CN105315332A - CIPPC-AA-OBzl, and preparation, nano structure, activity and application thereof - Google Patents
CIPPC-AA-OBzl, and preparation, nano structure, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (5aS,12S,14aS)-5,14-dione-12-(2-tryptophanyl amino acid benzyl ester-ethyl-1-yl)-1,2,3,5,5a,6,11,12,14,14a-decahydro-5H,14H-pyrrole[1,2:4,5]-pyrazino[1,2:1,6]pyridino[3,4-b]indole, and a preparation method, a nano structure and an anti-tumor effect thereof, and discloses applications of the compound in medicine.
Description
Technical field
The present invention relates to (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine also [1,2:1,6] pyrido [3,4-b] indoles (being called for short CIPPC-AA-OBzl).Relate to their preparation method, relate to their nanostructure, relate to their antitumor action, illustrate their application in medical science.The invention belongs to biomedicine field.
Technical background
Biological nano system can be observed intuitively.The progress of nanotechnology decades is in the past mainly reflected in delivery system, as liposome.Contriver is devoted to the small molecules nanostructure developed, and is the invention being totally independent of delivery system.
It is one of conditioning agent main in fibrinolytic system that the urokinase type plasminogen activator (uPA) that plasminogen activation (PA) system comprises is not only, and closely related with tumour.In a lot of malignant tumour, the overexpression of uPA can make tumor progression.Lower the potential strategy that uPA has become cancer therapy and prophylaxis of tumours transfer.But not corresponding invention is seen in document at present.
The health of the malignant tumour serious threat mankind.Except self is severe to the prognosis of tumour patient, the transfer of Complicated by Malignancy worsens the prognosis of patient further.Such as, the malignant tumor patient more than more than 90% is all die from metastases.
Contriver once openly descended (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophane base-ethyl-1-base)-1 of structure, 2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine also [1,2:1,6] pyrido [3,4-b] indoles (being called for short CIPPC) can suppress the plasmin activity of urokinase effectively, display anastalsis.The invention but never suppressing the anastalsis of urokinase plasmin activity to be converted into antitumor action CIPPC is seen in document.
Contriver is in the analysis structure of hundreds of compound and the basis of activity change, recognize that (AA is selected from L-Trp by AA-OBzl, L-Phe, L-Ser, L-Tyr, Lys (Z), L-Pro, L-Leu, L-Ile, L-Val and Gly residue) guide on the carboxyl of the tryptophan residue of CIPPC, CIPPC can be suppressed the anastalsis of urokinase plasmin activity be converted into antitumor action.Based on this understanding, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide (5aS, 12S, the 14aS)-5 of structure below, 14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine is [1,2:1,6] pyrido [3 also, 4-b] indoles (being called for short CIPPC-AA-OBzl), AA is selected from L-Trp, L-Phe, L-Ser, L-Tyr, Lys (Z), L-Pro, L-Leu, L-Ile, L-Val and Gly residue.
Second content of the present invention is to provide preparation (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine also [1,2:1,6] method of pyrido [3,4-b] indoles, the method is made up of following steps:
(1) in presence of hydrochloric acid, L-Trp methyl esters and the condensation of 1,1,3,3-tetramethoxy propane are 1-(2,2-dimethoxy-ethyl)-1,2,3,4-Tetrahydrocarboline-3-carboxylate methyl ester;
(2) 1-(2,2-dimethoxy-ethyl)-1,2,3 under diisopropylamine exists, 4-Tetrahydrocarboline-3-carboxylate methyl ester and Z-Pro-Cl condensation are (5aS, 12S/R, 14aS)-5,14-diketone-12-Methylal(dimethoxymethane)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-b] indoles (2);
(3) under the existence of triethylamine and anhydrous sodium sulphate, (5aS, 12S/R, 14aS)-5, 14-diketone-12-Methylal(dimethoxymethane)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles [1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-b] indoles (2) and HClTrp-OBzl condensation be (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3a) and (5aS, 12R, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3b),
(4) under ice bath in methyl alcohol (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3a) hydrolysis generation (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophane ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC),
(5) under ice bath in dry DMF, by N, N-dicyclohexylcarbodiimide (DCC) and anhydrous Na
2sO
4make dewatering agent.(5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophane ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC) and AA-OBzl N-methylmorpholine reconcile pH to 9, at room temperature coupling generates (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC-AA-OBzl).
3rd content of the present invention is mensuration (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B] indoles (CIPPC-AA-OBzl) is to the restraining effect of tumor cell proliferation.
4th content of the present invention is mensuration (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B] indoles (CIPPC-AA-OBzl) is to the restraining effect of tumor growth.
5th content of the present invention is mensuration (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] nanostructure of pyrido [3,4-B] indoles (CIPPC-AA-OBzl).
Accompanying drawing explanation
Fig. 1. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] the synthetic route .i of pyrido [3,4-B] indoles (CIPPC-AA-OBzl)) hydrochloric acid; Ii) diisopropylamine, Z-Pro-Cl; Iii) triethylamine, anhydrous sodium sulphate and HClAA-OBzl (AA is selected from L-Trp, L-Phe, L-Ser, L-Tyr, Lys (Z), L-Pro, L-Leu, L-Ile, L-Val and Gly residue); Iv) ice bath, methyl alcohol, dry DMF, N, N-dicyclohexylcarbodiimide (DCC), anhydrous Na
2sO
4and N-methylmorpholine.In 4a, AA is L-Trp residue; In 4b, AA is L-Phe residue; In 4c, AA is L-Ser residue; In 4d, AA is L-Tyr residue; In 4e, AA is Lys (Z), residue; In 4f, AA is L-Pro residue; In 4g, AA is L-Leu residue; In 4h, AA is L-Ile residue; In 4i, AA is Gly residue.
Fig. 2. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] (in 4a, AA is L-Trp residue to pyrido [3,4-B] indoles; In 4b, AA is L-Phe residue; In 4c, AA is L-Ser residue; In 4d, AA is L-Tyr residue; In 4e, AA is Lys (Z), residue; In 4f, AA is L-Pro residue; In 4g, AA is L-Leu residue; In 4h, AA is L-Ile residue; In 4i, AA is Gly residue) 1 × 10
-10transmission 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 (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline carboxylate methyl ester (1)
Be dissolved in 50mL methyl alcohol by 5.0gL-tryptophan methyl ester (24.5mmol) and 6.0mL1,1,3,3-tetramethoxy propane (23.6mmol), adjust pH to 2 with hydrochloric acid (5M), 45 DEG C are stirred 48 hours.Reaction mixture is at concentrating under reduced pressure, and residue 50mL water dissolution, the solution with ethyl acetate of formation extracts (30mL × 3).The ethyl acetate solution merged, uses 10%Na successively
2cO
3the aqueous solution (3 × 30mL) and the saturated NaCl aqueous solution (2 × 30mL) are washed, and then use anhydrous Na
2sO
4drying, filter, concentrating under reduced pressure, obtains title compound, ESI-MS (m/z): 319 [M+H]
+.
Embodiment 2 prepares (5aS, 12S/R, 14aS)-5,14-diketone-12-Methylal(dimethoxymethane)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine is [1,2:1,6] pyrido [3,4-b] indoles (2) also
4.3g (17.2mmol) Z-Pro is dropped in the reaction flask being connected with device for absorbing tail gas, 5ml oxalyl chloride and 2 dry DMF are dripped after dissolving with 30mL anhydrous methylene chloride, produce a large amount of bubble, react 5 hours, with acetic acid ethyl dissolution and concentrating under reduced pressure three times (5ml × 3) after compound of reaction concentrating under reduced pressure, residue ether soaks, and obtains the shallow white solid of Z-Pro-Cl, not purified, be directly used in next step reaction.
4.77g (15.0mmol) (3S)-1-(2, 2-dimethoxy ethyl)-2, 3, 4, 9-tetrahydro-beta-carboline carboxylate methyl ester 50mL anhydrous methylene chloride dissolves, ice-water bath cools, add the Z-Pro-Cl that 3.87g (14.3mmol) is just obtained, reaction solution pH9 is kept with diisopropylamine, stirring at room temperature 24 hours, TLC monitors raw material spot and disappears, pressure reducing and steaming solvent, 200mgPd/C and 1ml formic acid is added after resistates 50ml dissolve with ethanol, stirring at room temperature 12 hours, make cyclization while removing Z protecting group, TLC monitors raw material spot and disappears.Concentrating under reduced pressure, resistates silica gel column chromatography obtains 3.91g (61%) title compound.ESI-MS(m/z):338[M+H]
+。
Embodiment 3 prepares (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3a) and (5aS, 12R, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3b)
Toward 2.3g (6.8mmol) (5aS, 12S/R, 14aS)-5,14-diketone-12-Methylal-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,2.4g (6.8mmol) HClTrp-OBzl, 1.5ml triethylamine and 6g anhydrous sodium sulphate is added in the solution of 6] pyrido [3,4-b] indoles and 10 milliliters of DMF.Reaction mixture is at room temperature stirred 3 hours.The solution of 1g (18.4mmol) POTASSIUM BOROHYDRIDE and 10ml methyl alcohol in addition in reaction mixture, and stir 1 hour.By reaction mixture concentrating under reduced pressure, resistates is dissolved in 40ml ethyl acetate and 20ml deionized water.Two phase liquid 2ml hydrochloric acid (5M) process, the POTASSIUM BOROHYDRIDE of decomposing excessive, and regulate pH to 9 with ammoniacal liquor (5M).Separate ethyl acetate layer, aqueous phase is extracted with ethyl acetate (40ml × 3).The ethyl acetate merged is washed with the saturated NaCl aqueous solution of 40ml mutually, with anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Resistates column chromatography purification (CHCl
3/ CH
3oH, 30/10), obtain 1.3g (61%) 3a and 1.5g (71%) 3b.
3a:FT-MS(m/z):615.2830[M]
+;mp:175-176℃;
1HNMR(300MHz,CDCl
3):δ=8.223(s,1H),7.756-7.584(dd,J=7.5Hz,J=7.5Hz,2H),7.494-7.411(m,3H),7.411(m,3H),7.386-7.317(m,5H),7.155-7.149(m,3H),7.05(m,1H),6.084-6.057(d,J=8,1Hz,1H),5.538-5.488(q,J=4.8Hz,5.1Hz,1H),5.216(s,2H),4.174(m,1H),4.106(m,1H),4.004-3.988(d,J=4.8Hz,1H),3.559-3.542(m,1H),3.434-3.288(td,J=5.1Hz,J=3.0Hz,J=3.0Hz,2H),2.959-2.910(m,2H),2.886-2.757(m,2H),2.743-2.655(m,1H),2.466-2.376(m,1H),2.318-2.198(m,2H),2.098-1.913(m,2H);
13CNMR(75MHz,CDCl
3):δ=173.86,169.48,165.90,165.83,156.14,136.34,135.96,135.71,135.38,133.96,133.53,129.60,128.61,128.34,128.21,126.99,126.10,125.66,123.71,122.59,122.13,121.39,120.30,120.12,120.01,119.41,118.88,118.17,117.66,115.44,112.07,111.83,111.43,111.23,106.39,105.70,66.68,62.21,59.34,59.19,58.89,57.40,56.95,50.28,49.14,46.24,45.37,44.46,40.43,35.44,29.51,28.64,28.54,23.24,23.12,21.41,21.23,10.00;IR(KBr):3308,2978,2954,2880,1659,1454,1398,1335,1236,1096,745cm
-1。
3b:FT-MS(m/z):615.2845[M]
+;mp:105-106℃;
1HNMR(300MHz,CDCl
3):δ=11.087(s,1H),10.677(s,1H),7.458-7.404(dd,J=4.8Hz,J=5.2Hz,2H),7.295-7.250(m,7H),7.075-6.935(m,4H),6.068-6.040(dd,J=1.8Hz,J=1.8Hz,1H),5.216-5.134(dt,J=7.8Hz,J=7.8Hz,2H),4.765-4.734(dd,J=2.7Hz,J=2.4Hz,1H),4.258-4.235(d,J=6.9Hz,1H),4.193-4.138(m,2H),3.806-3.790(m,1H),3.428-3.388(dd,J=2.7Hz,J=2.7Hz,2H),3.333(m,4H)3.012-2.982(m,2H),2.875-2.727(m,1H),2.407-2.361(t,J=6.9Hz,J=6.9Hz,1H),2.226-2.209(t,J=2.4Hz,2.7Hz,1H),2.176-2.124(m,1H),1.934-1.918(m,1H),1.855-1.788(m,2H);
13CNMR(75MHz,CDCl
3):δ=174.03,165.51,164.42,136.66,136.55,136.29,135.99,133.66,128.81,128.29,127.82,127.13,126.58,121.68,121.14,119.23,118.82,118.26,118.02,111.61,111.25,106.00,105.56,66.04,58.77,53.54,52.90,46.90,46.40,45.06,29.93,28.63,25.22,21.46;IR(KBr):3251,3233,2957,2930,2857,1659,1454,1398,1150,748cm
-1。
Embodiment 4 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophane-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (CIPPC)
Under ice bath, by 1.3g (2.1mmol) (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophan benzyl ester group-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B] indoles (3a) is dissolved in 5ml methyl alcohol, and dropwise add the NaOH aqueous solution (4M) and regulate pH to 12, reaction mixture is stirred 2 hours under ice bath.With hydrochloric acid (2M), pH to 5 is adjusted in reaction, concentrating under reduced pressure, by residue over silica gel column separating purification, obtains 863mg (90%) title compound CIPPC.ESI-MS(m/z):526[M+H]
+;
1HNMR(400MHz,DMSO),δ(ppm)=11.27(s,1H),10.86(s,1H),7.54(dd,J=7.6,J=7.6Hz,2H),7.33(m,2H),7.13(s,1H),7.06(s,2H),6.92(t,J=7.2Hz,1H),5.38(s,1H),4.50(s,1H),4.29(m,2H),3.45-3.34(m,4H),3.24(s,1H),3.15(m,2H),2.83(m,1H),2.51(s,1H),2.22(s,1H),1.98-1.79(m,5H).
13CNMR(100MHz,DMSO),δ(ppm)=171.11,170.44,165.55,136.34,136.00,133.98,125.95,124.11,121.65,118.64,118.47,118.19,111,71,111.47,109.49,105.53,101.53,63.10,62.17,58.69,56.32,52.87,49.42,45.03,43.18,40.37,40.16,39.95,36.27,34.60,28.21,26.75,22.93,21.33.IR(KBr):3390.86,3269.34,3113,3057,3014,2954,2933,2877,1640,1465,1303,1130,1103,1008,762,702cm
-1。
Embodiment 5 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl tryptophan benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4a)
120mg (0.23mmol) CIPPC and 77mg (0.23mmol) Trp-OBzl is dissolved in 15ml dry DMF, adds 100mg (0.46mmol) DCC and 30mg anhydrous Na
2sO
4.Reaction mixture N-methylmorpholine is adjusted pH to 9, and at room temperature stirs 1 hour.By reaction mixture at vacuum rotary steam, resistates is dissolved in 20ml ethyl acetate, by solution 10%Na
2cO
3the aqueous solution is washed (15mL × 3), and uses anhydrous Na
2sO
4dry.After filtration, filtrate is through concentrating under reduced pressure, and by residue over silica gel column purification, obtaining 148mg (80%) title compound, is pale yellow powder.Mp.122-123℃;ESI-MS(m/z):803[M+H]
+;
1HNMR(300MHz,DMSO),δ(ppm)=11.05(S,1H),10.84(S,1H),10.66(S,1H),8.44(d,J=7.2Hz,1H),7.57(d,J=10.2Hz,1H),7.49(d,J=17.7Hz,1H),7.38(m,2H),7.31(m,1H),7.27(m,2H),6.99(m,2H),6.93(m,1H),6.20(d,J=6.9Hz,1H),4.99(s,2H),4.74(dd,J=3.9Hz,J=4.2Hz,1H),4.65(dd,J=7.2Hz,J=7.2Hz,1H),4.14(m,2H),3.85(t,J=5.7Hz,1H),3.75(m,1H),3.40(dd,J=4.5Hz,J=4.5Hz,1H),3.34(m,2H),3.26(d,J=7.5Hz,2H),2.94(d,J=5.1Hz,H),2.89(s,1H),2.76(m,2H),2.74(s,1H),2.39(t,J=12.6Hz,1H),2.17(dd,J=3.3Hz,J=3.9Hz,2H),1.78(m,3H),1.40(s,1H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=173.41,172.18,165.60,164.54,162.76,136.68,136.55,136.51,136.26,133.91,128.73,128.33,128.14,127.66,127.36,126.66,124.05,121.61,121.48,121.12,119.20,118.91,118.76,118.46,118.24,117.94,111.94,111.61,111.31,110.07,106.94,105.67,67.49,66.39,60.19,59.03,54.01,53.82,52.51,47.24,46.75,45.04,36.23,31.26,29.89,28.70,27.56,26.82,25.60;IR(KBr):3428,3254,2955,2928,2855,1659,1456,1422,1340,1234,842,146cm
-1。
Embodiment 6 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl phenylalanine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4b)
According to the method for embodiment 5, from 120mg (0.23mmol) CIPPC and 67mg (0.23mmol) Phe-OBzl
Obtaining 130mg (74%) title compound, is pale yellow powder.Mp.145-146℃;ESI-MS(m/z):764[M+H]
+;
1HNMR(300MHz,DMSO),δ(ppm)=8.32(s,1H),7.96(m,1H),7.46(m,4H),7.40(m,4H),7.25(m,5H),7.13(m,5H),5.98(s,1H),5.13(m,2H),4.98(m,1H),4.14(dd,J=4.2Hz,J=4.2Hz,1H),4.00(t,J=7.5Hz,1H),3.88(dd,J=4.8Hz,J=4.8Hz,1H),3.58(m,2H),3.48(dd,J=2.4Hz,J=2.7Hz,1H),3.38(d,J=4.8Hz,1H),3.33(d,J=5.1Hz,1H),3.24(dd,J=7.9Hz,J=7.9Hz,1H),3.07(dd,J=7.2Hz,J=7.2Hz,1H),2.97(m,2H),2.93(m,2H),2.60(m,1H),2.41(m,2H),2.20(m,2H),2.98(m,2H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=174.07,172.00,165.24,164.58,136.49,136.39,135.55,135.01,131.86,129.32,129.17,128.68,128.58,128.50,128.45,128.23,127.45,126.89,126.20,123.43,122.21,121.94,119.61,119.48,118.77,118.02,111.36,110.77,105.72,67.96,67.40,67.22,63.73,59.02,53.87,52.61,47.23,47.18,45.07,45.00,37.60,34.97,30.08,29.69,29.37,28.32,25.61,23.30,21.47,8.62;IR(KBr):3383,3233,2978,2955,1640,1456,1406,1339,1234,1207,745,702cm
-1。
Embodiment 7 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl Serine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4c)
According to the method for embodiment 5, obtaining 123mg (76%) title compound from 120mg (0.23mmol) CIPPC and 53mg (0.23mmol) Ser-OBzl, is pale yellow powder.Mp.137-138℃;ESI-MS(m/z):703[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=8.24(s,1H),7.86(d,J=7.2Hz,1H),7.44(m,2H),7.32(m,6H),7.30(m,1H),7.13(m,4H),6.61(s,1H),5.18(s,2H),4.73(dt,J=3.6Hz,J=4.2Hz,J=3.6Hz,1H),4.43(m,1H),4.03(m,2H),3.97(m,2H),3.44(m,2H),3.38(m,2H),3.22(m,2H),3.16(m,2H),2.96(m,2H),2.52(m,1H),2.38(m,2H),2.23(m,1H),1.99(m,2H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=175.05,170.49,170.37,165.90,136.42,135.67,135.14,133.91,128.59,128.50,128.25,12708,125.84,124.76,122.48,121.77,119.83,119.75,119.28,117.86,111.98,111.56,111.43,105.81,67.44,63.42,60.84,59.34,57.14,54.63,48.46,47.47,45.24,43.22,36.43,35.65,29.3,29.28,28.60,23.26,20.89,8.70;IR(KBr):3358,2957,2884,1649,1456,1417,1234,1024,748cm
-1。
Embodiment 8 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl tyrosine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4d)
According to the method for embodiment 5, from 120mg (0.23mmol) CIPPC and 71mg (0.23mmol) Tyr-OBzl
Obtaining 125mg (70%) title compound, is pale yellow powder.Mp.113-114℃;ESI-MS(m/z):780[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=7.97(s,1H),7.86(t,J=11.4Hz,J=7.5Hz,2H),7.43(t,J=7.8Hz,2H),7.33(m,5H),7.29(m,2H),7.16(d,J=11.4Hz,2H),7.11(m,1H),7.03(d,J=8.1Hz,2H),6.85(d,J=8.1Hz,2H),6.63(s,1H),5.12(dd,J=5.1Hz,J=5.1Hz,2H),4.13(d,J=7.2Hz,1H),4.00(t,J=8.1Hz,J=7.5Hz,1H),3.87(dd,J=4.8Hz,J=4.8Hz,1H),3.58(m,2H),3.37(m,1H),3.30(d,J=4.8Hz,1H),3.24(d,J=4.8Hz,1H),2.96(s,1H),2.89(s,1H),2.83(m,1H),2.74(m,1H),2.37(m,1H),2.19(m,3H),2.06(m,2H),1.97(m,1H),1.54(m,1H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=174.66,171.42,170.68,166.02,155.88,136.36,135.62,135.20,133.75,130.36,129.56,128.59,128.51,127.00,126.87,126.80,125.73,124.71,122.14,121.72,119.67,119.58,119.41,117.77,115.58,115.39,111.70,111.46,110.97,105.52,67.21,60.14,59.33,57.08,52.20,48.15,45.25,42.63,37.58,36.53,35.03,31.91,31.47,29.68,29.34,28.85,28.60,23.27,22.67,20.68,14.09;IR(KBr):3229,3215,2956,2887,1648,1454,1404,1296,1151,746cm
-1。
Embodiment 9 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl Methionin benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4e)
According to the method for embodiment 5, obtaining 103mg (60%) title compound from 120mg (0.23mmol) CIPPC and 54mg (0.23mmol) Lys-OBzl, is pale yellow powder.Mp.113-114℃;ESI-MS(m/z):745[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=8.42(s,1H),7.88(d,J=7.8Hzl,H),7.47(m,3H),7.32(m,12H),7.19(m,3H),7.14(m,1H),5.13(m,4H),4.96(m,1H),4.68(m,1H),4.32(m,1H),3.97(t,J=8.0Hz,H),3.90(dd,J=5.1Hz,J=4.8Hz,1H),3.62(m,2H),3.52(m,1H),3.47(m,1H),3.39(dd,J=4.5Hz,J=4.8Hz,1H),3.14(m,2H),2.95(m,2H),2.45(m,3H),2.25(m,1H),2.03(m,1H),1.95(m,2H),1.67(m,1H),1.50(m,3H),1.28(m,3H),1.21(m,2H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=174.52,172.25,170.58,165.87,156.50,136.63,136.51,135.55,135.29,133.89,128.59,128.52,128.47,128.45,128.02,127.09,125.78,124.83,122.53,121.77,119.92,119.78,119.53,117.86,112.01,111.96,11.32,105.73,67.13,66.61,60.24,59.38,57.18,51.27,48.03,45.96,45.22,42.84,40.82,35.27,32.17,29.67,29.22,28.72,23.32,22.47,20.79;IR(KBr):3373,3323,2947,2868,1650,1456,1406,1335,1234,1202,1026,746cm
-1。
Embodiment 10 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl proline(Pro) benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4f)
According to the method for embodiment 5, obtaining 118mg (72%) title compound from 120mg (0.23mmol) CIPPC and 81mg (0.23mmol) Pro-OBzl, is pale yellow powder.Mp.112-113℃;ESI-MS(m/z):714[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=10.83(s,1H),10.72(s,1H),7.55(d,J=7.5Hz,1H),7.45(d,J=7.1Hz,1H),7.39(m,4H),7.24(m,3H),7.18(d,J=7.8Hz,1H),7.08(m,1H),7.02(m,2H),6.95(m,1H),5.08(m,2H),4.30(m,1H),4.28(m,1H),4.26(m,1H),3.62(m,2H),3.49(m,1H),3.09(m,2H),2.78(m,1H),2,74(m,1H),2.67(m,1H),2.35(m,1H),2.28(m,1H),2.22(m,1H),2.12(m,3H),1.95(m,2H),1.94(m,2H),1.86(m,1H),1.75(m,3H);IR(KBr):3433,3285,2955,2882,1741,1692,1456,1406,1339,1171,821,743cm
-1。
Embodiment 11 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl leucine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4g)
According to the method for embodiment 5, obtaining 118mg (80%) title compound from 120mg (0.23mmol) CIPPC and 59mg (0.23mmol) Leu-OBzl, is pale yellow powder.Mp.127-128℃;ESI-MS(m/z):730[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=8.20(s,1H),8.00(d,J=7.8Hz,1H),7.90(d,J=9.6Hz,1H),7.49(m,4H),7.36(d,J=2.1Hz,1H),7.33(m,5H),7.16(m,2H),7.06(m,1H),5.83(s,1H),5.13(dd,J=12Hz,J=4.8Hz,2H),4.82(m,1H),4.79(m,1H),4.09(dd,J=3.6Hz,J=3.6Hz,1H),4.02(t,J=7.9Hz,1H),3.92(dd,J=5.4Hz,J=5.1Hz,1H),3.64(m,2H),3.36(dd,J=5.1Hz,J=5.1Hz,1H),2.85(qq,J=11.7Hz,J=4.2Hz,2H),2.44(m,2H),2.32(m,2H),2.04(m,2H),1.67(m,4H),1.40(m,1H),1.24(dd,J=3.6Hz,J=6.9Hz,2H),1.11(m,1H),0.99(s,6H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=174.49,172.91,170.77,165.90,136.57,135.50,135.38,133.84,130.90,128.85,128.54,128.41,126.96,125.73,124.95,122.65,121.77,120.00,119.78,119.72,117.83,112.30,112.08,111.32,105.64,67.05,65.57,60.04,59.41,59.12,57.22,50.14,47.66,45.42,45.22,42.56,41.47,34.93,30.59,30.02,29.69,29.35,28.76,24.94,23.36,22.99,21.71,20.68,19.19,13.72,11.03;
IR(KBr):3397,2934,1653,1456,1398,1148,743cm
-1。
Embodiment 12 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl Isoleucine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4h)
According to the method for embodiment 5, obtaining 119mg (82%) title compound from 120mg (0.23mmol) CIPPC and 59mg (0.23mmol) Ile-OBzl, is pale yellow powder.Mp.129-130℃;ESI-MS(m/z):730[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=8.31(s,1H),7.99(s,1H),7.93(s,1H),7.44(m,4H),7.33(s,5H),7.28(m,2H),7.17(m,2H),6.93(m,1H),5.13(dd,J=12Hz,J=19.8Hz,2H),4.70(dd,J=4.8Hz,J=4.2Hz,1H),4.16(s,1H),3.97(t,J=8.0Hz,H),3.86(dd,J=4.5Hz,J=4.5Hz,1H),3.65(m,2H),3.56(m,2H),3.36(dd,J=5.4Hz,J=4.5Hz,1H),2.84(m,2H),2.35(m,4H),2.01(m,3H),0.96(m,6H);13C-NMR(75Hz,DMSO-d6δ(ppm)=174.34,171.85,170.69,165.88,136.57,135.54,135.38,133.84,128.62,128.59,128.53,128.46,128.42,126.95,125.76,124.90,122.59,121.77,119.95,119.78,119.61,117.83,112.15,112.03,111.36,105.69,66.92,60.28,59.38,57.18,56.14,47.75,45.19,42.67,37.88,34.97,30.07,28.69,25.01,23.31,20.70,15.69,11.50;IR(KBr):3367,3347,2961,2926,2874,1649,1456,1409,1234,1150,745cm
-1。
Embodiment 13 prepares (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl-glycine benzyl ester-ethyl-1-base)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B]-indoles (4i)
According to the method for embodiment 5, obtaining 136mg (88%) title compound from 120mg (0.23mmol) CIPPC and 46mg (0.23mmol) Gly-OBzl, is pale yellow powder.Mp.132-133℃;ESI-MS(m/z):674[M+H]
+;
1H-NMR(300MHz,DMSO),δ(ppm)=8.24(s,1H),8.10(dd,J=9.6Hz,J=7.2Hz,1H),7.44(m,3H),7.37(m,1H),7.32(m,5H),7.28(m,3H),7.11(d,J=3.9Hz,1H),7.08(m,1H),6.12(s,1H),5.17(s,2H),4.72(dd,J=2.4Hz,J=4.0Hz,1H),4.47(m,1H),4.23(dd,J=4.2Hz,J=4.5Hz,1H),4.01(t,J=8.7Hz,H),3.90(dd,J=4.8Hz,J=5.1Hz,1H),3.65(m,2H),3.56(m,1H),3.49(m,1H),3.37(dd,J=5.1Hz,J=5.1Hz,1H),3.16(q,J=7.5Hz,1H),2.87(m,2H),2.40(m,2H),2.30(m,1H),2.04(m,3H);
13C-NMR(75Hz,DMSO-d6δ(ppm)=175.09,170.61,169.86,165.91,136.55,135.53,135.24,133.80,128.62,128.52,128.42,127.03,125.77,125.00,122.53,121.81,119.90,119.81,119.52,117.86,112.01,111.93,111.34,105.72,67.14,65.83,60.29,59.32,57.09,47.92,45.21,42.99,40.93,35.28,29.74,28.68,23.28,20.74,15.25;IR(KBr):3397,2959,2926,2855,1649,1456,1412,1207,1146,748cm
-1。
Experimental example 1 assessing compound 4a-j is to the restraining effect of tumor cell proliferation
1) substratum of compound 4a-j of the present invention containing 0.1%DMSO is mixed with desired concn.
2) tumour cell of experiment is HL60 and HT-29.
3) cultivate and MTT with 96 hole microtiter plates, [(3-4,5-dimethylthiazole-2-base)-2,5-phenylbenzene nitrogen azoles bromine salt] Thiazolyl blue dyeing, operates according to standard program.HL60 and HT-29 cell (5 × 10
4individual cells/well) be incubated at RPMI-1640 or DMEM substratum (containing 10%, v/v) foetal calf serum, 60 μ g/ml penicillin, and 100 μ g/ml Streptomycin sulphates.The DMSO solution substratum of CIPPCT is diluted to desired concn.Cell in 37 DEG C of incubators (containing 5%CO
2) cultivate 24 hours, then add the CIPPCT solution that final concentration is respectively 0,1,5,10,25,50 and 100 μM.Cultivate after 48 hours, add MTT solution (5 μ g/ml, 25 μ l/ holes), and cell is cultivated 4 hours again.Add 100 μ lDMSO, after dissolving MTT-first a ceremonial jade-ladle, used in libation product, measure the absorption value (O.D., n=6) at 570nm place by microplate reader.
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 CIPPC-AA-OBzl group average O.D. value/blank group) × 100%, experiment repetition 6 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.Result shows that compound 4a-k has obvious restraining effect to HL60 and HT-29 cell proliferation.
Table 1. compound 4a-j is on the impact (IC of HL60 and HT-29 cell proliferation
50, mean value ± SD μM)
Experimental example 2 assessing compound 4a-j is to the restraining effect of tumor growth
1) the compound 4a-j 0.3%CMC-Na aqueous solution of the present invention suspends, and Zorubicin physiological saline solution is as positive control, and the 0.3%CMC-Na aqueous solution makes negative control;
2) the 0.3%CMC-Na suspension of compound 4a-j and the equal gastric infusion of the 0.3%CMC-Na aqueous solution, the dosage of CIPPCT is the dosage of 4 μm of ol/kg, 0.3%CMC-Na aqueous solution is 0.2ml/20g, successive administration 7 days, altogether administration 7 times; Zorubicin abdominal injection, dosage is 2 μm of ol/kg, successive administration 7 days, altogether administration 7 times.
3) laboratory animal is ICR male mice (cleaning grade), body weight 20 ± 2g, often organizes 7 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, the 0.3%CMC-Na suspension for the treatment of group mouse oral CIPPCT every day, dosage is 4,0.8 and 0.16 μm of ol/kg.Naive mice oral 0.2ml0.3%CMC-Na aqueous solution every day.Positive controls mouse abdominal injection every day Zorubicin, dosage is 2 μm of ol/kg.Experiment proceeds to the 7th 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: tumour inhibiting rate %=(heavy-AIPPCT of the average knurl of 0.3%CMC-Na aqueous solution group organizes average knurl weight) the average knurl of/0.3%CMC-Na aqueous solution group heavy × 100%.Experimental data adopts t inspection and variance analysis, knurl heavy with (
) represent.The results are shown in Table 2.As can be seen from Table 2, under the oral dosage of 4 μm of ol/kg, except compound 4h, outside i, in compound 4a-j, the knurl of all the other compounds for treating mouse weighs tool significant difference compared with 0.3%CMC-Na aqueous solution group, illustrates that they have definite anti-tumor activity.In addition, the effective dose of compound 4b, j is low reaches 0.8 μm of ol/kg.Visible, by AA-OBzl, (AA is selected from L-Trp, L-Phe, L-Ser, L-Tyr, Lys (Z), L-Pro, L-Leu, L-Ile, L-Val and Gly residue) guide on the carboxyl of the tryptophan residue of CIPPC, can effectively be suppressed by CIPPC the anastalsis of urokinase plasmin activity to be converted into antitumor action.
The impact (mean value ± SDg) that table 2. compound 4a-j is heavy on S180 mouse tumor
Compound (dosage μm ol/kg) | Knurl weight | Compound (dosage μm ol/kg) | Knurl weight |
Zorubicin (2) | 0.91±0.42 a | CMC-Na | 1.55±0.48 |
Compound 4a (4) | 0.97±0.41 a | Compound 4f (4) | 1.22±0.52 b |
Compound 4b (0.8) | 1.05±0.27 a | Compound 4g (4) | 1.20±0.39 b |
Compound 4c (4) | 1.07±0.46 b | Compound 4h (4) | 1.25±0.39 |
Compound 4d (4) | 1.04±0.35 a | Compound 4i (4) | 1.60+0.38 |
Compound 4e (4) | 1.08±0.31 a | Compound 4j (0.8) | 1.13±0.37 b |
N=10; A) P < 0.01 is compared with CMC-Na group; B) P < 0.05. is compared with CMC-Na group
Experimental example 4 measures the transmission electron microscope photo of compound 4a-j
By compound 4a-j according to 1 × 10
-10the 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, compound 4a-j can form nano particle in water, and diameter is 50-200nm.
Claims (4)
1. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1 of below structure, 2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine also [1,2:1,6] pyrido [3,4-b] indoles
AA is selected from L-Trp, L-Phe, L-Ser, L-Tyr, Lys (Z), L-Pro, L-Leu, L-Ile, L-Val and Gly residue.
2. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1 of claim 1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5]-pyrazine also [1,2:1,6] preparation method of pyrido [3,4-b] indoles, the method is made up of following steps:
(1) in presence of hydrochloric acid, L-Trp methyl esters and the condensation of 1,1,3,3-tetramethoxy propane are 1-(2,2-dimethoxy-ethyl)-1,2,3,4-Tetrahydrocarboline-3-carboxylate methyl ester;
(2) 1-(2,2-dimethoxy-ethyl)-1,2,3 under diisopropylamine exists, 4-Tetrahydrocarboline-3-carboxylate methyl ester and Z-Pro-Cl condensation are (5aS, 12S/R, 14aS)-5,14-diketone-12-Methylal(dimethoxymethane)-1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles [1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-b] indoles (2);
(3) under the existence of triethylamine and anhydrous sodium sulphate, (5aS, 12S/R, 14aS)-5, 14-diketone-12-Methylal(dimethoxymethane)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles [1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-b] indoles (2) and HClTrp-OBzl condensation be (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3a) and (5aS, 12R, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3b),
(4) under ice bath in methyl alcohol (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophan benzyl ester group-N-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (3a) hydrolysis generation (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophane ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC),
(5) under ice bath in dry DMF, by N, N-dicyclohexylcarbodiimide (DCC) and anhydrous Na
2sO
4make dewatering agent.(5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophane ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC) and AA-OBzl N-methylmorpholine reconcile pH to 9, at room temperature coupling generates (5aS, 12S, 14aS)-5, 14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1, 2, 3, 5, 5a, 6, 11, 12, 14, 14a-decahydro-5H, 14H-pyrroles-[1, 2:4, 5] pyrazine also [1, 2:1, 6] pyrido [3, 4-B] indoles (CIPPC-AA-OBzl).
3. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1 of claim 1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] nanostructure of pyrido [3,4-B] indoles.
4. (5aS, 12S, 14aS)-5,14-diketone-12-(2-tryptophyl amino-acid benzyl ester group-ethyl-1-base)-1 of claim 1,2,3,5,5a, 6,11,12,14,14a-decahydro-5H, 14H-pyrroles-[1,2:4,5] pyrazine also [1,2:1,6] pyrido [3,4-B] indoles is preparing the application in antitumor drug.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107502623A (en) * | 2016-06-13 | 2017-12-22 | 首都医科大学 | VEGF siRNA Nano diamond is delivered, it is prepared, activity and application |
CN108976159A (en) * | 2017-05-30 | 2018-12-11 | 首都医科大学 | The indoles alcohol derivative of ArAA modification, synthesis, activity and application |
CN109081801A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of acidic amino acid modification, synthesis, activity and application |
CN109081802A (en) * | 2017-06-13 | 2018-12-25 | 首都医科大学 | The indoles alcohol derivative of basic amino acid modification, synthesis, activity and application |
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-
2014
- 2014-07-03 CN CN201410312102.7A patent/CN105315332A/en active Pending
Non-Patent Citations (4)
Title |
---|
FENGXIANG DU等: "Mechanism of forming trimer, self-assembling nano-particle and inhibiting tumor growth of small molecule CIPPCT", 《MED. CHEM. COMMUN.》 * |
JIANHUI WU等: "A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
JIAWANG LIU等: "Pyrolo[1,2:4,5]-1,4-dioxopyrazino[1,2:1,6]pyrido[3,4-b]indoles: A Group of Urokinase Inhibitors, their Synthesis,and Stereochemistry-Dependent Activity", 《CHEM MED CHEM》 * |
XIAOYI ZHANG等: "A class of Trp-Trp-AA-OBzl: Synthesis, in vitro anti-proliferation/in vivo anti-tumor evaluation, intercalation-mechanism investigation and 3D QSAR analysis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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