CN104211697A - Berberine derivative and use thereof - Google Patents
Berberine derivative and use thereof Download PDFInfo
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- CN104211697A CN104211697A CN201310218566.7A CN201310218566A CN104211697A CN 104211697 A CN104211697 A CN 104211697A CN 201310218566 A CN201310218566 A CN 201310218566A CN 104211697 A CN104211697 A CN 104211697A
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- Prior art keywords
- berberine
- salt
- compound
- cell
- alkyl
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- 150000003832 berberine derivatives Chemical class 0.000 title abstract 2
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229940093265 berberine Drugs 0.000 claims abstract description 43
- 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 abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 238000012377 drug delivery Methods 0.000 claims abstract description 5
- -1 vitriol Chemical compound 0.000 claims description 15
- 208000005017 glioblastoma Diseases 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229940038384 octadecane Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical group CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 44
- 230000009545 invasion Effects 0.000 abstract description 20
- 206010018338 Glioma Diseases 0.000 abstract description 16
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 208000029824 high grade glioma Diseases 0.000 abstract description 2
- 201000011614 malignant glioma Diseases 0.000 abstract description 2
- 210000003470 mitochondria Anatomy 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 230000009036 growth inhibition Effects 0.000 abstract 2
- 230000002438 mitochondrial effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
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- 208000032612 Glial tumor Diseases 0.000 description 14
- 230000005012 migration Effects 0.000 description 13
- 238000013508 migration Methods 0.000 description 13
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 13
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
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- 235000015097 nutrients Nutrition 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 108010082117 matrigel Proteins 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
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- 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 compound [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 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- YCOZIPAWZNQLMR-UHFFFAOYSA-N heptane - octane Natural products CCCCCCCCCCCCCCC YCOZIPAWZNQLMR-UHFFFAOYSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- NDJKXXJCMXVBJW-UHFFFAOYSA-N heptadecane Chemical compound CCCCCCCCCCCCCCCCC NDJKXXJCMXVBJW-UHFFFAOYSA-N 0.000 description 2
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 2
- IIYFAKIEWZDVMP-UHFFFAOYSA-N tridecane Chemical compound CCCCCCCCCCCCC IIYFAKIEWZDVMP-UHFFFAOYSA-N 0.000 description 2
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 1
- 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
- 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
- 0 COc(ccc1c2c[n+](CCc(c-3c4)cc5c4OCO5)c-3c1*)c2OC Chemical compound COc(ccc1c2c[n+](CCc(c-3c4)cc5c4OCO5)c-3c1*)c2OC 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 241000218202 Coptis Species 0.000 description 1
- 235000002991 Coptis groenlandica Nutrition 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010061188 Haematotoxicity Diseases 0.000 description 1
- FZAGOOYMTPGPGF-UHFFFAOYSA-N Lambertine Chemical compound C1=C2C3=CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 FZAGOOYMTPGPGF-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
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- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 description 1
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- 239000006285 cell suspension Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
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- 231100000433 cytotoxic Toxicity 0.000 description 1
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- 238000007917 intracranial administration Methods 0.000 description 1
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- 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
- 230000005748 tumor development Effects 0.000 description 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a compound shown in the formula (I) or a salt thereof and use of the compound and the salt, and R is C10-C18 alkyl or benzyl. The growth inhibition, growth inhibition, and invasion inhibition of the compound and the salt on malignant glioma cells are surprisingly better than that of a berberine derivative and berberine self. In addition, the compounds can be well positioned to mitochondria, so that the compounds can be used as a mitochondrial targeting drug delivery system.
Description
Technical field
The present invention relates to berberinc derivate and its production and use.
Background technology
Glioblastoma (Malignant Glioma) is modal primary malignant neoplasm in central nervous system, and sickness rate accounts for 46% of intracranial tumors.Operation is first-selected methods for the treatment of, but because it is infiltrative growth, without obvious boundary, operation is difficult to excision with normal cerebral tissue, and Postoperative recurrent rate is up to 96%.Even if be aided with radiation and chemotherapy, postoperative mean survival time (MST), is also no more than 14 months, poor prognosis.The property of the can not be cured migration and invasion ability strong with it of glioblastoma is closely related.Therefore, suppress the migration of glioma cell and attack the treatment of glioblastoma very crucial.Yet existing treatment means can not suppress migration and the invasion and attack of glioblastoma effectively, cause result for the treatment of not good, and have many defects such as neurotoxicity, hematotoxicity, resistance.
In addition, comprise tumour, the pathologic process of various diseases is relevant with injury of mitochondria.On structure and function, there is larger difference in tumour cell and Normocellular plastosome, in the cell directly related with plastosome, biochemical event is abnormal, such as change, ATP dyspoiesis, the calcium ion of carbohydrate metabolism pattern accumulate, oxidative stress etc. is all the major reason of tumor development in functional disorder in various degree.Meanwhile, in tumour cell, mtDNA sudden change and excessive ROS have also been in the news and promote tumour cell to shift.This makes drug targeting in the plastosome of tumour cell, and by plastosome, optionally acts on tumour cell and become possibility, and this is significant for the high invasive tumour of this class of targeted therapy glioblastoma.
Berberine (Berberine) is from the traditional Chinese medicine materials such as the coptis, to extract the separated a kind of isoquinoline alkaloid obtaining, and oral administration safety is high, takes in a large number for a long time without blood, cardiovascular and liver renal toxicity.Research shows, Berberine can suppress migration and the invasion and attack of liver cancer, people's tongue squama cancer, melanoma, mammary cancer, bladder cancer etc., but has no the report on the impact of glioma migration and invasion and attack.On the other hand, although Berberine has the inhibition activity to some tumour, its drug effect is not ideal.
The present invention intends the chemotherapeutics at a kind of safe, effective, low toxicity of exploitation, and this chemotherapeutics can effectively suppress migration and the invasion and attack of glioblastoma cell.
Summary of the invention
For addressing the above problem, the invention provides a kind of new treatment plan for glioblastoma, it is realized the unexpected inhibition of glioblastoma cell based on berberinc derivate.
According to a first aspect of the invention, the invention provides the compound or its salt of formula (I)
formula (I),
Wherein, R is C
10-C
18alkyl, or benzyl.Described C
10-C
18alkyl comprises C
10-C
18alkyl or their isomer.
In a preferred embodiment, R is C
10-C
18alkyl, for example decane base, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base.More preferably, R is C
10-C
14alkyl.More preferably, R is decane base or dodecyl.
In a preferred embodiment, described salt is selected from hydrobromate, hydriodate, hydrofluoride, hydrochloride, vitriol, nitrate, phosphoric acid salt, Citrate trianion, acetate and lactic acid salt, is preferably hydrobromate, hydrochloride or vitriol.
According to the preferred embodiment of the present invention, described compound is selected from: 13-decane base Berberine, 13-dodecyl Berberine, 13-n-hexadecyl Berberine, 13-Octadecane base Berberine, and 13-benzyl Berberine.
Another aspect of the present invention provides a kind of pharmaceutical composition, compound or its salt and pharmaceutical excipient that it contains the formula (I) for the treatment of significant quantity.Preferably, described pharmaceutical composition also can comprise that at least one is extra to the effective composition for the treatment of glioblastoma, to combine use with derivative of the present invention.
According to a third aspect of the present invention, the invention provides compound or its salt or the purposes of pharmaceutical composition in preparation treatment glioblastoma medicine of above-mentioned formula (I).
According to a fourth aspect of the present invention, the invention provides a kind of method for the treatment of glioblastoma, the method comprises the patient who the compound or its salt of the formula (I) for the treatment of significant quantity is applied to these needs.
According to a fifth aspect of the present invention, the application of the compound or its salt that the invention provides formula (I) in the Mitochondrially targeted drug delivery system of preparation.Described Mitochondrially targeted drug delivery system comprises at least one extra pharmaceutical cpd, and this pharmaceutical cpd self is difficult to enter plastosome conventionally, and with derivative of the present invention, harmful interaction does not occur.This extra pharmaceutical cpd can be positioned in plastosome under the effect of derivative of the present invention, thereby plays a role.
Contriver's discovery, the berberinc derivate of 13 chain alkyls that replace or benzyl suppresses to be better than unexpectedly other berberinc derivates and Berberine itself for growth-inhibiting, inhibition of metastasis and the invasion and attack of glioblastoma cell.The present invention found through experiments, and compared with the control, berberinc derivate can not only more effectively suppress the propagation of C 6 Cell of Glioma, more can effectively suppress migration and the invasive ability of cell simultaneously.Possible reason is, when lipophilic group (chain alkyl or benzyl) is when parent drug is combined, improved the fat-soluble of compound, by improving transmembrane transport, and compound is seen through to microbial film effectively, be transported in diseased region and cell, thereby strengthen drug effect.
In the present invention, C
10-C
18alkyl refers to the straight or branched alkyl with 10 to 18 carbon atoms, similarly, and C
10-C
14alkyl refers to the straight or branched alkyl with 10 to 14 carbon atoms.
Accompanying drawing explanation
Fig. 1 shows that Transwell migration experiment detects transfer ability (`x ± s, the n=3 of C6 glioma cell; * represent to compare with control group, P<0.05); B7 represents 13-ten alkyl berberines; B8 represents 13-dodecyl Berberine.
Fig. 2 shows that Transwell Matrigel detects invasive ability (`x ± s, the n=3 of C6 glioma cell; * represent to compare with control group, P<0.05); B7 represents 13-ten alkyl berberines; B8 represents 13-dodecyl Berberine.
Fig. 3 shows that Transwell migration experiment detects transfer ability (`x ± s, the n=3 of U87 glioma cell; * represent to compare with control group, P<0.05); B12 represents 9-O-ten alkyl berberines; B7 represents 13-ten alkyl berberines.
Fig. 4 shows that Transwell Matrigel detects invasive ability (`x ± s, the n=3 of U87 glioma cell; * represent to compare with control group, P<0.05); B12 represents 9-O-ten alkyl berberines; B7 represents 13-ten alkyl berberines.
Fig. 5 is the laser co-focusing observations of the plastosome location of Berberine lipophilic derivatives in C6 (A) and U87 (B) glioma cell.Mitotracker represents the plastosome of mitotracker green mark, is green fluorescence; Medicine represents Berberine and lipophilic derivatives thereof, is yellow fluorescence; Stack represents the stack of above two images.B8 represents 13-dodecyl Berberine; B9 represents 13-hexadecyl Berberine.
Embodiment
1. 13-replaces the synthetic of berberinc derivate and identifies
1.1 intermediate dihydroberberines (Dihydroberberine,
1b) synthetic with identify
Adopt reduction method to prepare intermediate
1b.
Be dried
16 g(0.0162 mol) be suspended in 50 mL pyridines stirring at room.Slowly add NaBH
4700 mg, while becoming reddish-brown settled solution immediately with frozen water 200 mL to reaction solution, filter to obtain intermediate
1b, outward appearance is buff powder, and 30 ℃ of vacuum-dryings are stand-by.ESI-MS?
m/z:?338?[M+H]
+。
1.2 13-ten alkyl berberine (B
7) synthetic with identify
Bromo decane 0.89 mL(4 e.q.
1b4 times of molar weights), sodium iodide (NaI) 0.60 g(4 e.q.), anhydrous acetonitrile 20 mL, be placed in the reaction under high pressure bottle of sealing, 80 ℃ reaction 24 h.Add
1b0.34 g(1 mmol, 1 e.q.), fill N
215 min, reaction 12 h.Afterwards, 60 ℃ of reflux 2 h, are fully oxidized it.Be cooled to room temperature, filter.Filtrate is spin-dried for, and crosses successively three times posts: neutral alumina column (sherwood oil-propyl carbinol 10:1), silicagel column (supernatant liquor of n-butanol-water-glacial acetic acid 50:3:3), gel column (methyl alcohol-methylene dichloride-anhydrous diethyl ether 1:1:1).Obtain yellow crystal
7, productive rate 15% left and right.
1H?NMR?(400?MHz,?DMSO)?δ:?9.90?(s,?1H),?8.21?(s,?2H),?7.31?(s,?1H),?7.17?(s,?1H),?6.20?(s,?2H),?4.81?(t,?
J=5.6Hz,?2H),?4.11?(s,?3H),?4.10?(s,?3H),?3.34?(m,?2H),?3.09?(t,?
J=5.6Hz,?2H),?1.74?(m,?2H),?1.38?(m,?2H),?1.24?(m,?12H),?0.87?(t,?J?=?6.6?Hz,?3H);?
13C?NMR?(101?MHz,?DMSO)?δ:?150.69,?149.49,?147.03,?144.90,?144.78,?136.24,?134.65,?134.56,?132.68,?126.41,?121.91,?121.71,?120.78,?109.58,?108.85,?102.60,?62.54,?57.49,?31.76,?30.88,?29.41,?29.12,?28.90,?27.87,?22.55,?14.43.?ESI-MS?
m/z:?476?[M-I]
+。
1.3 13-dodecyl Berberine (B
8) synthetic with identify
Bromododecane 1.00 mL(4 e.q.), NaI 0.60 g(4 e.q.), anhydrous acetonitrile 20 mL, be placed in the reaction under high pressure bottle of sealing, 80 ℃ reaction 24 h.Add
1b0.34 g(1 mmol, 1 e.q.), fill N
215 min, reaction 12 h.Afterwards, 60 ℃ of reflux 2 h, are fully oxidized it.Be cooled to room temperature, filter.Filtrate is spin-dried for, and crosses successively three times posts: neutral alumina column (sherwood oil-propyl carbinol 10:1), silicagel column (supernatant liquor of n-butanol-water-glacial acetic acid 50:3:3), gel column (methyl alcohol-methylene dichloride-anhydrous diethyl ether 1:1:1).Obtain yellow crystal
8, productive rate 10% left and right.
1H?NMR?(400?MHz,?DMSO)?δ:?9.92?(s,?1H),?8.20?(s,?2H),?7.29?(s,?1H),?7.16?(s,?1H),?6.18?(s,?2H),?4.81?(t,?
J=5.6Hz,?2H),?4.10?(s,?3H),?4.09?(s,?3H),?3.34?(m,?2H),?3.08?(t,?
J=5.6Hz,?2H),?1.75?(m,?2H),?1.37?(m,?2H),?1.23?(m,?16H),?0.85?(m,?3H);?
13C?NMR?(101?MHz,?DMSO)?δ:?150.69,?149.50,?147.04,?144.81,?144.75,?136.51,?136.26,?134.69,?134.53,?132.70,?126.39,?121.91,?121.71,?120.78,?109.60,?108.83,?102.59,?62.51,?57.47,?31.76,?30.86,?29.47,?29.44,?29.40,?29.16,?29.06,?28.88,?27.87,?22.56.?ESI-MS?
m/z:?504?[M-I]
+。
1.4 13-hexadecyl Berberine (B
9) synthetic with identify
Bromohexadecane 1.23 mL(4 e.q.), NaI 0.60 g(4 e.q.), anhydrous acetonitrile 20 mL, be placed in the reaction under high pressure bottle of sealing, 80 ℃ reaction 24 h.Add
1b0.34 g(1 mmol, 1 e.q.), fill N
215min, reaction 12h.Afterwards, 60 ℃ of reflux 2 h, are fully oxidized it.Be cooled to room temperature, filter.Filtrate is spin-dried for, and crosses successively three times posts: neutral alumina column (sherwood oil-propyl carbinol 500:75), silicagel column (supernatant liquor of n-butanol-water-glacial acetic acid 50:3:3), gel column (methyl alcohol-methylene dichloride-anhydrous diethyl ether 1:1:1).Obtain yellow crystal
9, productive rate 10% left and right.
1H?NMR?(400?MHz,?DMSO)?δ:?9.90?(s,?1H),?8.20?(s,?2H),?7.29?(s,?1H),?7.16?(s,?1H),?6.18?(s,?2H),?4.80?(t,?
J=5.6Hz,?2H),?4.10?(s,?3H),?4.09?(s,?3H),?3.34?(s,?2H),?3.08?(m,?2H),?1.77?–?1.71?(m,?2H),?1.36?(m,?2H),?1.23?(s,?24H),?0.86?(t,?J?=?5.8?Hz,?3H).?
13C?NMR?(101?MHz,?DMSO)?δ:?150.16,?148.98,?146.51,?144.29,?135.70,?134.09,?134.01,?132.17,?131.65,?131.40,?128.57,?125.88,?121.31,?121.19,?120.22,?108.99,?108.31,?102.06,?61.98,?56.94,?31.24,?30.38,?29.96,?29.00,?28.96,?28.65,?28.61,?28.40,?22.03,?18.59,?13.83,?13.45.ESI-MS?
m/z:?560?[M-I]
+。
1.5 13-octadecyl Berberine (B
10) synthetic with identify
Bromo-octadecane 1.35 mL(4 e.q.), NaI 0.60 g(4 e.q.), anhydrous acetonitrile 20 mL, be placed in the reaction under high pressure bottle of sealing, 80 ℃ reaction 24h.Add
1b0.34g(1 mmol, 1 e.q.), fill N
215min, reaction 12 h.Afterwards, 60 ℃ of reflux 2 h, are fully oxidized it.Be cooled to room temperature, filter.Filtrate is spin-dried for, and crosses successively three times posts: neutral alumina column (sherwood oil-propyl carbinol 500:65), silicagel column (supernatant liquor of n-butanol-water-glacial acetic acid 50:3:3), gel column (methyl alcohol-methylene dichloride-anhydrous diethyl ether 1:1:1).Obtain yellow crystal
10, productive rate 10% left and right.
1H?NMR?(400?MHz,?DMSO)?δ:?9.90?(s,?1H),?8.20?(s,?2H),?7.29?(s,?1H),?7.16?(s,?1H),?6.18?(s,?2H),?4.80?(s,?2H),?4.10?(s,?3H),?4.09?(s,?3H),?3.24?(d,?J?=?7.8?Hz,?2H),?3.08?(s,?2H),?1.83?–?1.70?(m,?2H),?1.37?(m,?2H),?1.23?(s,?28H),?0.85?(t,?J?=?6.8?Hz,?3H).?
13C?NMR?(101?MHz,?DMSO)?δ:?150.67,?149.49,?147.03,?144.81,?144.74,?136.25,?134.67,?134.52,?132.68,?126.38,?121.89,?121.70,?120.76,?109.58,?108.82,?102.58,?62.50,?57.47,?31.75,?30.87,?29.48,?29.16,?27.87,?22.55,?14.41.?ESI-MS?
m/z:?588?[M-I]
+。
1.6 13-benzyl Berberine (B
11) synthetic with identify
Cylite 0.48 mL(4 e.q.), NaI 0.60 g(4 e.q.), anhydrous acetonitrile 20 mL, be placed in the reaction under high pressure bottle of sealing, reaction 24 h.Add
1b0.34 g(1 mmol, 1 e.q.), fill N
215 min, reaction 12 h.Afterwards, 60 ℃ of reflux 2 h, are fully oxidized it.Be cooled to room temperature, filter.Filtrate is spin-dried for, and crosses successively three times posts: neutral alumina column (sherwood oil-propyl carbinol 500:70), silicagel column (supernatant liquor of n-butanol-water-glacial acetic acid 50:3:3), gel column (methyl alcohol-methylene dichloride-anhydrous diethyl ether 1:1:1).Obtain yellow crystal
11, productive rate 37% left and right.
1H?NMR?(400?MHz,?DMSO)?δ:?10.06?(s,?1H),?8.11?(d,?J?=?9.2?Hz,?1H),?7.80?(d,?J?=?9.3?Hz,?1H),?7.38?(t,?J?=?7.3?Hz,?2H),?7.31?(d,?J?=?7.1?Hz,?1H),?7.18?(s,?3H),?6.98?(s,?1H),?6.09?(s,?2H),?4.90?(s,?2H),?4.76?(s,?2H),?4.13?(s,?3H),?4.04?(s,?3H),?3.17?(s,?2H).?13C?NMR?(101?MHz,?DMSO)?δ:?150.69,?149.69,?146.88,?145.99,?144.74,?139.63,?137.64,?134.55,?133.23,?130.48,?129.57,?128.49,?127.27,?126.64,?122.15,?121.74,?120.49,?108.97,?108.60,?102.53,?62.55,?57.41,?35.98,?27.76.?ESI-MS?
m/z:?426?[M-I]
+。
the functional verification of berberinc derivate
2.1 cell cultures
C6 and U87 glioma cell are incubated at the DMEM high glucose medium of 10% foetal calf serum (FBS), at 5% CO
2, cultivate under the condition of 37 ℃.Every 48 h, change nutrient solution, the cultivation of going down to posterity.
migration test
Tryptic digestion is also collected C6 or U87 cell, and the DMEM nutrient solution that contains 10% FBS washs 3 times, the resuspended (cell count 2.5 * 10 of DMEM nutrient solution of serum-free
5/ mL).Evenly add the 100 supreme chambers of μ L cell suspension, add the drug solution of suitable concentration simultaneously; Lower chamber adds the DMEM nutrient solution 600 μ L containing 10% FBS.Meanwhile, with 96 orifice plates of same cell count, carry out MTT experiment to detect cell quantity variation.37 ℃, 5% CO
2cultivate after 24 h, chamber in taking-up, wipes upper ventricular cell with cotton swab, and 4% paraformaldehyde is fixed 30 min, 0.2% Viola crystallina dye liquor, 10 min that dye, and distillation washing three times, chooses at random 9 visuals field and takes the photograph sheet counting under microscope (* 200); Every group parallel establishes 3 apertures, and experiment repeats 3 times.Finally, the mobility evaluation of the transfer ability of cell, total cell count * 100% of MTT under mobility=migrating cell number/isoconcentration.Each ratio of organizing mobility and control group mobility is relative mobility.
invasion and attack test
Matrigel (BS Biosciences) 5 mL are placed in 4 ℃ and spend the night and thaw, with the serum-free DMEM nutrient solution of 4 ℃ of precoolings, according to DMEM:Matrigel=3:1, dilute, the Matrigel 50 μ L that get dilution add the upper chamber of Transwell of precooling, and 37 ℃ of incubation 4 h make gel formation.Below operation is same
2.2it is described that (upper chamber inoculating cell amount is 5 * 10
5/ 100 μ L).Finally, the invasive ability of cell is evaluated by invasion and attack rate, total cell count * 100% of MTT under invasion and attack rate=invasion and attack cell count/isoconcentration.Each organizes invasion and attack rate is relative invasion and attack rate with the ratio of control group invasion and attack rate.
Result as shown in Figure 1, compd B
7with compd B
8the cell count that group migrates to lower chamber be all less than control group (
pand compd B <0.05),
7migrating cell number minimum.
After drug treating, C6 cell is obviously less than control group through the cell count of Recombinant Artificial basilar membrane, and invasive ability is suppressed, difference have statistical significance (
p<0.05).Wherein, compd B
7with compd B
8group is obviously better than control group (bulk drug Berberine) to the restraining effect of invasion and attack, and compd B
7group is to the restraining effect of invasion and attack more obviously (Fig. 2).
Compound B-11 2(9-O-decane Berberine) and compd B as shown in Figure 3,
7the cell count that group migrates to lower chamber be all less than control group (
pand compd B <0.05),
7migrating cell number minimum.
As shown in Figure 4.After drug treating, U87 glioma cell is obviously less than control group through the cell count of Recombinant Artificial basilar membrane, and invasive ability is suppressed, difference have statistical significance (
p<0.05).Compound B-11 2(9-O-decane Berberine) and compd B wherein,
7group is obviously better than control group (bulk drug Berberine) to the restraining effect of invasion and attack, and compd B
7group is more obvious to the restraining effect of invasion and attack.
Above data are all applied SPSS 13.0 statistics software analysis.Average check adopts variance analysis,
p< 0.05 has statistical significance for difference.
Strong migration is the key factor that restriction glioblastoma patient obtains long lifetime with invasive ability.Yet current a large amount of cytotoxic drugs not only can not suppress migration and the invasion and attack of glioma effectively, contrary resistance, bone marrow depression effect limits its clinical application.Contriver finds Berberine lipophilic derivatives provided by the invention, and the lipotropy that increases Berberine can strengthen its restraining effect to the propagation of C6 and U87 glioma cell, migration and invasion and attack.Its mechanism it be unclear that, and possible is former because with respect to Berberine, derivative is enhanced to biomembranous cross-film effect, thereby has improved physiologically active.
3. the Mitochondrially targeted property of berberinc derivate
The C6 taking the logarithm vegetative period or U87 cell, with 4 * 10
5individual/ware is seeded at the bottom of the special-purpose glass of laser confocal microscope and cultivates 24h in culture dish.Remove substratum, add respectively the Berberine containing 1 μ M, the nutrient solution of 13-dodecyl Berberine or 13-dodecyl Berberine, hatches 24h.Suck supernatant liquor, PBS (pH 7.4) washing three times, with Mitotracker Green FM (500nM) dyeing 30min, ice-cold PBS washing three times, observes under laser confocal microscope and takes pictures.
Under laser co-focusing, observe, in C6 (Fig. 5 A) and U87 (Fig. 5 B) glioma cell Berberine and lipophilic derivatives thereof and plastosome, locate altogether.The plastosome of C6 and U87 glioma cell is by the mitotracker green location (be green) of dyeing, and carries out laser co-focusing observation after Berberine and derivative (being yellow) thereof are hatched 24 hours.In all stacking diagrams (combined), show, yellow have good ubcellular to locate altogether with green, is shown as yellow-green colour after stack.
In C6 cell, Berberine is comparatively evenly distributed in whole cell and (comprises tenuigenin and nucleus part), and fluorescence intensity a little less than, shown weak Mitochondrially targeted property.Comparatively speaking, berberinc derivate B8(13-dodecyl Berberine) and B9(13-dodecyl Berberine) fluorescence distribution overlaps substantially completely with mitotracker green fluorescence, in nucleus part, substantially there is no fluorescence, shown the Mitochondrially targeted property stronger compared with Berberine.In U87 cell, B8 and B9 not only navigate in the plastosome of cell exactly, and fluorescence intensity is stronger, show that it has been distributed to plastosome in large quantities, have shown than Mitochondrially targeted property stronger in C6 cell.
Claims (11)
1. the compound or its salt of formula (I),
formula (I),
Wherein R is C
10-C
18alkyl, or R is benzyl.
2. compound or its salt according to claim 1, wherein said R is C
10-C
18alkyl.
3. compound or its salt according to claim 1, wherein, R is C
10-C
14alkyl.
4. compound or its salt according to claim 1, wherein, R is decane base or dodecyl.
5. the compound or its salt described in any one according to claim 1 to 4, wherein said salt is selected from hydrobromate, hydriodate, hydrofluoride, hydrochloride, vitriol, nitrate, phosphoric acid salt, Citrate trianion, acetate and lactic acid salt.
6. compound or its salt according to claim 1, wherein said compound is selected from: 13-decane base Berberine, 13-dodecyl Berberine, 13-n-hexadecyl Berberine, 13-Octadecane base Berberine, and 13-benzyl Berberine.
7. a pharmaceutical composition, the compound or its salt that it contains one or more claims 1 for the treatment of significant quantity, and pharmaceutical excipient.
8. the compound or its salt of claim 1 is treated the purposes in glioblastoma medicine in preparation.
9. purposes according to claim 8, wherein said pharmaceutical pack is containing pharmaceutical excipient.
The compound or its salt of claim 1 in preparation the purposes in Mitochondrially targeted drug delivery system.
11. purposes according to claim 10, wherein said Mitochondrially targeted drug delivery system comprises at least one extra pharmaceutical cpd.
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| WO2021212691A1 (en) * | 2020-04-22 | 2021-10-28 | 山东大学 | Mitochondria targeting compound, preparation method therefor and use thereof |
| WO2023174381A1 (en) * | 2022-03-16 | 2023-09-21 | 南京施江医药科技有限公司 | Nitrogen-containing heterocyclic compound and use thereof |
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Cited By (6)
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| CN110960506A (en) * | 2018-09-28 | 2020-04-07 | 中山大学 | Nanosuppreparation for the treatment of diseases caused by mitochondrial dysfunction |
| WO2021212691A1 (en) * | 2020-04-22 | 2021-10-28 | 山东大学 | Mitochondria targeting compound, preparation method therefor and use thereof |
| WO2023174381A1 (en) * | 2022-03-16 | 2023-09-21 | 南京施江医药科技有限公司 | Nitrogen-containing heterocyclic compound and use thereof |
| WO2023174377A1 (en) * | 2022-03-16 | 2023-09-21 | 南京施江医药科技有限公司 | Tetracyclic compound and use thereof |
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