CN107686507A - RGDS adriamycins, it is synthesized, activity and application - Google Patents
RGDS adriamycins, it is synthesized, activity and application Download PDFInfo
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- CN107686507A CN107686507A CN201610634499.0A CN201610634499A CN107686507A CN 107686507 A CN107686507 A CN 107686507A CN 201610634499 A CN201610634499 A CN 201610634499A CN 107686507 A CN107686507 A CN 107686507A
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- adriamycin
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- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 title claims abstract description 26
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 title claims abstract description 19
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 title claims abstract description 19
- 230000000694 effects Effects 0.000 title abstract description 17
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims abstract description 79
- 229940009456 adriamycin Drugs 0.000 claims abstract description 35
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- -1 glutaryl Chemical group 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 238000012546 transfer Methods 0.000 claims abstract description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- 108010089975 arginyl-glycyl-aspartyl-serine Proteins 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 4
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 3
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- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 3
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- 150000001412 amines Chemical class 0.000 description 3
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 3
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 3
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- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
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- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 1
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- 108010082126 Alanine transaminase Proteins 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
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- 230000002526 effect on cardiovascular system Effects 0.000 description 1
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- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1019—Tetrapeptides with the first amino acid being basic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Using glutaryl it is linking arm by 3 NH of adriamycin the invention discloses following formula2The compound (abbreviation RGDS adriamycins) connected and composed with RGDS, discloses its preparation method, discloses its anti-Lewis lung cancer metastasis activity, discloses it to treating the superiority of mouse survival state and internal organs security than adriamycin.Thus the invention discloses its application in medicine for anti transfer of tumor is prepared.
Description
Technical field
The present invention relates to be linking arm by 3 NH of adriamycin using glutaryl2The compound connected and composed with RGDS is (referred to as
RGDS- adriamycins), it is related to its preparation method, is related to its anti-Lewis lung cancer metastasis activity, is related to it to treatment mouse life
Deposit the superiority of state and internal organs security than adriamycin.Thus the invention discloses it in medicine for anti transfer of tumor is prepared
Using.The invention belongs to biomedicine field.
Background technology
Malignant tumour serious threat human health, the death rate of malignant tumour are only second to cardiovascular and cerebrovascular disease, in all diseases
Second is occupied in disease.Malignant tumor patient is mostly with metastasis of cancer.The Lung metastases of metastasis of cancer, especially cancer face tumor patient
More severe prognosis.Invention has antitumor and Anticancer metastasis action medicine simultaneously, is the advanced subject of new drug discovery.It is many
Well known, clinically adriamycin, which is widely used in, treats a variety of solid tumors and neoplastic hematologic disorder.But the hepatotoxicity wind agitation of adriamycin, kidney
Toxicity and cardiac toxic have a strong impact on the clinical efficacy of adriamycin.Once took various chemical modifications, attempt to reduce Ah
Hepatotoxicity wind agitation, renal toxicity and the cardiac toxic of mycin.But, effect is little.Such as the patent having is by the carboxyl and amino of lysine
3 bit aminos of adriamycin and the carboxyl of cholic acid are connected respectively.But this patent is not disclosed in this connection on animal model
Mode has any advantage in terms of antitumor activity, anti-inflammatory activity and toxicity.In order to confirm whether reasonable, the inventor of this connection
Connected mode according to it is prepared for the carboxyl of lysine and amino connects 3 bit aminos of adriamycin and the carboxyl of cholic acid respectively
Compound.Although inventor has repeated anti-tumour cell proliferative activity disclosed in the patent on cell model,
The carboxyl of lysine and amino connect 3 ammonia of adriamycin respectively on S180 mouse tumor models and ear swelling inflammation mouse model
The compound of the carboxyl of base and cholic acid is really without any activity.In addition, not carrying out structural modification to adriamycin so far causes
The report of anti-tumor metastasis.In order to invent with the effect of antitumor Lung metastases, the hepatotoxicity wind agitation that adriamycin has been completely eliminated, kidney poison
The doxorubicin derivative of property and cardiac toxic, inventor groped by 5 years.Inventor has found, by RGDS to N-terminal amino and Ah mould
Element 3 bit aminos be connected respectively with glutaryl generate compound have on Lewis lung cancer tumor-bearing mice metastasis models it is anti-
Metastasis of cancer activity, and hepatotoxicity wind agitation, renal toxicity and the cardiac toxic of adriamycin is completely eliminated.Carried according to this discovery inventor
The present invention is gone out.
The content of the invention
What first content of the present invention was to provide following formula is linking arm by 3 NH of adriamycin using glutaryl2With RGDS
The compound (abbreviation RGDS- adriamycins) connected and composed.
Second content of the present invention is to provide the synthetic method of RGDS- adriamycins, and this method includes:
(1) dicyclohexylcarbodiimide (DCC) is used as condensing agent, and 1- hydroxy benzo triazoles (HOBt) are catalyst
The method of liquid phase condensations, synthesis Boc-Arg (NO2)-Gly-OBzl;
(2) the C-terminal protection group for sloughing Boc-Arg (NO2)-Gly-OBzl prepares Boc-Arg (NO2)-Gly;
(3) dicyclohexylcarbodiimide (DCC) is used as condensing agent, and 1- hydroxy benzo triazoles (HOBt) are catalyst
The method of liquid phase condensations, synthesize Boc-Asp (OBzl)-Ser-OBzl;
(4) the N-terminal protection group for sloughing Boc-Asp (OBzl)-Ser-OBzl prepares Asp (OBzl)-Ser-OBzl;
(5) Boc-Arg (NO2)-Gly and Asp (OBzl)-Ser-OBzl couplings prepare Boc-Arg (NO2)-Gly-Asp
(OBzl)-Ser-OBzl;
(6) Boc-Arg (NO are removed in trifluoracetic acid/trifluoromethanesulfonic acid2)-Gly-Asp (OBzl)-Ser-OBzl institute
There is protection group to prepare Arg-Gly-Asp-Ser (RGDS);
(7) 3 '-NH of adriamycin2It is coupled glutaric acid generation monoamides;
(8) 3 '-NH of adriamycin2It is coupled glutaric acid and generates monoamides in DCC, n-hydroxysuccinimide (HOSu) condition
The lower 3 '-NH for forming adriamycin2It is coupled the active esters of glutaryl amine OSu;
(9) 3 '-NH of adriamycin2The coupling active esters of glutaryl amine OSu are condensed to yield with Arg-Gly-Asp-Ser
The Arg-Gly-Asp-Ser- glutaryls-- NH of adriamycin -3 '2(RGDS- adriamycins).
The 3rd content of the present invention is to evaluate the Anti-tumor metastasis activity of RGDS- adriamycins.
The 4th content of the present invention is that evaluation single-bolus high-dose gives RGDS- adriamycins to mouse survival state and each dirty
The influence of device.
Brief description of the drawings
The synthetic route of Fig. 1 .RGDS- adriamycins.I) dicyclohexyl carbonyl diimine (DCC), 1- hydroxy benzo triazole
(HOBt), anhydrous tetrahydro furan (THF), N-methylmorpholine (NMM), ice bath;Ii) sodium hydroxide-methanol solution (1M), ice bath;
Iii) hydrogen chloride-ethyl acetate solution (6M), ice bath;Iv) trifluoracetic acid:Trifluoromethanesulfonic acid 3:1, ice bath;V) glutaric anhydride
(GA), diisopropylethylamine (DIPEA), anhydrous N,N-dimethylformamide (DMF), ice bath, lucifuge;Vi) N- hydroxysuccinimidyls acyl
Imines (HOSu), DCC, dry DMF, ice bath, lucifuge;Vii) dry DMF, DIPEA, ice bath, lucifuge.
Influence of Fig. 2 .RGDS- adriamycins to mouse survival rate.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares Boc-Arg (NO2)-Gly-OBzl(1)
By 9.58g (30mmol) Boc-Arg (NO2) dissolved with 150mL anhydrous tetrahydro furans (THF), ice bath stirring, Xiang get
To solution in sequentially add 4.25g (31.5mmol) N- hydroxy benzo triazoles (HOBt) and the rings of 7.42g (31.3mmol) two
Hexyl carbonyl diimine (DCC), 10min is stirred under ice bath.10.6g (36mmol) TosGly-OBzl is added, uses N-methylmorpholine
(NMM) pH 8 is adjusted, 8h is stirred at room temperature.TLC (methylene chloride/methanol, 15:1) monitoring reaction is completed.Reactant mixture decompression is dense
Contracting, yellow oil are washed with petroleum ether, stand and abandon supernatant.Residue 250mL ethyl acetate dissolves, and crosses and filters out dicyclohexyl
Urea (DCU).Filtrate uses 5%NaHCO successively3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution washes 2 times, 5%KHSO4The aqueous solution washes 3
Secondary, the saturation NaCl aqueous solution washes 2 times, 5%NaHCO3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution is washed 3 times (100mL/ times).Second
Acetoacetic ester mutually uses anhydrous Na2SO4It is dried overnight, filters, filtrate decompression concentration, yellow oil adds 200mL dichloromethane to dissolve,
Ultrasound, stand.It is filtered under diminished pressure, collects colorless powder filter cake.Filtrate decompression concentrates, and residue purifies (dichloromethane through column chromatography
Alkane/methanol, 35:1).Column chromatography purified and colorless powder filter cake merge, and 13.4g (96%) colorless powder mark is obtained
Inscribe compound.ESI-MS(m/e):467[M+H]+。
Embodiment 2 prepares Boc-Arg (NO2)-Gly(2)
By 20.0g (42.9mmol) Boc-Arg (NO2)-Gly-OBzl is dissolved in 100mL methanol, ice bath stirring, use hydrogen
Sodium oxide molybdena-methanol solution (1M) adjusts pH 12, ice bath stirring 5h.TLC (methylene chloride/methanol, 15:1, add 2 drop glacial acetic acid) prison
Reaction is surveyed to complete.Reaction solution saturation KHSO4PH7 is neutralized to, is concentrated under reduced pressure and removes methanol, it is water-soluble that residue adds 50mL distillations
Solution, washed 2 times with 100mL ethyl acetate extraction afterwards.Water layer saturation KHSO4PH 2 is acidified to, 3 are extracted with 100mL ethyl acetate
It is secondary.Ethyl acetate phase is concentrated under reduced pressure into about 150mL, is washed 3 times with the 50mL saturation NaCl aqueous solution, uses anhydrous Na2SO4It is dried overnight,
Filtering, filtrate decompression are concentrated to dryness, and obtain 9.03g (56%) colorless powder title compound.ESI-MS(m/e):375[M-
H]-。
Embodiment 3 prepares Boc-Asp (OBzl)-Ser-OBzl (3)
By 12.9g (40mmol) Boc-Asp (OBzl) the anhydrous THF dissolvings of 150mL, ice bath stirring, 5.67g is sequentially added
(42mmol) HOBt and 9.89g (48mmol) DCC.Reaction solution ice bath stirs 10min, adds 9.22g (42mmol) TosSer-
OBzl, pH 8 is adjusted with NMM, 8h is stirred at room temperature.TLC (methylene chloride/methanol, 20:1, add 2 drop glacial acetic acid) monitor and reacted
Into.Reactant mixture is concentrated under reduced pressure, and yellow oil is washed with petroleum ether, is stood and is abandoned supernatant.Residue 250mL ethyl acetate
Dissolving, cross and filter out DCU.Filtrate uses 5%NaHCO successively3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution washes 2 times, 5%KHSO4It is water-soluble
Liquid is washed 3 times, and the saturation NaCl aqueous solution washes 2 times, 5%NaHCO3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution washes 3 (100mL/
It is secondary).Ethyl acetate phase anhydrous Na2SO4It is dried overnight, filters, after filtrate decompression concentration, residue purifies (dichloro through column chromatography
Methane/methanol, 30:1) 8.14g (41%) colorless powder title compound, is obtained.ESI-MS(m/e):501[M+H]+。
Embodiment 4 prepares HClAsp (OBzl)-Ser-OBzl (4)
24.4g (48.8mmol) Boc-Asp (OBzl)-Ser-OBzl is dissolved in 200mL hydrogen chloride-ethyl acetate solution
In (6M), and ice bath stirring 8h, TLC (methylene chloride/methanol, 15:1) monitoring reaction is completed.Ice bath stirs, and adds the anhydrous second of 250mL
Ether, filtering, obtains 18.4g (86%) colorless powder title compound.ESI-MS(m/e):401[M+H]+。
Embodiment 5 prepares Boc-Arg (NO2)-Gly-Asp(OBzl)-Ser-OBzl(5)
By 7.90g (21mmol) Boc-Arg (NO2)-Gly anhydrous THF and 40mL the N,N-dimethylformamides of 60mL
(DMF) dissolve, stirred under ice bath.Obtained solution adds 2.97g (22mmol) HOBt and 4.94g (24mmol) DCC successively.Reaction
Liquid ice bath stirs 10min, adds 8.74g (20mmol) HClAsp (OBzl) Ser-OBzl, adjusts pH 8 with NMM, is stirred at room temperature
8h.TLC (methylene chloride/methanol, 10:1, add 2 drop glacial acetic acid) monitoring reaction completion.Reactant mixture is concentrated under reduced pressure, yellow oil
Shape thing is washed with petroleum ether, is stood and is abandoned supernatant.Residue 200mL ethyl acetate dissolves, and crosses and filters out DCU.Filtrate is successively with 5%
NaHCO3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution washes 2 times, 5%KHSO4The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution is washed 2 times,
5%NaHCO3The aqueous solution is washed 3 times, and the saturation NaCl aqueous solution is washed 3 times (70mL/ times).Ethyl acetate phase anhydrous Na2SO4It is dried
Night, filtering, filtrate decompression concentration, purify through column chromatography (methylene chloride/methanol, 40:1) 12.4g (41%) colourless powder, is obtained
Shape title compound.ESI-MS(m/e):757[M+H]+。
Embodiment 6 prepares Arg-Gly-Asp-Ser (6)
By 1g (1.32mmol) Boc-Arg (NO2)-Gly-Asp (OBzl)-Ser-OBzl is dissolved in 12mL trifluoracetic acids
(TFA) in, ice bath is stirred to dissolve to achromaticity and clarification, adds 4mL trifluoromethanesulfonic acids (TFMSA), reacts 40min, TLC (EA/
H2O/HAc,2:1:1) monitoring reaction is completed.Decompression extracts acid gas 10min, ice bath stirring, pours into advance the new of ice bath cooling and opens
Absolute ether is sealed, is stood, is abandoned supernatant, be concentrated under reduced pressure.Obtained khaki powder is under ice bath plus the dissolving of 2mL tri-distilled waters, use are dense
Ammoniacal liquor adjusts pH and freezed to neutrality, filtering, filtrate with SephadexG-10 desalinations, fraction, obtains 513mg (90%) colorless powder
Title compound.1H NMR(300MHz,D2O):δ/ppm=4.57 (dd, J=8.4Hz, J=4.5Hz, 1H), 4.18 (t, J=
4.5Hz, 1H), 4.062-3.884 (m, 3H), 3.76 (d, J=4.8Hz, 2H), 3.15 (t, J=6.75Hz, 2H), 2.66 (dd,
J=16.2Hz, J=4.5Hz, 1H), 2.55 (dd, J=16.2Hz, J=8.4Hz, 1H), 1.88 (m, 2H), 1.63 (m, 2H);
ESI-MS(m/e):434[M+H]+。
Embodiment 7 prepares adriamycin -3 '-amino-glutaryl amine (7)
1.16g (2mmol) doxorubicin hydrochloride is dissolved in 10mL dry DMFs, ice bath stirring, 500 μ L diisopropyls are added dropwise
Base ethamine (DIPEA), addition 228mg (2mmol) glutaric anhydride, ice bath stirring 24h, TLC (methylene chloride/methanol, 15:1, add 2
Drip glacial acetic acid) monitoring reaction completion.Reactant mixture is washed with petroleum ether-ether, and standing abandons supernatant, obtained dark red oil
(methylene chloride/methanol, 30/1) is purified through column chromatography, obtains 731mg (56%) red powder title compound.ESI-MS
(m/e):656[M-H]-。
Embodiment 8 prepares adriamycin -3 '-amino-active esters of glutaryl amine-OSu (8)
By 1.05g (1.6mmol) adriamycin -3 '-amino-glutaryl amine solvent in 10mL dry DMFs, ice bath stirs
Mix, add 202mg (1.76mmol) HOSu, add 272mg (1.92mmol) DCC, ice bath stirring 24h, TLC (methylene chloride/methanol,
15:1, add 2 drop glacial acetic acid) monitoring reaction completion.Reactant mixture is washed with petroleum ether-ether, is stood and is abandoned supernatant, what is obtained is dark
Red oil purify through column chromatography (methylene chloride/methanol, 30:1) 791mg (33%) red powder title compound, is obtained
Thing.ESI-MS(m/e):753[M-H]-。
Embodiment 9 prepares Arg-Gly-Asp-Ser- glutaryls-- NH of adriamycin -3 '2(RGDS- adriamycins)
755mg (1mmol) adriamycin -3 '-amino-glutaryl amine-OSu is dissolved in 12mL dry DMFs, added
500mg (1.15mmol) RGDS, ice bath stirring, with DIPEA adjust pH 8, ice bath stirring 48h, TLC (acetonitrile/water/acetic acid, 5/
1/1) monitoring reaction is completed.Reactant mixture is washed with petroleum ether-ether, is stood and is abandoned supernatant, and obtained dark red solid is through half
Post purifying (acetonitrile/water/acetic acid, 20/1 adds 1 ‰ acetic acid) is prepared, it is lyophilized to obtain 42mg (4%) red powder title compound.
ESI-MS(m/e):1071.390[M-H]-.Mp:224-225℃;IR(cm-1):
3281.91,2937.50,1722.93,1639.30,1537.51,1405.02,1280.38,1233.05,1207.84,
1017.67,982.29,785.32,762.97;1H NMR(800MHz,DMSO-d6):δ/ppm=13.984 (s, 1H), 13.227
(s, 1H), 9.857 (s, 1H), 8.520 (d, J=8.0Hz, 1H), 8.417 (s, 1H), 7.993 (s, 1H), 7.874 (d, J=
7.2Hz, 1H), 7.858 (s, 1H), 7.605 (d, J=7.2Hz, 1H), 7.535 (d, J=8.0Hz, 1H), 7.328 (s, 1H),
7.024(s,2H),5.438(s,1H),5.217(s,1H),4.911(s,1H),4.859(s,1H),4.581(s,2H),4.433
(dd, J=12.8Hz, J=5.6Hz, 1H), 4.204-4.164 (m, 2H), 3.984 (m, 2H), 3.966 (s, 3H), 3.770 (m,
1H),3.617-3.543(m,3H),3.411(s,2H),3.129(m,1H),2.9987-2.884(m,3H),2.560(m,1H),
2.431 (m, 1H), 2.204 (d, J=13.6Hz, 1H), 2.104-2.027 (m, 5H), 1.878-1.829 (m, 2H), 1.655-
1.628 (m, 2H), 1.572 (m, 1H), 1.509 (m, 1H), 1.434 (m, 2H), 1.131 (d, J=6.4Hz, 3H);13C NMR
(200MHz,DMSO-d6):δ/ppm=214.28,186.92,186.82,173.35,172.58,171.61,170.94,
169.11,161.22,157.65,156.55,154.95,136.64,135.95,135.06,134.50,120.40,120.16,
119.42,111.19,111.05,100.90,75.42,70.37,68.56,67.16,64.16,62.47,57.02,55.71,
52.75,50.08,45.39,42.99,40.95,37.04,35.18,34.87,32.51,30.15,30.02,25.13,
22.07,21.55,17.49;HPLC purity be 99% (mobile phase is acetonitrile/water/acetic acid, 20/1 plus 1 ‰ acetic acid;Chromatographic column is
Watres5 μm of MS C18,2.1 × 150mm Column;Flow velocity is 0.3mL/min, UV=478nm;Retention time
For 9.3min).
Embodiment 10 evaluates the activity of resisting tumor metastasis of RGDS- adriamycins
Lewis murine lung cancer cells (LLC), purchased from ATCC.From DMEM high glucose medium cultures, contain 10% in culture medium
Hyclone through inactivation and 1 × 105U/L penicillin and 100mg/L streptomysins.According to attached cell cultural method, every two days
Passage once, passes on enrichment of cell three times.When cell growth state it is good, in exponential phase when, vitellophag.Use physiology
Salt solution adjusts cell concentration to 1 × 107Viable count is shown in individual/mL, trypan blue exclusion experiment>95%.Take inbred strais male
C57BL/6 mouse, with 75% ethanol disinfection mouse right fore skin of axillary fossa, subcutaneously noted in the right armpit of mouse with 1mL asepsis injectors
Tumor cell suspension is penetrated, 0.2mL/ only (is about 2 × 10 containing tumor cell number6Individual/only).Diameter can be grown into about within 14 days after inoculation
2cm tumour, it is standby.14 days well-grown Lewis lung cancer tumor-bearing mices of inoculation are taken, after etherization at cervical dislocation
Extremely, with 75% ethanol soaking disinfection 5min, knurl body, the good tumor tissue of growth selection, sterile are peeled off on superclean bench
Shred, be positioned in glass tissue homogenizer in plate, added in the ratio that tumor mass weight (g)/physiological saline volume (mL) is 1/3
The physiological saline of 4 DEG C of precoolings is lightly ground, and cell suspension is made, and crosses 200 mesh nylon wires and single cell suspension is made, use physiological saline
Cell concentration is adjusted to 1 × 107Individual/mL.Male inbred strais C57BL/6 mouse are taken, left hand fixes mouse, with 75% ethanol disinfection
Mouse right fore skin of axillary fossa, the right hand hold 1mL asepsis injectors and tumor cell suspension 0.2mL are subcutaneously injected (containing swollen in mouse armpit
Oncocyte number is about 2 × 106Individual/only).The big tumour of mung bean grain can be grown within 8 days after inoculation, measures gross tumor volume, screening
The homogeneous mouse of gross tumor volume is grouped at random.Negative control is physiological saline, intraperitoneal injection, once a day, 0.2mL/20g, and even
Continuous administration 12 days, is administered 12 times altogether.Positive control is adriamycin, intraperitoneal injection, once a day, 2 μm of ol/kg, successive administration 12
My god, it is administered 12 times altogether.Positive control is RGDS, intraperitoneal injection, once a day, 20 μm of ol/kg, successive administration 12 days, administration altogether
12 times.The RGDS- adriamycins of the present invention, intraperitoneal injection, once a day, 0.2 μm of ol/kg, successive administration 12 days, are administered 12 altogether
It is secondary.Each group mouse weighed body weight (body weight before execution) in the 13rd day, plucks eyeball and takes blood, blunt through being taken off after etherization at cervical vertebra
Property peel off and tumour and weigh Take out neoplasm metastasis number on lung and number lung.Data are included in table 1.As a result show,
0.2 μm of ol/kg RGDS- adriamycin can significantly inhibit Lewis lung cancer metastasis to the tubercle of lung as 20 μm of ol/kg RGDS
Number, it is that RGDS suppresses Lewis lung cancer metastasis to lung to illustrate that adriamycin-RGDSg suppresses Lewis lung cancer metastasis to the activity of lung
Active 200 times.And adriamycin does not suppress Lewis lung cancer metastasis to the activity of lung.Illustrate, in the way of the present invention
The amino of 3 bit aminos and RGDS that connect adriamycin respectively with glutaryl can strengthen RGDS and adriamycin Lewis lung cancer metastasis extremely
The activity of lung.
Influence of the table 1RGDS- adriamycins to Lewis lung cancer tumor-bearing mice metastases
N=12;A) p is compared with physiological saline group<0.01;B) p is compared with physiological saline group>0.05;C) p is compared with physiological saline group
<0.01, compare p with 20 μm of ol/kg RGDS groups>0.05.
The single-bolus high-dose of embodiment 11 gives toxicity of the RGDS- adriamycins to mouse
Body weight is 20~22g ICR male mices, and adaptability is fed 2 days, is randomly divided into physiological saline group, adriamycin group
With RGDS- adriamycin groups, every group 10.Three groups of mouse difference disposable celiac injecting normal salines, 34.5 μm of ol/kg adriamycins
With 34.5 μm of ol/kg RGDS- adriamycins.Continuous Observation 6 days afterwards, observe diet, fur and energy of each group mouse etc..
Record body weight and survival rate daily.Eyeball is plucked after being weighed in the 6th day and takes blood, is centrifuged after standing 2h in 4 DEG C of refrigerators, centrifuging temperature 10
DEG C, rotating speed 3000r/min, centrifugation 15min takes supernatant, turns with glutamic-pyruvic transaminase (ALT) kit measurement Serum ALT, with millet straw
Ammonia enzyme (AST) kit measurement serum AST;Surveyed with urea nitrogen (BUN) kit measurement serum BUN, with creatinine (Cr) kit
Determine change of serum C r;With creatine kinase isozyme (CK-MB) kit measurement Serum CK-MB, surveyed with lactic dehydrogenase (LDH) kit
Determine Serum LDH, serum cTnI is determined with cardiac muscle troponin I (cTnI) enzyme-linked immunologic detecting kit, with mouse myoglobins
(MB) enzyme-linked immunologic detecting kit measure serum MB.
Measurement result shows, physiological saline group and RGDS- adriamycin group mouse ingest normal, movable normal, hair smoothing,
Mouse 100% survives.Adriamycin group mouse engender hair is dry and astringent, reduction of ingesting, the phenomenon of activity reduction, the 5th day dead 1
Only, the 6th day dead 6, survival rate 30%.
Influence of the RGDS- adriamycins to mice serum ALT and AST is shown in Table 2.It is different from adriamycin, 34.5 μm of ol/
KgRGDS- adriamycins do not raise Serum ALT and AST, without hepatotoxicity.
Fig. 2 shows that single-bolus high-dose is to physiological saline group in the 6 day time of observation post administration and RGDS- adriamycin group mouse
Without death, survival rate 100%.Dead 2 of adriamycin group the 5th day, the 6th day dead 5, to the 6th day survival rate only 30%.
Influence of the table 2RGDS- adriamycins to mice serum ALT and AST
Adriamycin group n=3, physiological saline group and CBAORGDS groups n=10;A) p is compared with physiological saline group<0.01;B) with
Adriamycin group compares p<0.01, compare p with physiological saline group>0.05.
Influence of the RGDS- adriamycins to mice serum is shown in Table 3.It is different from adriamycin, 34.5 μm of ol/kg RGDS- adriamycins
Change of serum C r and BUN are not raised, without Toxicity of Kidney.
Influence of the table 3RGDS- adriamycins to mice serum Cr and BUN
Adriamycin group n=3, physiological saline group and CBAORGDS groups n=10;A) p is compared with physiological saline group<0.01;B) with
Adriamycin group compares p<0.01, compare p with physiological saline group>0.05.
Influence of the RGDS- adriamycins to mice serum CK-MB, LDH, cTnI and MB is shown in Table 4.It is different from adriamycin, 34.5 μ
Mol/kg RGDS- adriamycins do not raise Serum CK-MB, LDH, cTnI and MB, without cardiac toxic.
Influence of the table 4RGDS- adriamycins to mice serum CK-MB, LDH, cTnI and MB
Adriamycin group n=3, physiological saline group and CBAORGDS groups n=10;A) p is compared with physiological saline group<0.01;B) with
Adriamycin group compares p<0.01, compare p with physiological saline group>0.05.
In a word, the amino of 3 bit aminos and RGDS that connect adriamycin respectively with glutaryl in the way of the present invention can increase
The activity of resisting tumor metastasis of strong adriamycin, can strengthen RGDS activity of resisting tumor metastasis, liver, the kidney of adriamycin has been completely eliminated
And cardiac toxic.Thus, present invention obtains unexpected technique effect.
Claims (3)
1. following formula is linking arm by 3 NH of adriamycin using glutaryl2The compound connected and composed with RGDS,
2. claim 1 is linking arm by 3 NH of adriamycin using glutaryl2With the preparation of the RGDS compounds connected and composed
Method, this method include:
(1) dicyclohexylcarbodiimide (DCC) is used as condensing agent, and 1- hydroxy benzo triazoles (HOBt) are the liquid phase of catalyst
The method of condensation, synthesis Boc-Arg (NO2)-Gly-OBzl;
(2) the C-terminal protection group for sloughing Boc-Arg (NO2)-Gly-OBzl prepares Boc-Arg (NO2)-Gly;
(3) dicyclohexylcarbodiimide (DCC) is used as condensing agent, and 1- hydroxy benzo triazoles (HOBt) are the liquid phase of catalyst
The method of condensation, synthesize Boc-Asp (OBzl)-Ser-OBzl;
(4) the N-terminal protection group for sloughing Boc-Asp (OBzl)-Ser-OBzl prepares Asp (OBzl)-Ser-OBzl;
(5) Boc-Arg (NO2)-Gly and Asp (OBzl)-Ser-OBzl couplings prepare Boc-Arg (NO2)-Gly-Asp
(OBzl)-Ser-OBzl;
(6) Boc-Arg (NO are removed in trifluoracetic acid/trifluoromethanesulfonic acid2)-Gly-Asp (OBzl)-Ser-OBzl all guarantors
Protect base and prepare Arg-Gly-Asp-Ser (RGDS);
(7) 3 '-NH of adriamycin2It is coupled glutaric acid generation monoamides;
(8) 3 '-NH of adriamycin2It is coupled glutaric acid generation monoamides shape under the conditions of DCC, n-hydroxysuccinimide (HOSu)
Into 3 '-NH of adriamycin2It is coupled the active esters of glutaryl amine OSu;
(9) 3 '-NH of adriamycin2The coupling active esters of glutaryl amine OSu are condensed to yield Arg- with Arg-Gly-Asp-Ser
The Gly-Asp-Ser- glutaryls-- NH of adriamycin -3 '2(RGDS- adriamycins).
3. claim 1 is linking arm by 3 NH of adriamycin using glutaryl2Prepared with the compound that RGDS is connected and composed
Application in medicine for anti transfer of tumor.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998017319A2 (en) * | 1996-10-21 | 1998-04-30 | Quadrant Healthcare (Uk) Limited | Platelet substitutes and conjugation methods suitable for their preparation |
CN1800238A (en) * | 2005-12-05 | 2006-07-12 | 中国科学院长春应用化学研究所 | Aliphatic polyester-polyamino acids copolymer with biological function and its synthesis method |
CN103908677A (en) * | 2014-04-04 | 2014-07-09 | 南京医科大学 | Tumor targeted polypeptide-adriamycin amycin derivative as well as preparation method and application thereof |
-
2016
- 2016-08-05 CN CN201610634499.0A patent/CN107686507B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998017319A2 (en) * | 1996-10-21 | 1998-04-30 | Quadrant Healthcare (Uk) Limited | Platelet substitutes and conjugation methods suitable for their preparation |
CN1800238A (en) * | 2005-12-05 | 2006-07-12 | 中国科学院长春应用化学研究所 | Aliphatic polyester-polyamino acids copolymer with biological function and its synthesis method |
CN103908677A (en) * | 2014-04-04 | 2014-07-09 | 南京医科大学 | Tumor targeted polypeptide-adriamycin amycin derivative as well as preparation method and application thereof |
Non-Patent Citations (2)
Title |
---|
KE WANG ET AL.,: "Tumor penetrability and anti-angiogenesis using iRGD-mediated delivery of doxorubicin-polymer conjugates", 《BIOMATERIALS》 * |
顾玲等: "RGD类肽抑制高转移舌癌细胞粘附、迁移的实验研究", 《口腔颌面外科杂志》 * |
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