CN104208061A - Medical application of berberine derivative - Google Patents
Medical application of berberine derivative Download PDFInfo
- Publication number
- CN104208061A CN104208061A CN201310218544.0A CN201310218544A CN104208061A CN 104208061 A CN104208061 A CN 104208061A CN 201310218544 A CN201310218544 A CN 201310218544A CN 104208061 A CN104208061 A CN 104208061A
- Authority
- CN
- China
- Prior art keywords
- berberine
- cells
- group
- migration
- derivatives
- 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
- 150000003832 berberine derivatives Chemical class 0.000 title abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 230000002438 mitochondrial effect Effects 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 230000008685 targeting Effects 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 48
- 229940093265 berberine Drugs 0.000 claims description 48
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 28
- -1 n-dodecyl Chemical group 0.000 claims description 23
- 208000005017 glioblastoma Diseases 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 62
- 206010018338 Glioma Diseases 0.000 abstract description 22
- 230000005012 migration Effects 0.000 abstract description 21
- 238000013508 migration Methods 0.000 abstract description 21
- 230000009545 invasion Effects 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 16
- 208000032612 Glial tumor Diseases 0.000 abstract description 13
- 210000003470 mitochondria Anatomy 0.000 abstract description 12
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 208000029824 high grade glioma Diseases 0.000 abstract description 6
- 201000011614 malignant glioma Diseases 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 238000012377 drug delivery Methods 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 230000005764 inhibitory process Effects 0.000 description 12
- 230000037230 mobility Effects 0.000 description 12
- QUMABAVFRFZKGC-UHFFFAOYSA-N chembl2365996 Chemical compound C12=CC=3OCOC=3C=C2CC[N+]2=C1C=C1C=CC(OC)=C(OCCCCCCCCCCCC)C1=C2 QUMABAVFRFZKGC-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- 238000012258 culturing Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- GYFSYEVKFOOLFZ-UHFFFAOYSA-N Berberrubine Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(O)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 GYFSYEVKFOOLFZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 150000003836 berberines Chemical group 0.000 description 4
- 230000012292 cell migration Effects 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RUVJFMSQTCEAAB-UHFFFAOYSA-M 2-[3-[5,6-dichloro-1,3-bis[[4-(chloromethyl)phenyl]methyl]benzimidazol-2-ylidene]prop-1-enyl]-3-methyl-1,3-benzoxazol-3-ium;chloride Chemical group [Cl-].O1C2=CC=CC=C2[N+](C)=C1C=CC=C(N(C1=CC(Cl)=C(Cl)C=C11)CC=2C=CC(CCl)=CC=2)N1CC1=CC=C(CCl)C=C1 RUVJFMSQTCEAAB-UHFFFAOYSA-M 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229960001322 trypsin Drugs 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 1
- HNTGIJLWHDPAFN-UHFFFAOYSA-N 1-bromohexadecane Chemical compound CCCCCCCCCCCCCCCCBr HNTGIJLWHDPAFN-UHFFFAOYSA-N 0.000 description 1
- WSULSMOGMLRGKU-UHFFFAOYSA-N 1-bromooctadecane Chemical compound CCCCCCCCCCCCCCCCCCBr WSULSMOGMLRGKU-UHFFFAOYSA-N 0.000 description 1
- 230000002407 ATP formation Effects 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000037740 Coptis chinensis Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GLYPKDKODVRYGP-UHFFFAOYSA-O berberrubine Natural products C1=C2CC[N+]3=CC4=C(O)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 GLYPKDKODVRYGP-UHFFFAOYSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GLYPKDKODVRYGP-UHFFFAOYSA-N burberrubine Natural products C12=CC=3OCOC=3C=C2CCN2C1=CC1=CC=C(OC)C(=O)C1=C2 GLYPKDKODVRYGP-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 230000025608 mitochondrion localization Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000013152 negative regulation of cell migration Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000032895 transmembrane transport Effects 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides application of a compound shown in the formula (I) or a salt thereof in the aspects of preparing of medicines for treating malignant glioma or a mitochondrial targeting drug delivery system, and in the formula (I), R is C10-C18 alkyl, or R is benzyl. The experiments find that compared with a control, a berberine derivative not only can more effectively inhibit glioma cell proliferation, and can also effectively inhibit the migration and invasion ability of cells. In addition, the compounds can be well positioned to mitochondria, so that the compounds can be used as the mitochondrial targeting drug delivery system.
Description
Technical Field
The invention relates to a new application of berberine derivatives, in particular to a new application of C9-O substituted long-chain alkyl or benzyl derivatives in the aspect of treating malignant glioma.
Background
Glioblastomas (Malignant gliomas) are the most common primary malignancies in the central nervous system, with a prevalence rate of 46% of intracranial tumors. Surgery is the preferred treatment method, but because the brain tissue grows infiltratively and has no obvious limit with normal brain tissue, the brain tissue is difficult to excise by the surgery, and the postoperative recurrence rate is as high as 96%. Even if radiotherapy and chemotherapy are assisted, the mean survival period after operation does not exceed 14 months, and the prognosis is very poor. The incurability of malignant gliomas is closely related to their strong migration and invasion capacity. Therefore, inhibition of glioma cell migration and invasion is crucial for the treatment of malignant gliomas. However, the existing therapeutic methods cannot effectively inhibit the migration and invasion of malignant glioma, resulting in poor therapeutic effect, and also have many defects of neurotoxicity, blood toxicity, drug resistance and the like.
In addition, the pathological processes of various diseases, including tumors, are associated with mitochondrial damage. Mitochondria of tumor cells and normal cells have large differences in structure and function, and abnormalities of intracellular biochemical events directly related to mitochondria, such as changes in sugar metabolic patterns, ATP production disorders, calcium ion accumulation, oxidative stress, and other functional disorders at various degrees, are important causes of tumorigenesis and development. Also, mtDNA mutations in tumor cells and excess ROS have been reported to promote tumor cell metastasis. The drug can be targeted to the mitochondria of the tumor cells and selectively act on the tumor cells through the mitochondria, which has important significance for targeted therapy of high invasive tumors such as glioblastomas.
Berberine (Berberine) is an isoquinoline alkaloid extracted and separated from traditional Chinese medicinal materials such as coptis chinensis, has high oral administration safety and does not have blood, cardiovascular and liver and kidney toxicity after long-term large-scale administration. Research shows that berberine can inhibit migration and invasion of liver cancer, human tongue squamous carcinoma, melanoma, breast cancer, bladder cancer and the like, but no report on the influence on the migration and invasion of glioma is found. On the other hand, berberine has inhibitory activity against some tumors, but its efficacy is not ideal.
The invention aims to develop a safe, effective and low-toxicity chemotherapeutic drug which can effectively inhibit the migration and invasion of malignant glioma cells.
Disclosure of Invention
To solve the above problems, the present invention provides a new therapeutic regimen for glioblastoma based on the unexpected inhibitory effect of berberine derivatives on glioblastoma cells.
According to a first aspect of the present invention, there is provided the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for the treatment of glioblastoma:
，
wherein R is C10-C18Alkyl, or R is benzyl. Said C is10-C18The alkyl group comprising C10-C18N-alkyl or isomers thereof.
In a preferred embodiment, R is C10-C18N-alkyl, for example n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl. More preferably C10-C16An n-alkyl group. More preferably, R is C12-C16An n-alkyl group. More preferably, R is n-dodecyl or n-hexadecyl.
In a preferred embodiment, the salt is selected from the group consisting of hydrobromide, hydroiodide, hydrofluoride, hydrochloride, sulfate, nitrate, phosphate, citrate, acetate and lactate, preferably the hydrobromide, hydrochloride or sulfate.
According to a preferred embodiment of the invention, the compound is selected from: 9-O-n-decaalkyl berberine, 9-O-n-dodecyl berberine, 9-O-n-hexadecyl berberine, 9-O-n-octadecyl berberine, and 9-O-benzyl berberine.
According to one embodiment of the invention, the medicament comprises at least one additional ingredient effective for the treatment of glioblastomas, for use in combination with the derivative of the invention. According to one embodiment of the invention, the medicament comprises pharmaceutically acceptable excipients to formulate the medicament into a suitable dosage form.
The inventors have found that 9-O substituted long chain alkyl or benzyl berberine derivatives surprisingly show better growth inhibition, migration inhibition and invasion inhibition of malignant glioma cells than other berberine derivatives as well as berberine itself. Experiments show that compared with a control, the berberine derivative can effectively inhibit the proliferation of glioma C6 cells and can effectively inhibit the migration and invasion capacity of the cells. The possible reason is that when lipophilic groups (long-chain alkyl or benzyl) are combined with berberine as a parent drug by ether bond, the lipid solubility of the compound is improved, and the compound is effectively transported to the diseased site and the cell through the biological membrane by improving the transmembrane transport, thereby enhancing the drug effect.
According to a second aspect of the invention, there is provided the use of a compound of formula (I) or a salt thereof in the preparation of a mitochondrial targeting delivery system:
，
r is C10-C18Alkyl or benzyl. Said C is10-C18The alkyl group comprising C10-C18N-alkyl or isomers thereof.
In a preferred embodiment, R is C10-C18N-alkyl, for example n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl. More preferably C10-C16An n-alkyl group. More preferably, R is C12-C16An n-alkyl group. More preferably, R is n-dodecyl or n-hexadecyl.
According to a preferred embodiment of the invention, the compound is selected from: 9-O-decaalkyl berberine, 9-O-dodecyl berberine, 9-O-hexadecyl berberine, 9-O-octadecyl berberine, and 9-O-benzyl berberine.
In a preferred embodiment, the salt is selected from the group consisting of hydrobromide, hydroiodide, hydrofluoride, hydrochloride, sulfate, nitrate, phosphate, citrate, acetate and lactate, preferably the hydrobromide, hydrochloride or sulfate.
The mitochondrial targeting delivery system comprises at least one additional pharmaceutical ingredient which is generally difficult to access mitochondria by itself and which does not interact detrimentally with the derivatives of the invention. The additional pharmaceutical ingredient may be localized to the mitochondria to act under the action of the derivative of the invention.
According to a third aspect of the present invention there is provided a method of treating glioblastoma comprising administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to a patient in need thereof.
In the present invention, C10-C18Alkyl means a straight or branched chain alkyl group having 10 to 18 carbon atoms, similarly, C12-C16Alkyl refers to straight or branched chain alkyl groups having 12 to 16 carbon atoms.
Drawings
FIG. 1 shows the change of cell survival rate of berberine and its derivatives acting on C6 cells for 24h at different concentrations.
FIG. 2 shows the cell survival rate changes of berberine derivatives with different concentrations after 24h, 48 h and 72 h of C6 cells, wherein (A) 9-O-dodecyl berberine is called B3, (B) 9-O-hexadecyl berberine is called B4, (C) 9-O-octadecyl berberine is called B5, and (D) 9-O-benzyl berberine is called B6.
Figure 3 shows the results of the berberine and its derivatives C6 cell scratch test, (a) cell migration after 0h and 24h for control group, berberine group and berberine derivatives group, (B) relative mobility comparisons between groups, compared to control, indicating P < 0.05; denotes P < 0.01; denotes P < 0.001. B3 represents 9-O-dodecyl berberine; b4 represents 9-O-hexadecyl berberine; b5 represents 9-O-octadecylberrin; b6 represents 9-O-benzylberberine.
FIG. 4 shows the results of Transwell migration experiments on berberine and its derivative C6 cells, (A) cell migration among control group, berberine group and berberine derivative group, (B) relative mobility comparisons among groups, with control, indicating P < 0.05; denotes P < 0.01; denotes P < 0.001. B3 represents 9-O-dodecyl berberine; b4 represents 9-O-hexadecyl berberine; b5 represents 9-O-octadecylberrin; b6 represents 9-O-benzylberberine.
FIG. 5 shows the results of Transwell invasion experiments of berberine and its derivatives C6 cells, (A) inhibition of invasion of cells by control group, berberine group and berberine derivative group; (B) relative mobility comparisons between groups, compared to control, indicate P < 0.05; denotes P < 0.01; denotes P < 0.001. B3 represents 9-O-dodecyl berberine; b4 represents 9-O-hexadecyl berberine; b5 represents 9-O-octadecylberrin; b6 represents 9-O-benzylberberine.
Figure 6 is a confocal observation of the mitochondrial localization of lipophilic derivatives of berberine in C6(a) and U87(B) glioma cells. mitotracker represents mitotracker green-labeled mitochondria, and is green-fluorescent; the drug represents berberine and lipophilic derivatives thereof, and is yellow fluorescence; the superimposition represents a superimposition of the above two images. B3 represents 9-O-dodecyl berberine; b4 represents 9-O-hexadecyl berberine.
Detailed Description
Synthesis and identification of berberine derivatives
The berberine hydrochloride is purchased from the science and technology limited company of the Xian grass plant and has the purity of 97 percent; bromododecane, bromohexadecane, bromooctadecane and benzyl bromide are all analytically pure and purchased from Aladdin reagents GmbH; n, N-Dimethylformamide (DMF) is analytically pure, is dried by a molecular sieve and purchased from Tianjin Fuyu fine chemical industry Co., Ltd; the neutral alumina for chromatography is a product of the national medicine group; DMEM medium (R10-013-cv), Fetal Bovine Serum (FBS), trypsin, penicillin and streptomycin were purchased from cellgro, USA; tetramethylazo salts (MTT) and dimethyl sulfoxide (DMSO) were purchased from Sigma, USA; 4% Paraformaldehyde was purchased from Guangzhou Jingxin science and technology, Inc.; the experimental water was ultrapure water. Rat glioma C6 cells, human glioma U87 cells were from the U.S. ATCC cell bank. Millicell Cell Culture Inserts (8.0 μm PET) are products of Millipore, USA. AvanceⅢThe 400MHz nuclear magnetic resonance spectrometer is a product of Bruker company in America; an ultra-high performance liquid chromatography tandem mass spectrometer UPLC-MS/MS (TSQ Quantum Access Max) is a U.S. Thermo scientific product; a high speed refrigerated centrifuge (LEGEND MICRO 17R) is a product of Thermo scientific corporation of America; the Microplate Reader is a product of BIO-RAD company in America; inverted research grade microscope (IX 71) is a product of OLYMPUS corporation, japan; water jacket type CO2The incubator (HEPA class 100) is a product of Thermo scientific corporation of America.
An exemplary synthetic route for berberine derivatives of the invention is as follows:
1.1 Synthesis and characterization of Berberrubine (B2)
Synthesis of intermediate B by high-temperature cracking method2。
Taking 10 g (0.0269 mol) of dried berberine hydrochloride in N2Pyrolysis is carried out for 5 h at 190 ℃ under protection. Cooled to room temperature and washed with 50 mL of acetone to give 7.48 g of red crystals with 87% yield.1H NMR (400 MHz, CD3OD) δ: 9.22 (s, 1H), 7.96 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 6.02 (s, 2H), 4.52-4.62 (t, J = 6.3 Hz, 2H), 3.86 (s, 3H), 3.05-3.14 (t, J = 6.3 Hz, 2H); 13C NMR (101 MHz, CD3OD) δ: 151.11, 150.85, 149.47, 147.31, 135.54, 133.74, 130.66, 124.21, 122.90, 121.71, 119.63, 109.20, 108.17, 105.81, 103.25, 56.79, 55.53, 28.96; ESI-MS m/z: 322 [M+H]+。
Synthesis and identification of berberine derivatives B3, B4, B5, B6 and B12
Will be provided withB2Respectively reacting with corresponding bromide to obtainB3, B4, B5, B6 and B12。
GetB2 0.32 g (1 mmol) in 5 mL DMF in N2Reacting with 4 mmol of corresponding bromide at 80 ℃ for 2-24 h under protection, filtering, taking precipitate, loading by a dry method, and purifying by a neutral alumina column (chloroform-methanol 200 ℃)100: 1), respectively obtaining yellow crystalsB3, B4，B5, B6 and B12.The yield is 70% -80%.
9-O-dodecyl Berberine (A)B3）1H NMR (400 MHz, DMSO) δ: 9.76 (s, 1H), 8.95 (s, 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.91 (t, J = 6.7 Hz, 2H), 4.28 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.24 (t, J = 6.7 Hz, 2H), 1.81-1.94 (m, 2H), 1.42-1.52 (m, 2H), 1.39-1.22 (m, 16H), 0.85 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, DMSO) δ: 150.34, 149.76, 147.62, 145.20, 142.84, 137.36, 133.01, 130.58, 126.62, 123.26, 121.61, 120.37, 120.16, 108.35, 105.38, 102.03, 74.22, 57.00, 55.30, 31.23, 29.43, 28.97, 28.77, 28.65, 26.30, 25.21, 22.03, 13.87; ESI-MS m/z: 490 [M-Br]+。
9-O-hexadecyl berberine (A)B4）1H NMR (400 MHz, DMSO) δ: 9.75 (s, 1H) 8.94 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.18 (s, 2H), 4.95 (t, J = 6.7 Hz, 2H), 4.29 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.23 (t, J = 6.7 Hz, 2H), 1.87-1.96 (m, 2H), 1.48-1.58 (m, 2H), 1.24 (s, 24 H), 0.85 (t, J = 3.4 Hz, 3H);13C NMR (101 MHz, DMSO) δ: 150.36, 149.78, 147.65, 145.23, 142.86, 137.40, 133.02, 130.62, 126.68, 123.24, 121.63, 120.40, 120.18, 108.36, 105.39, 102.05, 74.21, 57.01, 55.29, 31.23, 29.43, 28.99, 28.78, 28.64, 26.31, 25.22, 22.03, 13.87; ESI-MS m/z: 546 [M-Br]+。
9-O-octadecylberrin (A)B5）
1H NMR (400 MHz, DMSO) δ: 9.75 (s, 1H), 8.94 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.95 (t, J = 6.4 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H), 4.05 (s, 3H), 3.23 (t, J = 5.3 Hz, 2H), 1.83-1.92 (m, 2H), 1.42-1.52 (m, 2H), 1.39-1.25 (m, 28H), 0.86 (t, J = 4.9 Hz, 3H); 13C NMR (101 MHz, DMSO) δ: 150.37, 149.80, 147.66, 145.22, 142.87, 137.44, 133.03, 130.63, 126.70, 123.26, 121.65, 120.40, 120.18, 108.37, 105.39, 102.04, 74.22, 57.01, 55.30, 31.21, 29.41, 28.95, 28.75, 28.62, 26.31, 25.21, 22.01, 13.87; ESI-MS m/z: 574 [M-Br]+。
9-O-benzylberberine (A)B6）1H NMR (400 MHz, DMSO) δ: 9.73 (s, 1H), 8.93 (s, 1H), 8.21 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.38 (dt, J = 8.5, 5.1 Hz, 3H), 7.08 (s, 1H), 6.17 (s, 2H), 5.36 (s, 2H), 4.91 (t, J = 6.7 Hz, 2H), 4.08 (s, 3H), 3.21 (t, J = 6.7 Hz, 2H); 13C NMR (101 MHz, DMSO) δ: 150.66, 149.78, 147.63, 145.24, 141.95, 137.30, 136.40, 132.89, 130.57, 128.75, 128.37, 128.31, 126.49, 123.71, 121.77, 120.32, 120.15, 108.36, 105.39, 102.04, 75.32, 57.03, 55.33, 26.31; ESI-MS m/z: 412 [M-Br]+。
9-O-decaalkyl berberine (C)B12）1H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.93 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.78 (s, 1H), 7.08 (s, 1H), 6.16 (s, 2H), 4.94 (t, J = 6.3 Hz, 2H), 4.26 (t, J = 6.7 Hz, 2H), 4.04 (s, 3H), 3.20 (s, 3H), 1.91 – 1.81 (m, 2H), 1.45 (d, J = 7.3 Hz, 2H), 1.24 (s, 12H), 0.84 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, DMSO) δ: 150.34, 149.72, 147.59, 145.23, 142.82, 137.32, 132.99, 130.57, 126.57, 123.27, 121.59, 120.38, 120.19, 108.33, 105.39, 102.03, 74.21, 56.99, 55.24, 31.26, 29.45, 28.96, 28.81, 28.67, 26.29, 25.23, 22.05, 13.90; ESI-MS m/z: 462 [M-Br]+。
2. Functional verification of berberine derivatives
2.1 cell culture
C6 and U87 glioma cells were cultured in DMEM high-glucose medium with 10% Fetal Bovine Serum (FBS) at 5% CO2And cultured at 37 ℃. Changing culture solution every 48 h, and subculturing.
Method for detecting survival rate of cells
A control group and 5 drug groups with different concentrations are set, and each group has 3 multiple wells. Digesting and counting C6 cells in logarithmic phase, inoculating in 96-well plate according to 10000 cell/well, culturing at 37 deg.C and 5% CO2After 24h in the incubator, drug solutions of different concentrations were added. After further culturing for 24h, 48 h and 72 h, 20. mu.L of tetrazolium salt solution (MTT, 5 mg/mL) is added into each well for further culturing for 4h, the supernatant is removed by aspiration, 100. mu.L of DMSO is added into each well, the mixture is shaken for 10 min, and the absorbance (A) at 570 nm is measured on an enzyme-labeling instrument. Cell survival (%) ═ aDrug group／AControl groupX 100%. The results are shown in FIGS. 1 and 2. As can be seen from FIG. 1, berberine and its derivatives are dose-dependent on the proliferation inhibition of C6 cells, and the difference in cell survival rate between the different concentration groups (0, 5, 10, 20, 40 μ M) is statistically significant (1)P<0.05). Compared with the control group, the berberine shows obvious proliferation inhibition effect when the concentration is more than 20 mu M (P<0.05). The berberine derivatives (B3, B4, B5 and B6) have significant inhibition effect on cell proliferation compared with berberine (B)P<0.05). Among them, B3 has the strongest inhibitory effect on proliferation, 5 μ M on cellsThe proliferation activity of the berberine derivative is obviously influenced, and the survival rate of the cells at each concentration is obviously lower than that of the berberine and other derivatives: (P<0.05). FIG. 2 shows the change in cell survival rates of C6 cells at different concentrations of B3, B4, B5 and B6 after 24h, 48 h and 72 h. The berberine derivative has obvious dosage and time dependence on the inhibition effect of C6 cell proliferation (P<0.05）。
Cell scratch test
C6 cells in logarithmic growth phase are taken and inoculated in a 6-hole plate, the plate is placed in an incubator, after the cells grow to be about 90% of a monolayer, a sterilized 20 mL pipette tip is used for uniformly scratching the cells, Phosphate Buffer Solution (PBS) is used for washing cell fragments for 3 times, the Solution is replaced by serum-free culture Solution, and a control group and a drug group are arranged, wherein the drug concentration of the drug group culture Solution is 5 mmol/L. After 24h, the extent of migration of the cells was observed with an inverted microscope (x 40) and photographed. The cell migration distance was measured using Image J2x (version 2.1.4.7) software. The relative migration distance of each group was calculated as the relative migration distance of cells = (0 h scratch width-24 h scratch width)/0 h scratch width × 100%, and then the relative migration rate of the drug group was calculated with the relative migration distance of the control group as 100%. The results are shown in FIG. 3. FIG. 3A shows that the control group and berberine group cells are scratched and almost covered by migrated cells after 24h, and the coverage area is over 90%; whereas the scratched area of each derivative group was still clearly visible. Comparing the relative mobility between each group (fig. 3B), the drug group and the control group have significant difference, and the inhibition effect of the derivative on the migration is obviously stronger than that of bulk drug berberine (P < 0.05). Among them, B3 showed the strongest migration inhibition effect on C6 cells, and the relative mobility (13.75% + -4.86%) was significantly lower than that of other derivatives (P < 0.05). The relative mobility of group B4 was 23.56% ± 8.67%, and the inhibition of cell migration was second only to B3, and was stronger than B5 and B6 (relative mobilities 35.46% ± 2.33% and 46.89% ± 10.56%, respectively).
Migration test
Trypsin eliminatorCells were lysed and collected, washed 3 times in 10% FBS-containing DMEM medium, and resuspended in serum-free DMEM medium (cell number 2.5X 10)5/mL). Uniformly adding 100 mu L of cell suspension into the upper chamber, and simultaneously adding a drug solution with proper concentration; the lower chamber was filled with 600. mu.L of DMEM medium containing 10% FBS. Meanwhile, MTT assay was performed using 96-well plates of the same cell number to detect the change in cell number. 37 ℃ and 5% CO2Culturing for 24h, taking out the upper chamber, wiping off the upper chamber cells with a cotton swab, fixing with 4% paraformaldehyde for 30min, dyeing with 0.2% crystal violet dye solution for 10 min, washing with distilled water for three times, randomly selecting 9 visual fields under a microscope (x 200), and counting; each group was provided with 3 parallel small holes and the experiment was repeated 3 times. Finally, the migration ability of the cells was evaluated by mobility = number of migrated cells/number of MTT total cells at equal concentration × 100%. The ratio of the mobility of each group to the mobility of the control group is the relative mobility. The results are shown in FIG. 4. As shown in figure 4A of the drawings,B3andB4the number of cells that migrated to the lower chamber is minimized (P<0.001）。
Invasion test
Matrigel (bs biosciences) 5 mL was thawed overnight at 4 ℃, pre-cooled at 4 ℃ in serum-free DMEM medium at DMEM: matrigel =3:1 dilution, 50 μ L of diluted Matrigel was added to a pre-cooled Transwell upper chamber and incubated at 37 ℃ for 4h to allow gel formation. The following operations are performed2.4The cell amount in the upper chamber is 5X 105 100 μ L). Finally, the invasion capacity of the cells was evaluated by the invasion rate = number of invaded cells/number of total MTT cells at equal concentration × 100%. The ratio of the attack rate of each group to the attack rate of the control group is the relative attack rate.
The results are shown in FIG. 5. After drug treatment, the number of cells of C6 cells passing through the recombinant artificial basement membrane is obviously less than that of the control group, the invasion capacity is inhibited, and the difference has statistical significance (P<0.05). Wherein,B3andB4(the relative invasion rates are respectively 40.78% + -3.72% and 20.36% + -5.84%), the inhibition effect on invasion is obviously stronger than that of bulk drug berberine (the relative mobility is 56.17% + -4.00%).
The data above were analyzed using SPSS 13.0 statistical software. The mean value test was performed using an analysis of variance,Pdifferences <0.05 are statistically significant.
The strong migration and invasion capacity is a key factor for restricting the life-prolonging period of a patient with malignant glioma. However, the current large number of cytotoxic drugs cannot effectively inhibit the migration and invasion of glioma, and on the contrary, drug resistance and myelosuppression effect limit the clinical application of glioma. The inventor finds that the lipophilic berberine derivative provided by the invention can enhance the inhibition effect of the lipophilic berberine on the proliferation, migration and invasion of C6 glioma cells while increasing the lipophilicity of the berberine.
3. Mitochondrial targeting of berberine derivatives
Taking C6 and U87 cells in logarithmic growth phase, and culturing at 4 × 105And inoculating the seeds/dish into a glass bottom culture dish special for a laser confocal microscope for culturing for 24 hours. Removing culture medium, adding culture solution containing 1 μ M berberine, 9-O-dodecyl berberine or 9-O-hexadecyl berberine, respectively, and incubating for 24 hr. The supernatant was aspirated, washed three times with PBS (pH 7.4), stained with Mitotracker Green FM (500nM) for 30min, washed three times with ice-cold PBS, observed under a confocal laser microscope and photographed.
It was observed under confocal laser observation that berberine and its lipophilic derivatives were able to selectively aggregate in mitochondria in C6 (fig. 6A) and U87 (fig. 6B) glioma cells. Mitochondria of C6 and U87 glioma cells were stained by mitocker green (green) and confocal laser observation after incubation of berberine and its derivatives (yellow) for 24 hours. In all superimposed graphs (combined), yellow and green showed good subcellular co-localization, and the superposition showed yellow-green.
In C6 cells, berberine was more evenly distributed throughout the cell (including cytoplasm and nucleus), and the fluorescence intensity was weaker, indicating weaker mitochondrial targeting. In comparison, the fluorescence distribution of the berberine derivatives B3 and B4 is basically completely coincided with the mitotracker green fluorescence, and basically no fluorescence exists in the nuclear part, thereby showing stronger mitochondrial targeting compared with berberine. In U87 cells, B3 and B4 not only localized exactly into the cell mitochondria, but also showed strong fluorescence intensity, indicating that they were distributed to mitochondria in large numbers, showing stronger mitochondrial targeting than in C6 cells.
Claims (9)
1. Use of a compound of formula (I) or a salt thereof in the manufacture of a medicament or a mitochondrial targeting delivery system for the treatment of glioblastoma:
a compound of the formula (I),
wherein R is C10-C18Alkyl, or benzyl.
2. Use according to claim 1, wherein R is C10-C18An n-alkyl group.
3. Use according to claim 1, wherein R is C12-C16An n-alkyl group.
4. Use according to claim 1, wherein R is n-dodecyl or n-hexadecyl.
5. Use according to any one of claims 1 to 4, wherein the salt is selected from the group consisting of hydrobromide, hydroiodide, hydrofluoride, hydrochloride, sulphate, nitrate, phosphate, citrate, acetate and lactate.
6. Use according to claim 1, wherein the compound is selected from: 9-O-n-decaalkyl berberine, 9-O-n-dodecyl berberine, 9-O-n-hexadecyl berberine, 9-O-n-octadecyl berberine, and 9-O-benzyl berberine.
7. The use of claim 1, wherein the medicament comprises at least one additional ingredient effective for the treatment of glioblastoma.
8. The use of claim 1, wherein the medicament comprises a pharmaceutically acceptable excipient.
9. The use of claim 1, wherein the mitochondrial targeting delivery system comprises at least one additional pharmaceutical ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310218544.0A CN104208061B (en) | 2013-06-04 | 2013-06-04 | The medical usage of berberinc derivate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310218544.0A CN104208061B (en) | 2013-06-04 | 2013-06-04 | The medical usage of berberinc derivate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104208061A true CN104208061A (en) | 2014-12-17 |
| CN104208061B CN104208061B (en) | 2016-08-31 |
Family
ID=52090239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310218544.0A Active CN104208061B (en) | 2013-06-04 | 2013-06-04 | The medical usage of berberinc derivate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104208061B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853416A (en) * | 2015-01-21 | 2016-08-17 | 复旦大学 | Application of berberine to the preparation of Hedgehong signaling pathway inhibitor |
| CN107281180A (en) * | 2016-04-05 | 2017-10-24 | 西南大学 | Application of the 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared |
| CN109232557A (en) * | 2018-11-14 | 2019-01-18 | 常州大学 | A kind of 9-O- aryl replaces the synthesis and purposes of berberinc derivate |
| CN110960506A (en) * | 2018-09-28 | 2020-04-07 | 中山大学 | Nanosuppreparation for the treatment of diseases caused by mitochondrial dysfunction |
| CN111377913A (en) * | 2020-03-19 | 2020-07-07 | 西南大学 | 9-alkoxy berberine salt, synthesis method and application |
| CN112679492A (en) * | 2019-10-17 | 2021-04-20 | 中国科学院上海药物研究所 | Berberine derivative, preparation method and application thereof |
| CN113633786A (en) * | 2021-10-18 | 2021-11-12 | 齐鲁工业大学 | Bovine serum albumin-hydrophobic modified chitosan nano microcapsule and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050213A (en) * | 2007-05-14 | 2007-10-10 | 中山大学 | Fat amido substitutional berberine derviation, preparation method, and application of anticancer drugs |
-
2013
- 2013-06-04 CN CN201310218544.0A patent/CN104208061B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050213A (en) * | 2007-05-14 | 2007-10-10 | 中山大学 | Fat amido substitutional berberine derviation, preparation method, and application of anticancer drugs |
Non-Patent Citations (3)
| Title |
|---|
| CHIH-YU LO等: "Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives: A lipophilic substitute role", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| GONCALO C. PEREIRA等: "Mitochondrially Targeted Effects of Berberine [Natural Yellow 18,5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 Mouse Melanoma Cells: Comparison with Direct Effects on Isolated Mitochondrial Fractions", 《THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 * |
| 吴丽 等: "黄连素对神经胶质瘤细胞增殖和细胞周期的影响", 《中药材》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853416A (en) * | 2015-01-21 | 2016-08-17 | 复旦大学 | Application of berberine to the preparation of Hedgehong signaling pathway inhibitor |
| CN105853416B (en) * | 2015-01-21 | 2019-04-05 | 复旦大学 | Jamaicin is preparing the purposes in Hedgehong signal pathway inhibitor |
| CN107281180A (en) * | 2016-04-05 | 2017-10-24 | 西南大学 | Application of the 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared |
| CN110960506A (en) * | 2018-09-28 | 2020-04-07 | 中山大学 | Nanosuppreparation for the treatment of diseases caused by mitochondrial dysfunction |
| CN109232557A (en) * | 2018-11-14 | 2019-01-18 | 常州大学 | A kind of 9-O- aryl replaces the synthesis and purposes of berberinc derivate |
| CN109232557B (en) * | 2018-11-14 | 2021-01-29 | 常州大学 | Synthesis and application of 9-O-aryl substituted berberine derivative |
| CN112679492A (en) * | 2019-10-17 | 2021-04-20 | 中国科学院上海药物研究所 | Berberine derivative, preparation method and application thereof |
| CN112679492B (en) * | 2019-10-17 | 2022-03-18 | 中国科学院上海药物研究所 | Berberine derivative, preparation method and application thereof |
| CN111377913A (en) * | 2020-03-19 | 2020-07-07 | 西南大学 | 9-alkoxy berberine salt, synthesis method and application |
| CN111377913B (en) * | 2020-03-19 | 2021-11-05 | 西南大学 | 9-alkoxy berberine salt, synthesis method and application |
| CN113633786A (en) * | 2021-10-18 | 2021-11-12 | 齐鲁工业大学 | Bovine serum albumin-hydrophobic modified chitosan nano microcapsule and preparation method thereof |
| CN113633786B (en) * | 2021-10-18 | 2022-07-19 | 齐鲁工业大学 | Bovine serum albumin-hydrophobic modified chitosan nano microcapsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104208061B (en) | 2016-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104208061B (en) | The medical usage of berberinc derivate | |
| US20220218605A1 (en) | Bifunctional nucleoside hydrogel, preparation method therefor and use thereof | |
| CN111072727B (en) | Iridium complex constructed based on 8-hydroxyquinoline derivative and 2-phenylpyridine iridium dimer as well as synthetic method and application thereof | |
| CN105189474A (en) | Methods and compositions for inhibiting human copper trafficking proteins atox1 and ccs | |
| CN108440583A (en) | A kind of new boronic acid derivatives and its pharmaceutical composition | |
| Ma et al. | A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent | |
| CN114195779B (en) | Synthesis method of 9-0-ethyl ether berberine and application thereof in preparation of antitumor drugs | |
| CN111116667B (en) | Iridium complex constructed based on 8-hydroxyquinoline derivative and 1-phenylpyrazole iridium dimer as well as synthetic method and application thereof | |
| CN106831812B (en) | Simultaneously pyrimidine or pyrazine compounds and its application of the heterocycle of the amide structure containing biaryl | |
| CN104211697B (en) | Berberinc derivate and application thereof | |
| Fan et al. | Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma | |
| CN110857295B (en) | Flavone-ligustrazine compound CH-X with selective anti-liver cancer effect and preparation method and application thereof | |
| CN107383015B (en) | Alkylthio-terminal-group oligo-PEG-modified amino pyrazolo [3,4-d ] pyrimidine derivative and application thereof in resisting non-small cell lung cancer | |
| JP6239103B2 (en) | Substance having tyrosine kinase inhibitory activity and preparation method and use thereof | |
| CN114573459B (en) | Beta-elemene diamido substituted derivative and preparation method and application thereof | |
| WO2018058863A1 (en) | Use of polyether compounds | |
| CN115634223A (en) | DII-tt-DTT and application thereof in preparation of anti-colorectal cancer drugs | |
| CN105566147B (en) | A kind of compound and its production and use and corresponding targeting drug delivery system and chemotherapeutics | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| CN109223801B (en) | Novel gastric cancer tumor stem cell killing agent and application thereof | |
| CN106995368B (en) | non-ATP competitive FGFR1 inhibitor and application thereof | |
| CN111518065A (en) | Parthenolide derivative and preparation method and application thereof | |
| CN106866684B (en) | Macrocyclic derivatives for the treatment of tumors | |
| KR20200063443A (en) | Pharmaceutical compositions for preventing or treating cancers comprising the PLK1 inhibitor | |
| CN118161509B (en) | Application of MAPK12 inhibitor and derivatives thereof in preparation of antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |