CN105218638A - The indoles quinolizine that RGDS modifies, its preparation, nanostructure, active and application - Google Patents
The indoles quinolizine that RGDS modifies, its preparation, nanostructure, active and application Download PDFInfo
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Abstract
The invention discloses (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of structure below.The regular abbreviation of Arg-Gly-Asp-Ser is RGDS.Disclose its preparation method, disclose its nanostructure, disclose its antitumor action, disclose the effect of its antitumor cell Adhesion, Invasion and migration, illustrate its application in medical science.
Description
Technical field
The present invention relates to (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser, the regular abbreviation of Arg-Gly-Asp-Ser is RGDS.Relate to its preparation method, relate to its nanostructure, relate to its inside and outside antitumor action, relate to the effect of its antitumor cell Adhesion, Invasion and migration.Thus the present invention relates to it and preparing antitumor drug, prepare the application in antitumor cell Adhesion, Invasion and migration medicine.The invention belongs to biomedicine field.
Technical background
The health of the malignant tumour serious threat mankind.Except self is severe to the prognosis of tumour patient, the inflammation of Complicated by Malignancy, thrombus and transfer worsen the prognosis of patient further.Such as, the malignant tumor patient more than more than 90% is all die from metastases.Metastases depends on 4 factors: 1) tumor cell surface forms microthrombus, escapes macrophage phagocytic, moves to far-end by blood circulation; 2) tumor cell adhesion of far-end is moved to vessel wall; 3) cell adhesion enters healthy tissues to the tumour cell of vessel wall by attacking out blood vessel.
Because existing antitumor drug does not possess anti-metastasis effect, so curative effect is undesirable.It is clinical active demand that invention has antitumor, anti-inflammatory, antithrombotic and inhibiting effect on tumor metastasis medicine simultaneously.
RGD tetrapeptide, namely RGDS, RGDF and RGDV are integrin alpha ∨ β
3blocker, there is antithrombotic and Anti cell adhesion active.Arg-Gly-Asp-Ser then possesses antitumor cell transporting action.Applicant is once RGD tetrapeptide and oestrogenic hormon coupling, and preparation does not have the osteoporosis agent of blood coagulation side effect.Applicant once prepared efficient antithrombotic agent RGD tetrapeptide and the coupling of tetrahydro-beta-carboline-3-carboxylic acid.Applicant is also once with the β-carboline-3-carboxylic acid that amino acid modified tetrahydro-beta-carboline-3-carboxylic acid, β-carboline-3-carboxylic acid and 1-position replace, and the β-carboline-3-carboxylic acid of the tetrahydro-beta-carboline-3-carboxylic acid or the replacement of l-position that comprise the replacement of 1-position prepares efficient antithrombotic agent or antineoplastic agent.Here is the representative of the structure type that contriver creates.Although contriver has paid large quantity research energy, screen hundreds of compound, never there is antitumor and compound that is inhibiting effect on tumor metastasis simultaneously.
Contriver is in the analysis structure of hundreds of compound and the basis of activity change; recognize Arg-Gly-Asp-Ser and (6S)-3-ethanoyl-4-oxo-4; 6; 7; 12-tetrahydro indole [2; 3-a] coupling of quinolizine-6-carboxylic acid, the compound of formation can have antitumor and inhibiting effect on tumor metastasis simultaneously.Based on this understanding, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of structure below.
Second content of the present invention is to provide the preparation method of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser, and the method comprises:
(1) under the existence of polyphosphoric acid, L-Trp and phenylcarbinol reaction, generate L-Trp benzyl ester;
(2) under the existence of trifluoroacetic acid, in methylene dichloride, 1,1,3,3-tetramethoxy propane and the ester condensation of L-Trp benzyl are (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
(3) in the presence of triethyl amine, ketene dimer and (3S)-1-(2 in acetone, 2-dimethoxy ethyl)-2, the condensation of 3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate is (3S)-1-(2,2-dimethoxy ethyl)-2-acetoacetyl-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
(4) under the existence of aqueous hydrochloric acid (2M), (3S)-1-(2 in acetone, 2-dimethoxy ethyl)-2-acetoacetyl-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate dioxide giving is (6S)-phenyl-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylicesters;
(5) under ice bath in the aqueous solution (2M) of NaOH and methyl alcohol, (6S)-phenyl-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylicesters is converted into (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylic acid;
(6) adopt progressively condensation method, under the existence of N, N-dicyclohexylcarbodiimide and N-hydroxyl benzotriazole, react in dry tetrahydrofuran, obtain full guard peptide sequence Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(7) under ice bath in the ethyl acetate solution (4M) of hydrogenchloride, full guard peptide sequence Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl removes Boc and obtain Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(8) under 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxyl benzotriazole exist; at anhydrous N; (6S)-3-ethanoyl-4-oxo-4 in dinethylformamide; 6; 7; 12-tetrahydro indole [2,3-a] quinolizine-6-carboxylic acid and Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl condensation is (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(9) under ice bath in trifluoroacetic acid and trifluoromethanesulfonic acid, (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl is converted into (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser.
3rd content of the present invention is the nanostructure measuring (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser.
4th content of the present invention evaluates the effect of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser extracorporeal suppression tumor cell propagation.
5th content of the present invention evaluates (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser to the restraining effect of mice bearing S180 tumor growth.
6th content of the present invention evaluates the effect of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser extracorporeal suppression tumor cell Adhesion, Invasion and migration.
Accompanying drawing explanation
Fig. 1. the structure type representative of the antithrombotic that contriver creates or active compound for anti tumor, in formula, AA is L-amino acid or glycine.
Fig. 2. the synthetic route of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Lys-Glu.(i) polyphosphoric acid, phenylcarbinol, 80 DEG C; (ii) 1,1,3,3-tetramethoxy propane, trifluoroacetic acid, methylene dichloride; (iii) ketene dimer, triethylamine, acetone; (iv) aqueous hydrochloric acid (2M), acetone; (v) NaOH aqueous solution (2M), methyl alcohol, 0 DEG C; (vi) 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxyl benzotriazole, methylene dichloride/DMF; (vii) trifluoroacetic acid, trifluoromethanesulfonic acid, 0 DEG C; (viii) N-hydroxyl benzotriazole, N, N-dicyclohexylcarbodiimide, N-methylmorpholine, tetrahydrofuran (THF); (ix) ethyl acetate solution (4M) of hydrogenchloride, 0 DEG C; (x) NaOH aqueous solution (2M), methyl alcohol, 0 DEG C.
Fig. 3. compound 7 is in pure water solution 1 × 10
-8transmission electron microscope photo under M concentration.
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares L-Trp benzyl ester phosphoric acid salt (1)
20.4g (100mmol) L-Trp, 120mmol phenylcarbinol and 120mmol polyphosphoric acid are added successively in 500ml eggplant bottle, bottleneck installs prolong, is placed in oil bath and is heated to 80 DEG C, react 72 hours, TLC shows raw material completely dissolve, and reaction terminates.Reaction solution is cooled to room temperature, adds 30ml anhydrous diethyl ether, separate out white solid, stir 2 hours, reaction solution filtration under diminished pressure, obtains white solid, wears away 3 times with anhydrous diethyl ether, obtains 35.4g (90.4%) target compound, is white solid.ESI-MS(m/e)：393.1[M+H]
+。
Embodiment 2 prepares (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate (2)
By 250mlCH
2cl
2add in 500ml eggplant bottle, add 15ml1 successively under ice bath, 1,3,3-tetramethoxy propane and 14ml trifluoroacetic acid, stir 0.5 hour, add 20.0g (68mmol) L-Trp benzyl ester, stirring at room temperature 120 hours, reaction terminates.Ice bath stirs in downhill reaction liquid and slowly adds saturated Na
2cO
3the aqueous solution, vigorous stirring is 7 to water layer pH, separate dichloromethane layer, dichloromethane layer 5%NaHCO
3the aqueous solution and saturated NaCl aqueous solution extraction wash 3 times, dichloromethane layer anhydrous Na
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and through purification by silica gel column chromatography, (sherwood oil: acetone=3: 1), obtains 9.38g (35%) target compound to residue, is colorless oil.ESI-MS(m/e)：395.2[M+H]
+。
Embodiment 3 prepares (3S)-1-(2,2-dimethoxy ethyl)-2-acetoacetyl-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate (3)
By 9.38g (23.8mmol) (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate is dissolved in 200ml acetone, and ice bath adds 2.89ml ketene dimer and 1.81ml triethylamine, stirring at room temperature 18 hours under stirring, TLC shows raw material completely dissolve, and reaction terminates.Ice bath adds 10ml distilled water under stirring, and stirs 1 hour, and concentrating under reduced pressure removes acetone, and residue dichloromethane extraction 3 times, combined dichloromethane layer, uses 5%NaHCO successively
3the aqueous solution and saturated NaCl aqueous solution extraction wash 3 times, dichloromethane layer anhydrous Na
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and through purification by silica gel column chromatography, (sherwood oil: acetone=4: 1), obtains 8.88g (78%) target compound to residue, is colorless oil.ESI-MS(m/e)：479.2[M+H]
+。
Embodiment 4 prepares (6S)-phenyl-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylicesters (4)
By 8.88g (18.6mmol) (3S)-1-(2; 2-dimethoxy ethyl)-2-acetoacetyl-2; 3; 4; 9-tetrahydro-beta-carboline-3-benzyl carboxylate is dissolved in 200ml acetone, and ice bath adds 2.83ml aqueous hydrochloric acid (2M), stirring at room temperature 24 hours under stirring; TLC shows raw material completely dissolve, and reaction terminates.Ice bath stirs the saturated NaHCO of lower slowly dropping
3the aqueous solution regulates pH to 7, and concentrating under reduced pressure removing acetone, residue with Ethyl acetate extracts three times, combined ethyl acetate layer, uses saturated NaHCO successively
3the aqueous solution, the saturated NaCl aqueous solution, 5%KHSO
4the aqueous solution, the saturated NaCl aqueous solution, 5%NaHCO
3the aqueous solution and the saturated NaCl aqueous solution respectively extract washes 3 times, ethyl acetate layer anhydrous Na
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and through purification by silica gel column chromatography, (sherwood oil: acetone=4: 1), obtains 3.98g (52%) target compound to residue, is yellow solid.ESI-MS(m/e)：413.1[M+H]
+。
Embodiment 5 prepares (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylic acid (5)
By 3.98g (9.66mmol) (6S)-phenyl-3-ethanoyl-4-oxo-4; 6; 7; 12-tetrahydro indole [2; 3-a] quinolizine-6-carboxylicesters is dissolved in 100ml methyl alcohol, and ice bath stirs the lower NaOH aqueous solution (2M) that slowly drips and regulates pH to 12, and ice bath stirs 96 hours; TLC shows raw material completely dissolve, and reaction terminates.Ice bath stirs the saturated KHSO of lower slowly dropping
4the aqueous solution regulates pH to 7, concentrating under reduced pressure removing methyl alcohol, and residue adds 5ml distilled water diluting, slowly drips saturated KHSO under ice bath stirs
4the aqueous solution regulates pH to 3, and separate out yellow solid, filtration under diminished pressure, distilled water flushing filter cake, drying to obtain 2.43g (78%) target compound, is yellow solid.
Mp: 205.3-207.1 DEG C;
iR (KBr): 3319,3061,2291,2927,2586,1743,1656,1587,1546,1496,1438,1425,1363,1330,1284,1236,1201,1145,1111,1029,972,852,781,746,624,567em
-1; ESI-MS (m/e): 323.1 [M+H]
+;
1h-NMR (500MHz, DMSO-d
6): δ/ppm=11.92 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.44 (d, J=10.0Hz, 1H), 7.28 (t, J=6.0Hz, 1H), 7.09 (t, J=6.0Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 5.96 (d, J=6.0Hz, 1H), 3.32 (dd, J
1=9.5Hz, J
2=24.5Hz, 2H), 2.55 (s, 3H) .HPLC: determined wavelength 254nm, 4.6 × 250mmC
18chromatographic column, moving phase CH
3oH: H
2o=3: 2, flow velocity: 0.6mL/min, purity 95.8%.
Embodiment 6 prepares HClArg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl
1) Boc-Asp (OBzl)-Ser (Bzl)-OBzl is prepared
2.16g (6.69mmol) Boc-Asp (OBzl) is dissolved in dry tetrahydrofuran, ice bath adds 1.65g (8.03mmol) N of 1.08g (8.03mmol) N-hydroxyl benzotriazole and dry tetrahydrofuran dissolving successively under stirring, N-dicyclohexylcarbodiimide, stir 0.5 hour, obtain reaction solution.2.58g (8.03mmol) HClSer (Bzl)-OBzl is dissolved in dry tetrahydrofuran, regulates pH to 8 with N-methylmorpholine, add in the reaction solution just obtained, pH to 9 is regulated with N-methylmorpholine, stirring at room temperature 6 hours, TLC shows raw material completely dissolve, and reaction terminates.Reaction solution filtration under diminished pressure, filtrate reduced in volume, residue with Ethyl acetate dissolves, and uses saturated NaHCO successively
3the aqueous solution, the saturated NaCl aqueous solution, 5%KHSO
4the aqueous solution, the saturated NaCl aqueous solution, 5%NaHCO
3the aqueous solution and the saturated NaCl aqueous solution respectively extract washes 3 times.Ethyl acetate layer anhydrous Na
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and through purification by silica gel column chromatography, (sherwood oil: acetone=6: 1), obtains 3.56g (90.1%) target compound to residue, is colorless oil.ESI-MS(m/e)：590.2[M+H]
+。
2) HClAsp (OBzl)-Ser (Bzl)-OBzl is prepared
3.00g (5.08mmol) Boc-Asp (OBzl)-Ser (Bzl)-OBzl is placed in 250ml eggplant bottle, ice bath adds the ethyl acetate solution (4M) of 120ml hydrogenchloride under stirring, bottleneck adds drying tube, ice bath stirs 1 hour, TLC shows raw material completely dissolve, and reaction terminates.Decompressing and extracting reaction solution, adds a small amount of dry ethyl acetate, then drains, and repeats 3 times; Add a small amount of anhydrous diethyl ether, decompressing and extracting, repeating 3 times, obtain 2.54g (95.0%) target compound, is colorless oil.ESI-MS(m/e)：527.5[M+H]
+。
3) Boc-Arg (NO is prepared
2)-Gly-OBzl
By the preparation method of Boc-Asp (OBzl)-Ser (Bzl)-OBzl, by 4.44g (13.90mmol) Boc-Arg (NO
2), 4.92g (14.60mmol) TosGly-OBzl, 2.25g (16.68mmol) N-hydroxyl benzotriazole and 3.44g (16.68mmol) N, N-dicyclohexylcarbodiimide is reacted, through purification by silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtaining 5.77g (89.1%) target compound, is white solid.ESI-MS(m/e)：467.2[M+H}
+。
4) Boc-Arg (NO is prepared
2)-Gly
By 3.00g (6.44mmol) Boc-Arg (NO
2)-Gly-OBzl is dissolved in methyl alcohol, ice bath stirs and slowly drips the NaOH aqueous solution (2M) down, and ice bath stirs 5 hours, and TLC shows raw material completely dissolve, and reaction terminates.Ice bath stirs the saturated KHSO of lower slowly dropping
4the aqueous solution regulates pH to 7, and concentrating under reduced pressure removing methyl alcohol, remaining aqueous solution slowly drips saturated KHSO under ice bath stirs
4the aqueous solution regulates pH to 3, extraction into ethyl acetate three times, combined ethyl acetate layer, washes 3 times, ethyl acetate layer anhydrous Na by saturated NaCl aqueous solution extraction
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and obtaining 2.28g (94.3%) target compound, is white solid.ESI-MS(m/e)：377.2[M+H]
+。
5) Boc-Arg (NO is prepared
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl
By the preparation method of Boc-Asp (OBzl)-Ser (Bzl)-OBzl, by 1.87g (4.99mmol) Boc-Arg (NO
2)-Gly, 2.50g (4.75mmol) HClAsp (OBzl)-Ser (Bzl)-OBzl, 0.77g (5.70mmol) N-hydroxyl benzotriazole and 1.17g (5.70mmol) N, N-dicyclohexylcarbodiimide is reacted, through purification by silica gel column chromatography (methylene dichloride: methyl alcohol=20: 1), obtaining 1.99g (49.4%) target compound, is white solid.ESI-MS(m/e)：849.2[M+H]
+。
6) HClArg (NO is prepared
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl
By the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, by 1.50g (1.77mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl, 18ml hydrogenchloride ethyl acetate solution (4M) reaction, obtaining 1.34g (96.3%) target compound, is white solid.ESI-MS(m/e)：749.3[M+H]
+。
Embodiment 7 prepares (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl (6)
By 0.322g (1.00mmol) (S)-3-ethanoyl-4-oxo-4, 6, 7, 12-tetrahydro indole [2, 3-a] quinolizine-6-carboxylic acid is dissolved in the anhydrous N of 3ml, dinethylformamide, ice bath adds 0.162g (1.20mmol) N-hydroxyl benzotriazole under stirring, 0.273g (1.20mmol) 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is dissolved in 3ml methylene dichloride, drip N-methylmorpholine and regulate pH to 7, add in above-mentioned reaction solution, stir and obtain reaction solution in 0.5 hour, by 0.824g (1.05mmol) HClArg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl is dissolved in 5ml methylene dichloride, ice bath stirs lower dropping N-methylmorpholine and regulates pH to 8, add in the reaction solution just obtained, slow dropping N-methylmorpholine regulates pH to 9, stirring at room temperature 20 hours, TLC shows raw material completely dissolve, and reaction terminates.Ice bath adds the saturated NaCl aqueous solution of 20ml under stirring, and reaction solution dichloromethane extraction 3 times, combined dichloromethane layer, uses saturated NaHCO successively
3the aqueous solution, the saturated NaCl aqueous solution, 5%KHSO
4the aqueous solution, the saturated NaCl aqueous solution, 5%NaHCO
3the aqueous solution and the saturated NaCl aqueous solution respectively extract washes 3 times, dichloromethane layer anhydrous Na
2sO
4drying, filtration under diminished pressure, filtrate reduced in volume is to dry, and through purification by silica gel column chromatography, (methylene dichloride: methyl alcohol=20: 1), obtains 0.368g (35.0%) target compound, is yellow solid.ESI-MS(m/e)：1052.2[M+H]
+。
Embodiment 8 prepares (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser (7)
By 0.350g (0.33mmol) (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-acyl group-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl is placed in 100ml eggplant bottle, ice bath adds 4ml trifluoromethanesulfonic acid and 1ml trifluoroacetic acid under stirring successively, and ice bath stirs 1 hour, and reaction terminates.Ice bath adds 50ml anhydrous diethyl ether under stirring, separate out yellow fluffy solid, centrifugal, ether washes 3 times, obtains yellow solid, 2ml distilled water is dissolved under ice bath, drip 1% ammoniacal liquor and be adjusted to pH=5, filtration under diminished pressure removing insolubles, filtrate is through C18 column chromatography purification (methyl alcohol: water=8: 1), obtaining 0.051g (20.8%) target compound, is yellow solid.Mp:238.1-240.5 DEG C,
iR (KBr): 3406,3379,3232,3076,2999,2966,2887,1666,1639,1589,1546,1494,1444,1406,1328,1274,1242,1111,1060,1029,871,833,742,655,628,520,497cm
-1, ESI-MS (m/e): 738.3 [M+H]
+,
1h-NMR (500MHz, DMSO-d
6): δ/ppm=11.92 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.44 (d, J=10.0Hz, 1H), 7.28 (t, J=6.0Hz, 1H), 7.09 (t, J=6.0Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 5.96 (d, J=6.0Hz, 1H), 4.86 (d, J=6.0Hz, 1H), 4.76 (d, J=6.0Hz, 1H), 4.55 (d, J=6.0Hz, 1H), 4.14-3.89 (m, 2H), 3.56 (m, 1H), 3.32 (dd, J
1=9.5Hz, J
2=24.5Hz, 2H), 2.86-2.81 (m, 2H), 2.65-2.55 (m, 5H), 1.79 (m, 2H), 1.55 (m, 2H) .HPLC: determined wavelength 254nm, 4.6 × 250mmC
18chromatographic column, moving phase CH
3oH: H
2o=4: 1, flow velocity: 0.6mL/min, purity 95.3%.
Experimental example 1 measures the transmission electron microscope photo under compound Plasma Concentration
By compound 7 according to 1 × 10
-8the concentration configuration pure water solution of M, is layered on uniformly on copper mesh, observes the self-assembly property of compound under transmission electron microscope (TEM, JEM-1230, JEOL).The photo obtained is as Fig. 2.Result shows, 7 can form nano particle in water, and diameter is 40-160nm.
Experimental example 2 measures the cytotoxicity of compound 7 pairs of tumour cells
1) substratum of compound 7 of the present invention containing 0.1%DMSO is mixed with desired concn.
2) tumour cell of experiment is HL60 (human leukemia cell), A549 (human lung carcinoma cell), HeLa (human cervical carcinoma cell), HCT-8 (human colon cancer cell), MCF-7 (human breast cancer cell), SH-sy5y (human neuroblastoma cells), Haca-T (people's immortalization epidermic cell) and S180 (mouse ascites oncocyte).
3) experimental technique HL60, A549, HeLa, HCT-8, MCF-7, S180 cell selects RPMI-1640 substratum; SH-sy5y, Haca-T select DMEM substratum.In substratum all containing 10% through the foetal calf serum and 1 × 10 of deactivation
5u/L penicillin and 100mg/L Streptomycin sulphate.
The cultivation of attached cell A549, HeLa, HCT-8, MCF-7, SH-sy5y, Haca-T and half attached cell S180: respectively by good for growth conditions, be in the cell of logarithmic phase with 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, and every hole 100 μ L, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours, then add by the concentration gradient preset the solution that the compound 7 through sterilising treatment is mixed with the substratum containing 0.1%DMSO, every hole 25 μ L, control group adds the solvent of isopyknic sample dissolution.Continue cultivation after 48 hours, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours.After careful removing supernatant liquor, every hole adds the dimethyl sulfoxide (DMSO) of 100 μ L, and vibrate about 15 minutes dissolve purple residues (first a ceremonial jade-ladle, used in libation), and in microplate reader, detect O.D. (absorbancy) value immediately, wavelength is 570nm.
The cultivation of suspension cell HL60: by good for growth conditions, be in the cell of logarithmic phase with 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, then adds by the concentration gradient preset the solution that the compound 7 through sterilising treatment is mixed with the substratum containing 0.1%DMSO, every hole 25 μ L, control group adds the solvent of isopyknic sample dissolution, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 48 hours.Every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours.3000 leave the heart 15 minutes, careful sucking-off supernatant liquor, and every hole adds the dmso solution purple powder (first a ceremonial jade-ladle, used in libation) of 100 μ L, and in microplate reader, detect O.D. (absorbancy) value immediately, wavelength is 570nm.
The activity of compound 5 inhibition tumor cell propagation under each concentration is obtained by following formula:
Cell proliferation (%)=(the average O.D. value of compound 7 groups average O.D. value/control group) × 100%, experiment repetition 3 times, maps to drug level with cell proliferation, obtains IC by graphing method
50(half effective inhibition concentration) value.
4) the results are shown in Table 1-2.Result shows, compound 7 pairs of HL60 cell proliferations have certain restraining effect, IC
50value is 72.88 μMs, to A549, HeLa, HCT-8, MCF-7, SH-sy5y, Haca-T and S180 etc. 7 strain tumour cell without obvious cytotoxicity.
Table 1. compound 7 is on the impact (IC of HL60, A549, HeLa and HCT-8 cell proliferation
50, mean value ± SD μM)
n＝15
Table 2. compound 7 is on the impact (IC of MCF-7, SH-sy5y, Haca-T and S180 cell proliferation
50, mean value ± SD μM)
n＝15
The anti-tumor in vivo of experimental example 3 assessing compound 7 is active
1) physiological saline solution of compound 7 tween 80 of the present invention, Zorubicin and cytosine arabinoside physiological saline solution are as positive control, and the physiological saline of tween 80 is as negative control;
2) the equal gastric infusion of the physiological saline of compound 7 and tween 80, the dosage of compound 7 is 0.1 μm of ol/kg, and the dosage of the physiological saline of tween 80 is 0.2mL/20g, successive administration 10 days, altogether administration 10 times; Zorubicin intraperitoneal administration, dosage is 2 μm of ol/kg, successive administration 10 days, altogether administration 10 times; Cytosine arabinoside intraperitoneal administration, dosage is 8.2 μm of ol/kg, successive administration 10 days, altogether administration 10 times.
3) laboratory animal is ICR male mice (cleaning grade), body weight 20 ± 2g, often organizes 15 mouse.
4) knurl source is mouse S 180 sarcoma, purchased from Department Of Medicine, Peking University's animal experimental center, and maintenance of going down to posterity voluntarily.
5) extract and inoculate eugonic S180 ascitic tumor knurl liquid under animal model and treatment aseptic condition, the liquid of (1: 2) is become fully to mix with normal saline dilution, by freshly prepared 0.2% Trypan Blue of tumor cell suspension, by white blood cell count(WBC) method counting after mixing, contaminate blue person for dead cell, tinter is not viable cell, and is calculated as follows cell concn and cell survival rate.
Viable count/4 × 10 in the block plaid of cell concn=4
4× extension rate=cell count/mL
Cell survival rate=viable count/(viable count+dead cell number) × 100%
Knurl liquid homogenate method survival rate being greater than 90% is prepared into 2.0 × 10
7the cell suspension of individual/mL, in the subcutaneous vaccination of mouse armpit, 0.2mL/ only, manufactures S180 tumor-bearing mice.After tumor inoculation 24h, treatment group mouse oral administration of compound every day 7, dosage is 0.1 μm of ol/kg.The physiological saline of naive mice oral 0.2mL tween 80 every day.Positive controls mouse abdominal injection every day Zorubicin and cytosine arabinoside, dosage is 2 μm of ol/kg and 8.2 μm ol/kg.Experiment proceeds to the 11st day, claim Mouse Weight, etherization, de-cervical vertebra puts to death mouse, then fixes the right armpit tumor location of mouse with tweezers, cuts off skin, expose tumour, blunt separation, weighs, and is calculated as follows tumour inhibiting rate: the average knurl of tumour inhibiting rate %=(the average knurl of negative control group heavy-the average knurl weight of compound 7 groups)/negative control group heavy × 100%.Experimental data adopts t inspection and variance analysis, knurl heavy with
represent.The results are shown in Table 3.As can be seen from Table 3, under the oral dosage of 0.1 μm of ol/kg, the knurl of compound 7 treatment group mouse weighs tool significant difference compared with physiological saline group, and tumour inhibiting rate is 56.5%.
The anti-tumor in vivo of table 3. compound 7 is active
N=15; A) P < 0.01 compared with physiological saline group, P > 0.05 compared with cytosine arabinoside group.
The extracorporeal anti-tumor cell adhesion activity of experimental example 4 assessing compound 5 and 7
1) the DMEM substratum of compound 5 and 7 containing 0.1%DMSO is mixed with the solution that concentration is 100 μMs.
2) cell is HCCLM3 (high-transfer human liver cancer cell).
3) Fn (people's fibronectin).
4) experimental technique
With PBS, Fn is mixed with the solution that concentration is 100 μ g/mL, adds in 96 well culture plates by 100 μ L/ holes, culture plate is placed in 4 DEG C of refrigerator overnight.Next day, absorb and do not wrap by Fn solution, wash 1 time with PBS, every hole adds the PBS solution 30 μ L shrouding containing 2%FBS, at 37 DEG C and 5%CO
2incubator in hatch 3 hours, discard each hole solution.By good for growth conditions, be in the HCCLM3 cell of logarithmic phase with 5 × 10
4the density of individual/mL is inoculated in bag by 96 orifice plates of Fn, and every hole 100 μ L, adds the solution of 25 μ L compounds 5 or 7 simultaneously, makes its final concentration be 20nM, at 37 DEG C and 5%CO
2cultivate 2 hours in incubator, wash away the cell do not adhered to PBS, after discarding PBS, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, is placed in 37 DEG C and 5%CO
2hatch 4 hours in incubator, after careful removing supernatant liquor, every hole adds 100 μ LDMSO, and vibrate about 10min dissolution precipitation, detects O.D. (absorbancy) value immediately under microplate reader 570nm wavelength.The calculation formula of adherence inhibition rate is as follows: adherence inhibition rate (%)=[1-(the OD value of the OD value/blank group cell of compound 7 groups of cells)] × 100%; Experimental data statistics all adopts t inspection and variance analysis, and adherence inhibition rate represents with mean value ± SD.
5) the results are shown in Table 4.As can be seen from Table 4, compound 7 obviously suppresses HCCLM3 cell and Fn to adhere under 20nM concentration, and adherence inhibition rate is 20.75%.Be 1 μM compared with suppressing SACC-LM cell with the effective concentration of ECM and platelet adhesion reaction with RGDS disclosed in contriver, the effective concentration of compound 7 reduces 50 times.
The extracorporeal anti-tumor cell adhesion activity of table 4. compound 7
N=15; A) with compound 5 groups than P < 0.01.
The extracorporeal anti-tumor cell-invasive activity of experimental example 5 assessing compound 5 and 7
1) the DMEM substratum of compound 5 and 7 containing 0.1%DMSO is mixed with the solution that concentration is 100 μMs.
2) cell is HCCLM3 (high-transfer human liver cancer cell).
3) matrigel is matrigel.
4) experimental technique
The frozen matrigel matrigel4 DEG C in-20 DEG C of refrigerators is spent the night, liquefy; Get 720 μ L plasma-free DMEM medium, add 180 μ LMatrigel, mixing, room on the polycarbonate membrane being added to Transwell cell, 100 μ L/, put into 37 DEG C and 5%CO
25h is hatched in incubator.Absorb residual liquid in cell, every hole adds 50 μ LDMEM substratum, 37 DEG C and 5%CO
230min is hatched in incubator.
After HCCLM3 cell dissociation, wash 3 times with plasma-free DMEM medium, counting, be made into cell suspension, density is 5 × 10
5individual/mL.Every hole adds 100 μ L cell suspensions, adds the solution that 25 μ L add 25 μ L compounds 5 or 7 simultaneously simultaneously, makes its final concentration be 20nM.Blank adds the solution that 25 μ L prepare containing the DMEM substratum of 0.1%DMSO.Lower room adds 600 μ L plasma-free DMEM medium, at 37 DEG C and 5%CO
2cultivate 48 hours in incubator.
Discard room nutrient solution, clean 3 times with phosphoric acid buffer, discard phosphoric acid buffer.Separately get one 96 orifice plates, every hole adds the cell dissociation buffer of 150 μ L preheatings, by placed on it for upper room, and 37 DEG C and 5%CO
2cultivate 30 minutes in incubator, period jolts several times in front and back gently, guarantees that cell departs from completely, it is mixed with lower room corresponding aperture inner cell.Added by Lysis/Dye dye liquor above-mentioned containing in 96 orifice plates of cell, every hole 50 μ L, room temperature lucifuge leaves standstill 15 minutes.150 μ L are drawn in special 96 orifice plates of fluorescence in every hole, read O.D. value by microplate reader on 480/520nm wavelength, and are calculated as follows the invasion and attack inhibiting rate of medicine to cell:
Invasion and attack inhibiting rate=[blank group O.D. value-administration group O.D. value]/blank group O.D. value × 100%.
Experimental data statistics all adopts t inspection and variance analysis, and invasion and attack inhibiting rate represents with mean value ± SD.
5) the results are shown in Table 5.Can find out, compound 7 can suppress HCCLM3 cell to the invasion and attack of ECM under 20nM concentration, and inhibiting rate is 60.40%.Be compared with in the of 1 μM with RGDS disclosed in contriver suppressing the effective concentration of SACC-LM cell invasion, the effective concentration of compound 7 reduces 50 times.
The extracorporeal anti-tumor cell-invasive activity of table 5. compound 7
N=15; A) with compound 5 groups than P < 0.01.
The extracorporeal anti-tumor cell migration of experimental example 6 assessing compound 5 and 7 is active
1) the DMEM substratum of compound 5 and 7 containing 0.1%DMSO is mixed with the solution that concentration is 100 μMs.
2) cell is HCCLM3 (high-transfer human liver cancer cell).
3) experimental technique
After HCCLM3 cell dissociation, wash 3 times with plasma-free DMEM medium, counting, be made into cell suspension, density is 2 × 10
6individual/mL.Every hole adds 100 μ L cell suspensions, adds the solution that 25 μ L add 25 μ L compounds 5 or 7 simultaneously simultaneously, makes its final concentration be 20nM.Blank adds the solution that 25 μ L prepare containing the DMEM substratum of 0.1%DMSO.Lower room adds 600 μ L plasma-free DMEM medium, at 37 DEG C and 5%CO
2cultivate 6 hours in incubator.
Wipe the cell of matrigel and upper indoor with cotton swab after, with the paraformaldehyde fixed cell 30min of 4%.Absorb stationary liquid, wash 3 times with PBS, with the Viola crystallina dye liquor dyeing 30min of 0.1%.Absorb staining fluid, wash 3 times with PBS.
Choose 9 roughly the same visuals field at each cell to observe, take pictures, counting.Experimental data statistics all adopts t inspection and variance analysis, and the cell count of invasion and attack represents with mean value ± SD.
4) the results are shown in Table 6.Can find out, compound 7 can suppress HCCLM3 cell migration under 20nM dosage, and inhibiting rate is 58.82%.Be compared with in the of 1 μM with GRDS disclosed in contriver suppressing the effective concentration of SACC-LM cell migration, the effective concentration of compound 7 reduces 50 times.
The extracorporeal anti-tumor cell migration of table 6. compound 7 is active
N=15; A) with compound 5 groups than P < 0.01.
Claims (5)
1. (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of structure below.
2. the preparation method of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of claim 1, the method is made up of following steps:
(1) under the existence of polyphosphoric acid, L-Trp and phenylcarbinol reaction, generate L-Trp benzyl ester;
(2) under the existence of trifluoroacetic acid, in methylene dichloride, 1,1,3,3-tetramethoxy propane and the ester condensation of L-Trp benzyl are (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
(3) in the presence of triethyl amine, ketene dimer and (3S)-1-(2 in acetone, 2-dimethoxy ethyl)-2, the condensation of 3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate is (3S)-1-(2,2-dimethoxy ethyl)-2-acetoacetyl-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
(4) under the existence of aqueous hydrochloric acid (2M), (3S)-1-(2 in acetone, 2-dimethoxy ethyl)-2-acetoacetyl-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate dioxide giving is (6S)-phenyl-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylicesters;
(5) under ice bath in the aqueous solution (2M) of NaOH and methyl alcohol, (6S)-phenyl-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylicesters is converted into (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-carboxylic acid;
(6) adopt progressively condensation method, under the existence of N, N-dicyclohexylcarbodiimide and N-hydroxyl benzotriazole, react in dry tetrahydrofuran, obtain full guard peptide sequence Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(7) under ice bath in the ethyl acetate solution (4M) of hydrogenchloride, full guard peptide sequence Boc-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl removes Boc and obtain Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(8) under 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxyl benzotriazole exist; at anhydrous N; (6S)-3-ethanoyl-4-oxo-4 in dinethylformamide; 6; 7; 12-tetrahydro indole [2,3-a] quinolizine-6-carboxylic acid and Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl condensation is (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl;
(9) under ice bath in trifluoroacetic acid and trifluoromethanesulfonic acid, (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg (NO
2)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl is converted into (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser.
3. the nanostructure of (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of claim 1.
4. (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of claim 1 is preparing the application in antitumor drug.
5. (6S)-3-ethanoyl-4-oxo-4,6,7,12-tetrahydro indole [2,3-a] quinolizine-6-formyl-Arg-Gly-Asp-Ser of claim 1 is preparing the application in antitumor cell Adhesion, Invasion and migration medicine.
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