受赠于浙江大学肿瘤研究所；肝癌细胞株：HepG2(人肝癌细胞)
试剂：汉防己甲素标准品购自西安昊轩生物有限公司，本发明的主要试剂：本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素(TET-13)。主要仪器：细胞培养箱，酶标仪。
主要仪器：细胞培养箱(型号：Thermo Scientific 3111)，酶标仪(型号：Bio-RadiMark)。
(2)实验方法
取细胞培养液离心(1000rpm，5min)得到细胞沉淀，计数RPMI-8226细胞数，以10000/孔的细胞浓度接种到96孔细胞培养板孔内，培养液为含10％胎牛血清的1640细胞培养液，第二天加入不同浓度的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物，混匀后，置于含5％CO2的细胞培养箱，37℃培养72小时。然后用MTT法测定活细胞浓度，在本实验中对照组(不加化合物处理)细胞活力设为100％，并计算出化合物作用后细胞活力(％)和72小时骨髓瘤细胞半数生长抑制浓度(72小时IC 50值)。
取细胞培养液离心(1000rpm，5min)得到细胞沉淀，计数H9以5500/孔的细胞浓度接种到96孔细胞培养板孔内，培养液为含10％胎牛血清的1640细胞培养液，第二天加入不同浓度的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素(TET-13)，混匀后，置于含5％CO 2的细胞培养箱37℃培养72小时。然后用MTT法测定活细胞浓度，在本实验中对照组(不加化合物处理)细胞活力设为100％，并计算出化合物作用后细胞活力(％)和72小时白血病细胞半数生长抑制浓度(72小时IC 50值)。
贴壁细胞提前一天铺板，取细胞培养液离心(1000rpm，5min)得到细胞沉淀，计数HepG2细胞数，以3000/孔的细胞浓度接种到96孔细胞培养板孔内，培养液为含10％胎牛血清的DMEM细胞培养液，第二天加入不同浓度的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物，混匀后，置于二氧化碳(5％CO 2)细胞培养箱37℃培养72小时。然后用MTT法测定活细胞浓度，在本实验中对照组(不加化合物处理)细胞活力设为100％，并计算出化合物作用后细胞活力(％)和72小时肝癌细胞半数生长抑制浓度(72小时IC 50值)。
(3)实验结果
实验结果见图2及表1。
表1C5-位氨基磺化TET与TET治疗窗比较
| IC50(uM) | TET-0 | TET-13 |
| RPMI-8226 | 2.678 | 1.891 |
| H9 | 1.179 | 3.051 |
| HepG2 | 0.9353 | 3.456 |
表1显示本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物能有效的诱导多发性骨髓瘤细胞死亡，与汉防己甲素本身比较，本发明的5-(4-三氟甲基苯磺酰胺基)-汉防己甲素衍生物具有明显的抗细胞株活性，抗骨髓瘤RPMI-8226细胞株活性提高近2倍。
Claims (5)
1.C5-位取代汉防己甲素衍生物，其特征在于，为式(I)结构：
其中，X选自氮、氰基或醛基；
当X为氰基或醛基，n＝0；
当X为氮时，n＝1或2，X为氮，R独立地选自氢、烷基酰基、取代芳基酰基、取代芳基磺酰基。
2.根据权利要求1所述的C5-位取代汉防己甲素衍生物，其特征在于，为以下结构的化合物：
3.根据权利要求1所述的C5-位取代汉防己甲素衍生物的制备方法，其特征在于，包括以下步骤：
一、汉防己甲素用三溴吡啶鎓盐进行溴代，得到5-溴汉防己甲素；
二、5-溴汉防己甲素在L-脯氨酸、碘化亚铜和叠氮化钠的作用下转化为5-氨基汉防己甲素；
三、5-氨基汉防己甲素在碱的作用下与含X-(R)n基的化合物反应转化为式(I)结构的C5-位取代汉防己甲素衍生物。
4.根据权利要求1或2所述的C5-位取代汉防己甲素衍生物在制备抗肿瘤药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述肿瘤为白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、神经胶质瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤或前列腺癌。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584843.2A CN112480140B (zh) | 2020-12-28 | 2020-12-28 | C5-位取代汉防己甲素衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584843.2A CN112480140B (zh) | 2020-12-28 | 2020-12-28 | C5-位取代汉防己甲素衍生物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112480140A true CN112480140A (zh) | 2021-03-12 |
| CN112480140B CN112480140B (zh) | 2022-04-01 |
Family
ID=74915821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011584843.2A Active CN112480140B (zh) | 2020-12-28 | 2020-12-28 | C5-位取代汉防己甲素衍生物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112480140B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031623A (zh) * | 2021-11-12 | 2022-02-11 | 山西医科大学 | 一种c14位氨基取代粉防己碱衍生物及其制备和应用 |
| CN114933601A (zh) * | 2022-06-14 | 2022-08-23 | 黄河科技学院 | 汉防己甲素衍生物及其制备方法和应用 |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293196A (zh) * | 2000-09-08 | 2001-05-02 | 华西医科大学药物研究所 | 双苄基异喹啉类生物碱及其制备方法和药物组合物 |
| WO2004033418A2 (en) * | 2002-10-11 | 2004-04-22 | Actelion Pharmaceuticals Ltd. | Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists |
| CN102875560A (zh) * | 2011-07-15 | 2013-01-16 | 复旦大学 | 5-取代粉防己碱类化合物及其在制备抗癌药增敏剂中的用途 |
| CN103772404A (zh) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | 双苄基四氢异喹啉衍生物及其制备方法和应用 |
| CN103772405A (zh) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | 双苄基四氢异喹啉类生物碱及其制备方法和应用 |
| CN103635475B (zh) * | 2011-08-19 | 2016-06-08 | 杭州本生药业有限公司 | 5-位碳取代的汉防己甲素衍生物、及其制备方法和应用 |
| CN107033157A (zh) * | 2016-02-03 | 2017-08-11 | 贵州省中国科学院天然产物化学重点实验室 | 双苄基异喹啉衍生物及其在制备用于治疗或预防肿瘤的药物中的用途 |
| CN107207524A (zh) * | 2014-08-15 | 2017-09-26 | 贵州省中国科学院天然产物化学重点实验室 | 双苄基异喹啉衍生物、其制备方法及其在肝病的治疗与预防中的用途 |
| CN112125914A (zh) * | 2019-06-25 | 2020-12-25 | 杭州卫本药业有限公司 | 5-取代的小檗胺衍生物，其制备方法和应用 |
-
2020
- 2020-12-28 CN CN202011584843.2A patent/CN112480140B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293196A (zh) * | 2000-09-08 | 2001-05-02 | 华西医科大学药物研究所 | 双苄基异喹啉类生物碱及其制备方法和药物组合物 |
| WO2004033418A2 (en) * | 2002-10-11 | 2004-04-22 | Actelion Pharmaceuticals Ltd. | Sulfonylamino-acetic derivatives and their use as orexin receptor antagonists |
| CN102875560A (zh) * | 2011-07-15 | 2013-01-16 | 复旦大学 | 5-取代粉防己碱类化合物及其在制备抗癌药增敏剂中的用途 |
| CN103635475B (zh) * | 2011-08-19 | 2016-06-08 | 杭州本生药业有限公司 | 5-位碳取代的汉防己甲素衍生物、及其制备方法和应用 |
| CN103772404A (zh) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | 双苄基四氢异喹啉衍生物及其制备方法和应用 |
| CN103772405A (zh) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | 双苄基四氢异喹啉类生物碱及其制备方法和应用 |
| CN107207524A (zh) * | 2014-08-15 | 2017-09-26 | 贵州省中国科学院天然产物化学重点实验室 | 双苄基异喹啉衍生物、其制备方法及其在肝病的治疗与预防中的用途 |
| CN107033157A (zh) * | 2016-02-03 | 2017-08-11 | 贵州省中国科学院天然产物化学重点实验室 | 双苄基异喹啉衍生物及其在制备用于治疗或预防肿瘤的药物中的用途 |
| CN112125914A (zh) * | 2019-06-25 | 2020-12-25 | 杭州卫本药业有限公司 | 5-取代的小檗胺衍生物，其制备方法和应用 |
Non-Patent Citations (1)
| Title |
|---|
| TAO J ET AL.: "Synthesis of Tetrandrine Derivatives and their Anti-Tumor Activities", 《CHEMXPRESS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031623A (zh) * | 2021-11-12 | 2022-02-11 | 山西医科大学 | 一种c14位氨基取代粉防己碱衍生物及其制备和应用 |
| CN114933601A (zh) * | 2022-06-14 | 2022-08-23 | 黄河科技学院 | 汉防己甲素衍生物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112480140B (zh) | 2022-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cao et al. | Synthesis and structure–activity relationships of harmine derivatives as potential antitumor agents | |
| CN112480140B (zh) | C5-位取代汉防己甲素衍生物及其制备方法和应用 | |
| CN101323591A (zh) | 一类5-位或6-位取代的萘酰亚胺化合物及抗肿瘤应用 | |
| CN103804312B (zh) | 一类氮杂环化合物及其制备方法和用途 | |
| CN105829312A (zh) | 一种n-苄基色胺酮衍生物及其制备方法和应用 | |
| CN105315321B (zh) | 具有抗肿瘤作用的化合物及其制备方法和应用 | |
| CN108117516B (zh) | 一种多取代吡啶衍生物的制备方法及其应用 | |
| CN104292170A (zh) | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 | |
| CN105705493A (zh) | 喹唑啉衍生物、其制备方法、药物组合物和应用 | |
| JP2023504866A (ja) | 大環構造を有するフッ素含有複素環誘導体およびその用途 | |
| WO2015096640A1 (zh) | 含噻唑基雷帕霉素类衍生物及其应用 | |
| CN104072493A (zh) | 一类含2-巯基苯并噻唑和三唑杂环的萘酰亚胺化合物，其制备方法及其应用 | |
| CN111808117A (zh) | 青蒿素-苯胺基喹唑啉类d类衍生物及其药物组合物和应用 | |
| CN110642740B (zh) | 异斯特维醇酰胺衍生物及其制备方法 | |
| CN104829619B (zh) | 一种取代芳基苦参碱类化合物及其制备方法与应用 | |
| CN104586842B (zh) | 一种抗癌活性吲哚衍生物、合成方法及其用途 | |
| US20130225641A1 (en) | Anticancer compounds and preparation methods thereof | |
| CN115124531A (zh) | 一类4-氮杂色胺酮芳香硫醚衍生物、制备方法及应用 | |
| CN111909053B (zh) | 基于二芳胺单元的酰胺类衍生物及其制备方法和应用 | |
| CN106966986A (zh) | N‑苄基硝基杂环烯酮缩胺类衍生物及合成方法和抗肿瘤应用 | |
| CN113527391A (zh) | 一种梓醇衍生物及其制备方法和应用 | |
| CN107434781A (zh) | 一种1-烯基-异喹啉衍生物的制备方法及其应用 | |
| CN104177342B (zh) | 杂环基取代的吲哚并萘酮衍生物及其医药用途 | |
| CN107353287B (zh) | 一种喹喔啉并杂氮环丁酮类化合物及其在抗肿瘤中的应用 | |
| US11319328B2 (en) | 4β-amino substituted podophyllotoxin derivative and preparation method therefor and use thereof |
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 |