CN105777790B - A kind of adjacent carborane phenol derivatives and its preparation method and application - Google Patents
A kind of adjacent carborane phenol derivatives and its preparation method and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000002989 phenols Chemical class 0.000 title claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- SLGWESQGEUXWJQ-UHFFFAOYSA-N formaldehyde;phenol Chemical compound O=C.OC1=CC=CC=C1 SLGWESQGEUXWJQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920001568 phenolic resin Polymers 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims abstract description 3
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 65
- -1 ester hydrochloride Chemical class 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 229910000085 borane Inorganic materials 0.000 claims description 11
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 9
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- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical group OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- YPGXBBWRDMCJCM-JIZZDEOASA-N N=NC=NN.N=NC=NN.N[C@H](C(=O)O)CC(=O)O Chemical compound N=NC=NN.N=NC=NN.N[C@H](C(=O)O)CC(=O)O YPGXBBWRDMCJCM-JIZZDEOASA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- CZNJCCVKDVCRKF-UHFFFAOYSA-N Benzyl sulfate Chemical compound OS(=O)(=O)OCC1=CC=CC=C1 CZNJCCVKDVCRKF-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- PPPHYGCRGMTZNA-UHFFFAOYSA-N trifluoromethyl hydrogen sulfate Chemical compound OS(=O)(=O)OC(F)(F)F PPPHYGCRGMTZNA-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 23
- BXRMEWOQUXOLDH-LURJTMIESA-N L-Histidine methyl ester Chemical compound COC(=O)[C@@H](N)CC1=CN=CN1 BXRMEWOQUXOLDH-LURJTMIESA-N 0.000 abstract description 5
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- SWWBMHIMADRNIK-VKHMYHEASA-N (3s)-3-azaniumyl-4-methoxy-4-oxobutanoate Chemical compound COC(=O)[C@@H]([NH3+])CC([O-])=O SWWBMHIMADRNIK-VKHMYHEASA-N 0.000 abstract description 2
- SEWIYICDCVPBEW-BYPYZUCNSA-N L-glutamate methyl ester Chemical group COC(=O)[C@@H](N)CCC(O)=O SEWIYICDCVPBEW-BYPYZUCNSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 150000003254 radicals Chemical class 0.000 description 27
- 238000000034 method Methods 0.000 description 16
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- 150000004702 methyl esters Chemical class 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 239000012153 distilled water Substances 0.000 description 11
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 10
- 229910052796 boron Inorganic materials 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
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- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
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- MFUPLHQOVIUESQ-JEDNCBNOSA-N [(2s)-1,5-dimethoxy-1,5-dioxopentan-2-yl]azanium;chloride Chemical compound Cl.COC(=O)CC[C@H](N)C(=O)OC MFUPLHQOVIUESQ-JEDNCBNOSA-N 0.000 description 1
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- 150000001414 amino alcohols Chemical class 0.000 description 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- LTEHWCSSIHAVOQ-UHFFFAOYSA-N tripropyl borate Chemical compound CCCOB(OCCC)OCCC LTEHWCSSIHAVOQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of adjacent carborane phenol derivatives and its preparation method and application, the adjacent carborane phenol derivatives has the general structure as shown in formula (I).The preparation method, including：In organic solvent, under enzyme and acid condition, adjacent carborane phenol formaldehyde (PF) reacts with secondary amine acid esters, obtains the adjacent carborane derivative shown in formula (I)；Described two level propylhomoserin fat is glutamic acid methyl ester, aspartate methylester or histidine methylester.The invention also discloses the application of the adjacent carborane phenol derivatives.The invention discloses a kind of new adjacent carborane phenol derivatives, such compound is capable of being gathered in tumour cell of high concentration, and has hypotoxicity.
Description
Technical field
The present invention relates to antitumoral compounds, especially a kind of adjacent carborane phenol derivatives, its preparation method and application.
Background technology
Boron neutron capture therapy (BNCT) is exactly first by a kind of boracic (B10) compound injection to human body, passes through blood circulation
Into intracellular, because selected boron-containing compound and cancer, knurl has affinity characteristic, it is only enriched in lesion cancer or tumour is thin
In born of the same parents.Due to tissue barrier effect, B10It is few even to enter in normal cell tissue.When with neutron beam irradiate disease
When becoming position, B10(n、α)Li7Reaction generates the α particles and Li of high linear energy transfer7Core, they can kill the cancer of≤10 μ scopes
Or tumour cell, you can to use targeting dual nature (B in cell dimensions10Concentration, the energy of neutron streaming and strong
Degree) regulation, be that any conventional treatments are unrivaled in principle.
BNCT can realize strong targeting, the binary (boronation of high linear energy transfer (LET) in cell dimensions (micron order)
Medicine, neutron beam) radiotherapy, current surgical operation, radiotherapy, chemistry are superior in the principle for the treatment of malignant brain tumor and is treated
Method, immunotherapy and gene therapy, it is distinguished accurately to normal cell and cancer cell physics, is currently to control to human zero damage
Unique effective ways of glioma are treated, BNCT has turned into the focus that international nuclear medicine circle falls over each other research since turning into the nineties, I
State's blank so far.Treat various cancers and tumour with this therapy in the world at present turns into customary therapy, and particularly Japan is in the world
On occupy absolute technical advantage, home interior major medical institutions of Japan, generally carry out BNCT in research institute and colleges and universities
Clinical Treatment Test, and other internal organs tumours such as liver cancer, lung cancer, cancer of pancreas, prostate cancer, breast cancer are controlled with examination.By half a lifetime
The clinical practice of discipline, boron neutron capture therapy are founded the unprecedented record that 8 annual survival rates reach 42% in Japan, have been classified as first
Standard technique.Cranium is not opened, treats the extensive experimentation that deep position brain tumor D BNCT technologies have gone through clinical first and second stage,
Just march toward the phase III, i.e. efficacy experiment.In a word, " neutron capture therapy " (BNCT) is the new neck of modern age treatment of cancer research
Domain, have a extensive future.
In boron neutron capture therapy, when being given with therapeutically effective amount, boron-containing compound must be nontoxic or tool
There is hypotoxicity.Although BPA has the advantage of low chemical toxicity, the accumulated concentrations in tumor tissues are relatively low, limit it
Using.Therefore, to overcome above-mentioned BPA the defects of, it is necessary to develop new boron-containing compound.
The content of the invention
Goal of the invention：For problems of the prior art, the invention provides a kind of new adjacent carborane phenol to spread out
Biology, such compound is capable of being gathered in tumour cell of high concentration, and has hypotoxicity.
Technical scheme：A kind of adjacent carborane phenol derivatives, it has the general structure as shown in formula (I)：
Wherein, R is
●=C,
Zero=BH.
The invention also discloses the preparation method of described adjacent carborane phenol derivatives, including：
In organic solvent, under enzyme and acid condition, 2- aldehyde radical phenol borines react with secondary amine acid esters, obtain formula (I)
Shown adjacent carborane derivative；Wherein, the structure of the 2- aldehyde radicals phenol borine is：
●=C, zero=BH；
Described two level propylhomoserin fat is glutamic acid methyl ester, aspartate methylester or histidine methylester.
Described organic solvent includes one kind or several in benzene, dimethyl benzene, dimethylether, tetrahydrofuran and toluene
Kind.
Described enzyme includes sodium cyanoborohydride, cyano group potassium borohydride, tripropoxy sodium borohydride and tripropoxy-boron hydrogen
Change the one or more in potassium.
Acid includes formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, to benzyl sulfuric acid, methylsulfuric acid, trifluoroacetic acid with
One or more in trifluoromethyl sulfuric acid.
The reaction time is 24~48 hours, and reaction temperature is 120~150 DEG C.
The mol ratio of the organic solvent and adjacent carborane phenol formaldehyde (PF) is 5~10：1；Enzyme and adjacent carborane phenol formaldehyde (PF)
Mol ratio be 1~1.5：1.
The invention also discloses application of the described adjacent carborane phenol derivatives in antineoplastic is prepared.
Described medicinal application is in BNCT therapies.
A kind of medicine, include described adjacent carborane phenol derivatives.
Compared with prior art, beneficial effects of the present invention include：
The invention provides a kind of new adjacent caborane compounds, such compound low toxicity, can high concentration be gathered in tumour
In cell, therefore it individually or with other auxiliary elements pharmaceutically can be prepared antineoplastic, be treated for boron neutron absorption
In method treating cancer.
Preparation method route of the present invention is reasonable, and simply, reaction is easily-controllable, and yield is preferable.
Brief description of the drawings
Fig. 1 is each Compound Cytotoxicity result figure of embodiment 5；
Fig. 2 is that each compound boron of embodiment 5 absorbs result figure.
Embodiment
With reference to specific embodiment, the present invention is furture elucidated.
The synthetic reaction formula of neighbour's carborane phenol derivatives of the embodiment of the present invention is：
The structural formula of 1~compound of compound 4 respectively is：
●=C, zero=BH.
The hydrogen general survey test instrument used in the present invention in embodiment is：Burker 300Hz.
2- aldehyde radical phenol borine is known compound, and its synthetic method is referring to (New types of potential BNCT
agents,o-carboranyl aminoalcohols；Author is Chai-Ho Lee a, *, Guo Fan Jin etc.；Journal title
Referred to as：Tetrahedron Letters, 50 (2009) 2960-2963).
The preparation of the compound 1 (the double glutamic acid phenol borine methyl esters of 2- methyl) of embodiment 1
Method 1：Weigh 0.5g, 2- aldehyde radical phenol borine (Tetrahedron Letters, 50 (2009) 2960-2963),
Pidolidone diformazan ester hydrochloride (No. CAS is 23150-65-4) 0.5g is added, is added in two mouthfuls of bottles and is dissolved in dimethyl benzene
Among 100ml, sodium cyanoborohydride 0.18g is added, formic acid 3 drips, and temperature rises to 150 DEG C of reaction 48h, after question response, temperature
Degree is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and is extracted, obtained organic addition
Enter MgSO4To dry, filtrated stock is evaporated under reduced pressure to obtain 0.48g, the double glutamic acid phenol borine methyl esters=yields 46% of 2- methyl, with
2- aldehyde radical phenol borine meters.Detection parameters are：
1H-NMR:2.77 (t, J=5.5Hz, 2H), 3.26 (s, 3H), 3.43 (t, J=5.5Hz, 2H), 3.48 (s, 3H),
3.50 (t, J=5.4Hz, 2H), 3.62 (s, 3H), 3.72 (t, J=5.4Hz, 2H), 3.87 (s, 2H), 5.04 (s, 1H),
6.67-6.68 (d, J=8.5Hz, 1H), 7.32 (s, 1H), 7.36-7.38 (d, J=8.7Hz, 1H).
Method 2：0.5g is weighed, 2- aldehyde radical phenol borines, Pidolidone diformazan ester hydrochloride 0.5g is added, is added to two mouthfuls
It is dissolved in bottle among paraxylene 100ml, adds cyano group potassium borohydride 0.23g, acetic acid 3 drips, and temperature rises to 120 DEG C of reaction 48h,
After question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and is extracted
Take, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.47g, the double glutamic acid phenol borines of 2- methyl
Methyl esters=yield 46%, in terms of 2- aldehyde radical phenol borines.
Method 3：0.5g is weighed, 2- aldehyde radical phenol borines, Pidolidone diformazan ester hydrochloride 0.5g is added, is added to two mouthfuls
It is dissolved in bottle among paraxylene 100ml, adds sodium triacetoxyborohydride 0.37g, trifluoroacetic acid 3 drips, and temperature rises to 120 DEG C
48h is reacted, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml
Extracted, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.44g, the double glutamic acid benzene of 2- methyl
Phenol borine methyl esters=yield 43%, in terms of 2- aldehyde radical phenol borines.
The preparation of the compound 2 (preparation of 2- methyl glutamic acid phenol borine methyl esters) of embodiment 2
Method 1：0.5g is weighed, 2- aldehyde radical phenol borines, Pidolidone diformazan ester hydrochloride 0.25g is added, is added to two
It is dissolved in mouth bottle among dimethyl benzene 100ml, adding sodium cyanoborohydride 0.18g, formic acid 3 drips, and temperature rises to 150 DEG C of reactions
48h, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and carries out
Extraction, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.47g, 2- methyl glutamic acid phenol borines
Methyl esters=yield 59%, in terms of 2- aldehyde radical phenol borines.
1H-NMR:2.68 (t, J=5.5Hz, 2H), 3.28 (s, 3H), 3.41 (t, J=5.4Hz, 2H), 3.45 (s, 3H),
3.88 (s, 2H), 5.06 (s, 1H), 6.68-6.69 (d, J=8.5Hz, 1H), 7.30 (s, 1H), 7.34-7.35 (d, J=
8.6Hz,1H)。
Method 2：0.5g is weighed, 2- aldehyde radical phenol borines, Pidolidone diformazan ester hydrochloride 0.25g is added, is added to two
It is dissolved in mouth bottle among paraxylene 100ml, adds cyano group potassium borohydride 0.23g, trifluoroacetic acid 3 drips, and temperature rises to 120 DEG C instead
Answer 48h, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and enters
Row extraction, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.45g, 2- methyl glutamic acid phenol boron
Alkane methyl esters=yield 56%, in terms of 2- aldehyde radical phenol borines.
Method 3：0.5g is weighed, 2- aldehyde radical phenol borines, Pidolidone diformazan ester hydrochloride 0.25g is added, is added to two
It is dissolved in mouth bottle among paraxylene 100ml, adds sodium cyanoborohydride 0.18g, acetic acid 3 drips temperature and rises to 120 DEG C of reactions
48h, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and carries out
Extraction, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.43g, 2- methyl glutamic acid phenol borines
Methyl esters=yield 53%, in terms of 2- aldehyde radical phenol borines.
The preparation of the compound 3 (2- methylaspartic acid phenol borines methyl esters) of embodiment 3
Method 1：0.5g is weighed, 2- aldehyde radical phenol borines, adding L-Aspartic acid diformazan ester hydrochloride, (No. CAS is
32213-95-9) 0.46g, it is added in two mouthfuls of bottles and is dissolved among dimethyl benzene 100ml, adding sodium cyanoborohydride 0.18g,
Formic acid 3 drips, and temperature rises to 150 DEG C of reaction 48h, and after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distillation
Water 100ml is extracted with dichloromethane 100ml, and obtained organic solvent adds MgSO4Dry, filtrated stock is evaporated under reduced pressure to
To 0.55g, 2- methylaspartic acid phenol borines methyl esters=yield 71%, in terms of 2- aldehyde radical phenol borines.Detection parameters are：
1H-NMR:2.71 (s, 2H), 3.24 (s, 3H), 3.40 (s, 2H), 3.78 (s, 3H), 5.01 (s, 1H), 6.65-
6.67 (d, J=8.5Hz, 1H), 7.29 (s, 1H), 7.33-7.35 (d, J=8.6Hz, 1H).
Method 2：0.5g is weighed, 2- aldehyde radical phenol borines, L-Aspartic acid diformazan ester hydrochloride 0.46g is added, is added to
It is dissolved in two mouthfuls of bottles among paraxylene 100ml, adds cyano group potassium borohydride 0.23g, methylsulfuric acid (No. CAS is 75-75-2) 3
Drop, temperature rise to 120 DEG C of reaction 48h, and after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water
100ml is extracted with dichloromethane 100ml, and what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain
0.52g, 2- methylaspartic acid phenol borine methyl esters=yield 67%, in terms of 2- aldehyde radical phenol borines.
Method 3：0.5g is weighed, 2- aldehyde radical phenol borines, L-Aspartic acid diformazan ester hydrochloride 0.46g is added, is added to
It is dissolved in two mouthfuls of bottles among paraxylene 100ml, adds sodium cyanoborohydride 0.23g, acetic acid 3 drips, and temperature rises to 120 DEG C of reactions
48h, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and carries out
Extraction, what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.50g, 2- methylaspartic acid phenol boron
Alkane methyl esters=yield 64%, in terms of 2- aldehyde radical phenol borines.
The preparation of the compound 4 (2- methylhistidin phenol borines methyl esters) of embodiment 4
Method 1：0.5g is weighed, 2- aldehyde radical phenol borines, it is each to add histidine methylester (No. CAS is 6459-59-2) 0.48g
It is dissolved in from being added in two mouthfuls of bottles among dimethyl benzene 100ml, adding sodium cyanoborohydride 0.18g, formic acid 3 drips, temperature liter
To 150 DEG C of reaction 48h, after question response, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane
Alkane 100ml is extracted, and what is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure to obtain 0.48g, 2- methyl groups
Propylhomoserin phenol borine methyl esters=yield 62%, in terms of 2- aldehyde radical phenol borines.
1H-NMR:3.35 (s, 3H), 3.46 (s, 2H), 3.86 (s, 3H), 5.08 (s, 1H), 6.69-6.70 (d, J=
8.4Hz, 1H), 6.98 (s, 1H), 7.32 (s, 1H), 7.35-7.36 (d, J=8.4Hz, 1H), 8.25 (s, 1H).
Method 2：0.5g, 2- aldehyde radical phenol borines are weighed, addition histidine methylester 0.48g is each added to molten in two mouthfuls of bottles
Among paraxylene 100ml, cyano group potassium borohydride 0.23g is added, methylsulfuric acid 3 drips, and temperature rises to 120 DEG C of reaction 48h, band
After completion of the reaction, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and is extracted,
What is obtained organic is added to MgSO4Dry, filtrated stock is evaporated under reduced pressure and each obtains 0.45g, 2- methylhistidin phenol borines
Methyl esters=yield 58%, in terms of 2- aldehyde radical phenol borines.
Method 3：0.5g, 2- aldehyde radical phenol borines are weighed, addition histidine methylester 0.48g is each added to molten in two mouthfuls of bottles
Among to dimethyl benzene 100ml, sodium cyanoborohydride 0.18g is added, formic acid 3 drips, and temperature rises to 150 DEG C of reaction 48h, treats anti-
After answering, temperature is down to room temperature, is evaporated under reduced pressure solvent, adds distilled water 100ml and dichloromethane 100ml and is extracted, is obtained
The organic solvent arrived adds MgSO4Dry, filtrated stock is evaporated under reduced pressure and each obtains 0.46g, 2- methylhistidin phenol borines
Methyl esters=yield 59%, in terms of 2- aldehyde radical phenol borines.
Embodiment 5
Biological activity test of the adjacent carborane oxybenzene compound of the present invention in colon cancer cell.
Measure for compound related performance indicators is this area routine universal method.
1st, toxicity
Under different sample concentrations, after 48h is administered, by general mtt assay detection compound to colon cancer cell CT26
Growth inhibition situation, finally calculates IC50, by 50% (IC50), caused with suppressing the drug concentration needed for cell survival from half
Dead amount determines, and result represent average value ±..
MTT is tetramethyl azo azoles salt, is that one kind can receive hydrionic weld.Amber in living cells mitochondria
Acidohydrogenase (succinate dehydrogenase) and cromoci (cytochromeC), MTT generation bluish violets can be made
First a ceremonial jade-ladle, used in libation (formazan) crystallizes and separates out precipitation, and dead cell is without this function.The first a ceremonial jade-ladle, used in libation crystallization of generation is dissolved in dimethyl sulfoxide (DMSO)
(DMSO) after, the light absorption value of solution at 490nM or 570nM can be determined by enzyme-linked immunosorbent assay instrument, to monitor the generation of first a ceremonial jade-ladle, used in libation
Amount.And the growing amount of first a ceremonial jade-ladle, used in libation crystallization is directly proportional to viable count, therefore influence of the medicine to cell viability can be detected.This method because
High sensitivity, it is economical the features such as, be widely used in screening anti-tumor medicine test in.
Specifically experimental method is：5 × 10 are made into after colon cancer cell digestion centrifugation3Individual/mL cell suspension, in 96 holes
100 μ L cell suspensions are added in plate per hole, after cellar culture 24h, suck original fluid, add 200 μ L configured it is different terraced
Compound -1,2 of concentration is spent, each concentration of 3,4 or BPA samples does 4 multiple holes, the hole PBS sealing of holes of 96 orifice plate surroundings, and stays
Go out negative control group and blank control group, after compound effects 72h, the μ L of MTT solution 20 are added per hole, continue to cultivate 4h, carefully
Culture medium in hole is abandoned in suction, adds DMSO150 μ L concussion 10min, the OD values in each hole are determined at ELIASA 490nM, are counted as the following formula
Calculate inhibiting rate of the sample under various concentrations：Inhibiting rate=(control wells OD values-dosing holes OD values)/control wells OD values ×
100%.Finally, the IC50 values of sample are calculated using related software.
As a result as shown in figure 1 and table 1, the compounds of this invention to the toxicity of cell well below BPA.
The IC50 of 1 different compounds of table
2nd, boron absorbs
P-35 cells (5 × 103Cell) deposited in various compounds -1,2,3,4 or BPA (unified B concentration is 10.8ppm)
In lower administration processing 12 hours, after processing terminates, phosphate buffered saline solution was washed three times, then using inductively coupled plasma
Atomic emission spectrum (ICP-AES) determines intracellular boron concentration.Value be average value ±.
As a result as shown in table 2, the compounds of this invention can be accumulated in tumour cell, in addition to compound 3, other compounds
B concentration is above BPA.
Table 2
Claims (8)
1. a kind of adjacent carborane phenol derivatives, it is characterised in that it has the general structure as shown in formula (I)：
Wherein, R is
●=C,
Zero=BH.
2. the preparation method of adjacent carborane phenol derivatives according to claim 1, it is characterised in that including：Organic
In solvent, under accelerator and acid condition, 2- aldehyde radical phenol borines react with secondary amine acid esters, obtain the adjacent carbon shown in formula (I)
Borane derivative；Wherein, the structure of the 2- aldehyde radicals phenol borine is：
●=C, zero=BH；
Described two level propylhomoserin fat is Pidolidone diformazan ester hydrochloride, L-Aspartic acid diformazan ester hydrochloride or histidine first
Ester；Described accelerator is selected from sodium cyanoborohydride, cyano group potassium borohydride, tripropoxy sodium borohydride and tripropoxy hydroboration
One or more in potassium.
3. preparation method according to claim 2, it is characterised in that described organic solvent is selected from benzene, dimethyl benzene, two
One or more in Methyl ether, tetrahydrofuran and toluene.
4. preparation method according to claim 2, it is characterised in that acid is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid,
Nitric acid, to benzyl sulfuric acid, methylsulfuric acid, the one or more in trifluoroacetic acid and trifluoromethyl sulfuric acid.
5. preparation method according to claim 2, it is characterised in that the reaction time is 24~48 hours, and reaction temperature is
120~150 DEG C.
6. preparation method according to claim 2, it is characterised in that accelerator and the mol ratio of adjacent carborane phenol formaldehyde (PF)
For 1~1.5：1.
7. application of the adjacent carborane phenol derivatives according to claim 1 in antineoplastic is prepared.
8. a kind of medicine, it is characterised in that include adjacent carborane phenol derivatives as claimed in claim 1.
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