CN101560223B - Phosphoryl amino acid stilbene derivative, preparing method and application thereof - Google Patents
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Abstract
The invention discloses a phosphoryl amino acid stilbene derivative, a preparing method and an application thereof. The compound has a structure general formula shown in formula I, wherein R1 and R2 are both-OCH3 or-H, and AA1 is amino acid residue. The preparing method comprises the step: carrying out a reaction of 2 isopropoxide phosphoryl amino acids and trans-3,5-dimethoxy-4'-amino-stilbene ortrans-4-amino-stilbene in the presence of N, N'-dicyclohexyl carbodiimide and 1-hydroxy-triazole at room temperature for 12-14 hours, the molar ratio of the trans-3,5-dimethoxy-4'-amino-stilbene or the trans-4-amino-stilbene to the 2 isopropoxide phosphoryl amino acids is 1:1-1:1.1, the molar ratio is preferably 1:1.05, and solvents can be tetrahydrofuran or methylene dichloride. The compound hasgood anti-tumor effect and has important practical values and application prospects in the field of preparing anti-tumor medicaments.
Description
Technical field
The present invention relates to phosphoryl amino acid stilbene derivative and preparation method thereof and application.
Background technology
Tumour is a kind of common disease, frequently-occurring disease, and wherein malignant tumour is the most serious class disease of present harm humans health.Cancer is a kind of malignant tumour, human beings'health and life in cancer serious threat, traditional chemotherapeutic agent and combinations such as operation, radiotherapy, successful raising the curative ratio of multiple malignant tumour, but because stronger side effect and resistance makes that the research of seeking new drug is very urgent.
Trans-resveratrol (Resveratrol) is called for short RES, is a kind of natural compound.At first be found as far back as nineteen twenty-four, and in grape, found this compound in 1974.Now 21 sections, find to contain trans-resveratrol in 72 kind of plant in 31 genus.Trans-resveratrol has multiple biological activity, but for example preventing cardiovascular disease, anti-inflammatory, arteriosclerosis, anti-diabetic, anti-oxidant, antibiotic, antiviral, prevent diabetes DPN etc., wherein can impel the Malignant B apoptosis by activating the P38MAP kinase pathways, demonstrate important meaning (Shimizu, T. at anti-tumor aspect; Nakazato, T.; Xian, M.J.; Sagawa, M.; Ikeda, Y.; Kizaki, M., Resveratrolinduces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAPkinase pathways, biochemical pharmacology 2006,71,742-750).Phosphorus is the central element of life, and it is playing the part of crucial role in life chemistry.Phosphoryl is a kind of higher bioactive group that has, and studies confirm that much the phosphorylated group has important biological (Galardy, R.E.; Grobelny, D., Na-(Diphenoxyphosphoryl)-L-alanyl-L-proline, N～-[Bis (4-nitrophenoxy) phosphoryl]-～-alanyl-～-proline, and N
*-[(2-Phenylet hyl) phenoxyphosphoryl]-～-alanyl-～-proline:Releasersof Potent Inhibitors of Angiotensin Converting Enzyme at Physiological pH andTemperature, J.Med.Chem.1985,28,1422-1427; Bertenshaw, S.R.; Rogers, R.S.; Stern, M.K.; Norman, B.H., Phosphorus-Containing Inhibitors of Endothelin Converting Enzyme:Effects of the Electronic Nature of Phosphorus on Inhibitor Potency, J.Med.Chem.1993,36,173-176).Thereby, develop the Verakanol derivative that contains the phosphorylated group and have great importance at field of medicaments.
Summary of the invention
The purpose of this invention is to provide a kind of phosphoryl amino acid stilbene derivative and preparation method thereof and application.
Phosphoryl amino acid stilbene derivative provided by the invention, its general structure is suc as formula shown in the I:
Formula I
In the above-mentioned formula I general structure, R
1, R
2Be-OCH
3, or be-H; AA
1Be amino-acid residue.Work as R
1, R
2Be-OCH
3The time, its general structure is suc as formula shown in the II; Work as R
1, R
2When being H, its general structure is shown in formula III.
Wherein, AA
1Be in L-glycine, 3-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminocaprolc acid, L-L-Ala, L-Xie Ansuan, L-leucine, L-phenylalanine or the L-proline(Pro) any one.
The method of the phosphoryl amino acid stilbene derivative shown in the above-mentioned formula I general structure of preparation provided by the invention; be will be suc as formula the Diisopropoxy phosphoryl amino acid shown in the IV general structure at N; under N '-carbodicyclo hexylimide and the effect of 1-hydroxy benzo triazole; with trans 3; 5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene react, and obtain the described Diisopropoxy phosphoryl amino acid stilbene derivative of formula I general structure.
Wherein, N, N '-dicyclohexylcarbodiimide (DCC) does linking agent, connects the condensing agent of N-and carboxyl; 1-hydroxy benzo triazole (HOBt) stops the racemization in the amino acid reaction as connecting catalyzer.
Among this preparation method, trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and the amino acid whose mol ratio of Diisopropoxy phosphoryl are 1: 1-1: 1.1, and preferred 1: 1.05; Trans 3,5-dimethoxy-4 ' ' hydrogen base toluylene or trans 4-amino-stilbene and N, the mol ratio of N '-dicyclohexylcarbodiimide is 1: 1-1: 1.1, preferred 1: 1.05; Trans 3, the mol ratio of 5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and 1-hydroxy benzo triazole is 1: 1-1: 1.1, and preferred 1: 1.05.Temperature of reaction is a room temperature, and the reaction times is 12-14 hour; Dissolvant of reaction system can be tetrahydrofuran (THF) or methylene dichloride, preferred tetrahydrofuran (THF).After reaction finishes, can be earlier reaction system be filtered earlier, resistates washs with tetrahydrofuran (THF), adds saturated NaHCO after revolving steaming
3Solution fully stirs the back and uses chloroform extraction, uses saturated NaHCO more successively
3Solution, massfraction are that 10% aqueous citric acid solution, saturated NaCl solution wash, and use anhydrous Na afterwards
2SO
4Drying, resistates carries out separation and purification with silica gel column chromatography.
In addition, be the antitumor drug and the application of above-mentioned phosphoryl amino acid stilbene derivative in the preparation antitumor drug of activeconstituents with phosphoryl amino acid stilbene derivative shown in the formula I general structure, also belong to protection scope of the present invention.
Phosphoryl amino acid stilbene derivative provided by the invention, through the instrumental analysis test, structure is correct.The method of the above-mentioned phosphoryl amino acid stilbene derivative of preparation provided by the invention, raw material is easy to get, and reaction is simple, and synthesis step is easy, easy handling.This compound has good restraining tumor promotion effect, in the preparation field of antineoplastic medicaments, has important practical value and application prospect.
Description of drawings
Fig. 1 is the cell proliferation inhibition rate figure of the embodiment of the invention 3 cell of doing test.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Embodiment 1, synthesis of trans 3, the 5-dimethoxy-4 ' '-N-Diisopropoxy phosphoryl amino acid stilbene compound
In the 50mL flask, add 2mmol 3, the 5-dimethoxy-4 ' '-amino-stilbene 10mL exsiccant tetrahydrofuran (THF), stir adding 2.1mmol N-phosphoryl amino acid (Diisopropoxy phosphoryl amino acid) and 2.1mmolL down
-1HOBt (1-hydroxy benzo triazole) solution, ice-water bath drips condensing agent 2.1mmol DCC (N down, N '-dicyclohexylcarbodiimide) with the mixing solutions of 5mL exsiccant tetrahydrofuran (THF), the room temperature reaction after-filtration that spends the night, resistates washs three times with THF (tetrahydrofuran (THF)), merging filtrate and washing lotion are revolved to steam to remove and are desolvated, and resistates adds saturated NaHCO
3Solution fully stirs the back and uses chloroform extraction, and combining extraction liquid is used saturated NaHCO successively
3Solution, massfraction are 10% aqueous citric acid solution, saturated NaCl solution washing three times, anhydrous Na
2SO
4Dry, filter, wash, revolve to steam and remove chloroform, resistates carries out separation and purification with silica gel column chromatography, the used silica gel post is available from Beijing Xin Weier glassware company limited, this chromatography column model is C384630C, length is 305mm: 40mm with the internal diameter ratio, when being used to separate product of the present invention, used elutriant is that volume ratio is 1: 120-1: 60 the methyl alcohol and the mixed solution of chloroform, elutriant normal pressure current downflow (2ml/min), detect effluent liquid according to the TLC thin-layer chromatography, vacuum rotary steam gets product and is white or faint yellow, and productive rate is 55-71%.
Select for use other to contain AA
1Substituent N-phosphoryl amino acid (Diisopropoxy phosphoryl amino acid); adopt and last identical preparation method; obtain a series of trans 3, the 5-dimethoxy-4 ' '-N-Diisopropoxy phosphoryl amino acid stilbene, shown in compound coding RES-1 to RES-10 in the table 1.
Above-mentioned trans 3, the 5-dimethoxy-4 ' '-the hydrogen spectrum data of N-Diisopropoxy phosphoryl amino acid stilbene are as follows:
RES-1：
1H?NMR(CDCl
3，500MHz)：δ1.35(d，12H，J
13＝6.20Hz)，3.46(m，1H)，3.75(d，2H，J
13＝13.10Hz)，3.83(s，6H)，4.66(m，2H)，6.39(m，1H)，6.65(m，2H)，6.97(d，1H，J
13＝16.25Hz)，7.05(d，1H，J
13＝16.25Hz)，7.47(d，2H，J
13＝8.50Hz)，7.58(d，2H，J
13＝8.50Hz)，8.95(s，1H).
RES-2：
1H?NMR(CDCl
3，500MHz)：δ1.29(m，12H)，2.04(m，1H)，2.63(m，2H)，3.31(m，2H)，3.82(s，6H)，4.59(m，2H)，6.38(m，1H)，6.65(m，2H)，6.95(d，1H，J
13＝16.50Hz)，7.03(d，1H，J
13＝16.50Hz)，7.43(d，2H，J
13＝8.50Hz)，7.60(d，2H，J
13＝8.50Hz)，8.85(s，1H).
RES-3：
1H?NMR(CDCl
3，500MHz)：δ1.30(m，12H)，1.92(m，2H)，2.54(m，2H)，2.99(m，2H)，3.82(s，6H)，4.59(m，2H)，6.38(m，1H)，6.65(m，2H)，6.95(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.43(d，2H，J
13＝8.50Hz)，7.66(d，2H，J
13＝8.50Hz)，9.44(s，1H).
RES-4：
1H?NMR(CDCl
3，500MHz)：δ1.31(m，12H)，1.57(m，2H)，1.84(m，2H)，2.40(m，2H)，2.61(m，1H)，3.00(m，2H)，3.82(s，6H)，4.58(m，2H)，6.38(m，1H)，6.65(d，2H)，6.95(d，1H，J
13＝16.50Hz)，7.03(d，1H，J
13＝16.50Hz)，7.44(d，2H，J
13＝8.50Hz)，7.60(d，2H，J
13＝8.50Hz)，8.51(s，1H).
RES-5：
1H?NMR(CDCl
3，500MHz)：δ1.30(m，12H)，1.40(m，2H)，1.53(m，2H)，1.74(m，2H)，2.38(m，2H)，2.63(m，1H)，2.90(m，2H)，3.82(s，6H)，4.57(m，2H)，6.38(m，1H)，6.65(m，2H)，6.95(d，1H，J
13＝16.50Hz)，7.03(d，1H，J
13＝16.50Hz)，7.43(d，2H，J
13＝8.50Hz)，7.59(d，2H，J
13＝8.50Hz)，8.32(s，1H).
RES-6：
1H?NMR(CDCl
3，500MHz)：δ1.33(m，12H)，1.49(d，3H，J
13＝6.80Hz)，3.66(m，1H)，3.82(s，6H)，4.02(m，1H)，4.61(m，2H)，6.38(m，1H)，6.65(m，2H)，6.96(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.45(d，2H，J
13＝8.50Hz)，7.63(d，2H，J
13＝8.50Hz)，9.43(s，1H).
RES-7：
1H?NMR(CDCl
3，500MHz)：δ0.99(d，3H，J
13＝6.80Hz)，1.30(m，12H)，2.28(m，1H)，3.50(m，1H)，3.72(m，1H)，3.83(s，6H)，4.61(m，2H)，6.39(m，1H)，6.65(m，2H)，6.96(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.45(d，2H，J
13＝8.50Hz)，7.63(d，2H，J
13＝8.50Hz)，9.17(s，1H).
RES-8：
1H?NMR(CDCl
3，500MHz)：δ0.97(d，6H，J
13＝6.25Hz)，1.30(m，12H)，1.57(m，1H)，1.80(m，2H)，3.34(m，1H)，3.83(s，6H)，3.87(m，1H)，4.60(m，2H)，6.39(m，1H)，6.65(m，2H)，6.96(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.45(d，2H，J
13＝8.50Hz)，7.62(d，2H，J
13＝8.50Hz)，9.24(s，1H).
RES-9：
1H?NMR(CDCl
3，500MHz)：δ1.26(m，12H)，3.14(m，2H)，3.47(m，1H)，3.82(s，6H)，4.11(m，1H)，4.49(m，2H)，6.41(m，1H)，6.66(m，2H)，6.97(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.25(m，5H)，7.45(d，2H，J
13＝8.50Hz)，7.51(d，2H，J
13＝8.50Hz)，8.63(s，1H).
RES-10：
1H?NMR(CDCl
3，500MHz)：δ1.32(m，12H)，1.95(m，4H)，2.53(m，1H)，3.24(m，2H)，3.83(s，6H)，4.27(m，1H)，4.62(m，2H)，6.39(m，1H)，6.65(m，2H)，6.96(d，1H，J
13＝16.50Hz)，7.04(d，1H，J
13＝16.50Hz)，7.46(d，2H，J
13＝8.50Hz)，7.59(d，2H，J
13＝8.50Hz)，9.60(s，1H)。
Embodiment 2, synthesis of trans 4-N-Diisopropoxy phosphoryl amino acid stilbene compound
In the 50mL flask, add the trans 4-amino-stilbene of 2mmol 10mL exsiccant tetrahydrofuran (THF), stir adding 2.1mmol N-phosphoryl amino acid and 2.1mmolL down
-1HOBt (1-hydroxy benzo triazole), ice-water bath drips condensing agent 2.1mmol DCC (N down, N '-dicyclohexylcarbodiimide) with the mixing solutions of 5mL exsiccant tetrahydrofuran (THF), the room temperature reaction after-filtration that spends the night, resistates washs three times with tetrahydrofuran (THF), merging filtrate and washing lotion are revolved to steam to remove and are desolvated, and resistates adds saturated NaHCO
3Solution, fully stir 7 mix the back use chloroform extraction, combining extraction liquid is used saturated NaHCO successively
3Solution, massfraction is 10% citric acid solution, saturated NaCl solution washing three times, anhydrous Na 2SO4 drying, filter, washing, revolve to steam and remove chloroform, resistates carries out separation and purification with silica gel column chromatography, the used silica gel post is available from Beijing Xin Weier glassware company limited, this chromatography column model is C384630C, length is 305mm: 40mm with the internal diameter ratio, when being used to separate product of the present invention, used elutriant is that volume ratio is 1: 120-1: 60 the methyl alcohol and the mixed solution of chloroform, and elutriant normal pressure current downflow (2ml/min) detects effluent liquid according to the TLC thin-layer chromatography, vacuum rotary steam gets product and is white or faint yellow, and productive rate is 55～71%.
Select for use other to contain AA
1Substituent Diisopropoxy phosphoryl amino acid adopts and last identical preparation method, obtains a series of trans 4-N-Diisopropoxy phosphoryl amino acid stilbenes, shown in compound coding RES-11 to RES-20 in the table 1.
The hydrogen spectrum data of above-mentioned trans 4-N-Diisopropoxy phosphoryl amino acid stilbene are as follows:
RES-11：1H?NMR(CDCl
3，500MHz)：δ1.33(m，12H)，3.77(m，2H)，3.90(m，1H)，4.64(m，2H)，7.03(d，1H，J
13＝16.50Hz)，7.06(d，1H，J
13＝16.50Hz)，7.24(m，1H)，7.34(m，2H)，7.46(m，2H)，7.48(m，2H)，7.59(m，2H)，9.19(s，1H).
RES-12：
1H?NMR(CDCl
3，300MHz)：δ1.30(m，12H)，2.63(m，2H)，3.32(m，2H)，4.60(m，2H)，7.02(d，1H，J
13＝16.50Hz)，7.07(d，1H，J
13＝16.50Hz)，7.22(m，1H)，7.35(m，2H)，7.45(m，2H)，7.49(m，2H)，7.60(m，2H)，8.61(s，1H).
RES-13：
1H?NMR(CDCl
3，500MHz)：δ1.31(m，12H)，1.91(m，2H)，2.54(m，2H)，3.01(m，2H)，4.60(m，2H)，7.02(d，1H，J
13＝16.50Hz)，7.07(d，1H，J
13＝16.50Hz)，7.34(m，2H)，7.45(m，2H)，7.49(m，2H)，7.67(m，2H)，9.31(s，1H).
RES-14：
1H?NMR(CDCl
3，500MHz)：δ1.31(m，12H)，1.57(m，2H)，1.85(m，2H)，2.40(m，2H)，3.00(m，2H)，4.58(m，2H)，.7.02(d，1H，J
13＝16.50Hz)，7.06(d，1H，J
13＝16.50Hz)，7.25(m，1H)，7.34(m，2H)，7.45(d，2H)，7.49(m，2H)，7.61(m，2H)，8.43(s，1H).
RES-15：
1H?NMR(CDCl
3，500MHz)：δ1.31(m，12H)，1.43(m，2H)，1.56(m，2H)，1.76(m，2H)，2.38(m，2H)，2.50(m，1H)，2.92(m，2H)，4.58(m，2H)，7.02(d，1H，J
13＝16.50Hz)，7.07(d，1H，J
13＝16.50Hz)，7.23(m，1H)，7.34(m，2H)，7.46(m，2H)，7.49(m，2H)，7.56(m，2H)，7.77(s，1H).
RES-16：
1H?NMR(CDCl
3，300MHz)：δ1.32(m，12H)，1.50(d，3H，J
13＝6.85Hz)，3.87(m，1H)，4.05(m，1H)，4.61(m，2H)，7.02(d，1H，J
13＝16.50Hz)，7.08(d，1H，J
13＝16.50Hz)，7.23(m，1H)，7.34(m，2H)，7.47(m，4H)，7.65(m，2H)，9.58(s，1H).
RES-17：
1H?NMR(CDCl
3，500MHz)：δ0.99(d，3H，J
13＝6.80Hz)，1.05(d，3H，J
13＝6.80Hz)，1.31(m，12H)，2.29(m，1H)，3.46(m，1H)，3.68(m，1H)，4.61(m，2H)，7.03(d，1H，J
13＝16.50Hz)，7.08(d，1H，J
13＝16.50Hz)，7.24(m，1H)，7.35(m，2H)，7.46(m，2H)，7.50(m，2H)，7.62(d，2H)，9.09(s，1H).
RES-18：
1H?NMR(CDCl
3，500MHz)：δ0.97(d，6H，J
13＝6.35Hz)，1.30(m，12H)，1.58(m，1H)，1.80(m，2H)，3.48(m，1H)，3.88(m，1H)，4.62(m，2H)，7.03(d，1H，J
13＝16.50Hz)，7.07(d，1H，J
13＝16.50Hz)，7.23(m，1H)，7.34(m，2H)，7.46(m，2H)，7.49(m，2H)，7.63(m，2H)，9.31(s，1H).
RES-19：
1H?NMR(CDCl
3，300MHz)：δ1.26(m，12H)，3.11(m，2H)，3.48(m，1H)，4.11(m，1H)，4.49(m，2H)，7.06(m，2H)，7.26(m，6H)，7.35(m，2H)，7.50(m，6H)，8.58(s，1H).
RES-20：
1H?NMR(CDCl
3，300MHz)：δ1.31(m，12H)，1.96(m，4H)，2.52(m，1H)，3.25(m，2H)，4.27(m，1H)，4.63(m，2H)，7.03(d，1H，J
13＝16.50Hz)，7.07(d，1H，J
13＝16.50Hz)，7.24(m，1H)，7.34(m，2H)，7.46(m，2H)，7.49(m，2H)，7.59(m，2H)，9.59(s，1H)。
The phosphoryl amino acid stilbene derivative structural table that table 1 embodiment 1 and 2 prepares
| The compound coding | R 1 | R 2 | AA 1 |
Embodiment 3, mtt assay cell inhibitory effect screening active ingredients
CNE1 that takes the logarithm vegetative period and CNE2 cell (two strain human nasopharyngeal carcinoma tumor cell lines) are with 2 * 10
5The density of individual/mL is inoculated in 96 orifice plates, 99 μ L/well, and in 37 ℃, 5%CO
2Incubator in cultivate after 4 hours, every hole adds the compounds of the embodiment of the invention 1 and 2 preparations, makes its final concentration be respectively 200 μ mol/L, 100 μ mol/L, 50 μ mol/L, 25 μ mol/L, 10 μ mol/L, 5 μ mol/L, 2.5 μ mol/L, 8 concentration gradients of 1 μ mol/L.Every kind of compound is established three multiple holes, establishes feminine gender and positive control simultaneously, and wherein, negative control is that volume ratio is 1% methanol solution, and positive control is a trans-resveratrol.Act on and add MTT (5mg/ml) solution after 72 hours, 10 μ L/well continue to cultivate after 4-6 hour, 2000rpm, 4 ℃, centrifugal 5 minutes, inhale and go to add DMSO behind the supernatant, 100 μ L/well, about 10 minutes of 37 ℃ of insulations, and vibrate with micro oscillator and to make crystallization dissolving fully in about 5 minutes, with microplate reader in 595nm place measurement OD value, be calculated as follows cell proliferation inhibition rate (InhibitionRate, IR%):
IR%=(blank OD-sample OD)/blank OD * 100%
As calculated, trans-resveratrol is to 50 3nhibitory dose IC50 value difference 68.7 μ M/L, the 51.6 μ M/L of CNE1 and CNE2, and the compound that table 2 prepares for the embodiment of the invention 1 and 2 (compound coding RES-1 to RES-20) is to the 50 3nhibitory dose IC of the experiment in vitro of CNE1 and two kinds of tumor cell lines of CNE2
50Value; And to compound be encoded to RES-4, RES-5, RES-10, RES-14, RES-20 makes cell proliferation inhibition rate figure; as shown in Figure 1; as can be known, phosphoryl amino acid stilbene derivative provided by the invention has the good restraining effect to suppressing the tumour cell growth.
Table 2 The compounds of this invention is to the 50 3nhibitory dose IC of CNE1 and two kinds of tumor cell line experiment in vitro of CNE2
50Value (the μ M/L of unit)
| The compound coding | CNE1(IC 50) | CNE2(IC 50) | The compound coding | CNE1(IC 50) | CNE2(IC 50) |
| RES-1 | 12.2 | 7.1 | RES-11 | 11.0 | 13.5 |
| RES-2 | 13.5 | 12.4 | RES-12 | 25.6 | 11.1 |
| RES-3 | 14.6 | 26.7 | RES-13 | 12.9 | 9.2 |
| RES-4 | 6.8 | 5.8 | RES-14 | 7.6 | 7.2 |
| RES-5 | 8.8 | 7.3 | RES-15 | 12.3 | 25.3 |
| RES-6 | 38.7 | 14.3 | RES-16 | 49.1 | 15.4 |
| RES-7 | 115.2 | 70.5 | RES-17 | 48.5 | 85.0 |
| RES-8 | 50.4 | 17.8 | RES-18 | 52.2 | 57.6 |
| RES-9 | 44.9 | 11.8 | RES-19 | 72.8 | 87.4 |
| RES-10 | 11.4 | 11.8 | RES-20 | 13.0 | 15.5 |
Table 3 compound is to the 50 3nhibitory dose IC of CNE1 and two kinds of tumor cell line experiment in vitro of CNE2
50Value (the μ M/L of unit)
| The compound coding | CNE1(IC 50Value μ M/L) | CNE2(IC 50Value μ M/L) |
| RES-4 | 6.8 | 5.8 |
| RES-14 | 7.6 | 7.2 |
| RES-5 | 8.8 | 7.3 |
| RES-10 | 11.4 | 11.8 |
| RES-20 | 13.0 | 15.5 |
Claims (9)
1. phosphoryl amino acid stilbene derivative, its general structure is suc as formula shown in the I:
Wherein, in the described formula I general structure, R
1, R
2Be-OCH
3, or be-H; AA
1For-COCH
2-,-CO (CH
2)
2-,-CO (CH
2)
3-,-CO (CH
2)
4-,-CO (CH
2)
5-,-COCH (CH
3)-,-COCH (CH (CH
3)
2)-or-COCH (CH
2Ph)-.
2. method for preparing the described phosphoryl amino acid stilbene derivative of claim 1, be will be suc as formula the Diisopropoxy phosphoryl amino acid shown in the IV general structure at N, under the effect of N '-dicyclohexylcarbodiimide and 1-hydroxy benzo triazole, with trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene react, and obtain the described Diisopropoxy phosphoryl amino acid stilbene derivative of formula I general structure;
Wherein, in the described formula IV general structure, AA
1For-COCH
2-,-CO (CH
2)
2-,-CO (CH
2)
3-,-CO (CH
2)
4-,-CO (CH
2)
5-,-COCH (CH
3)-,-COCH (CH (CH
3)
2)-or-COCH (CH
2Ph)-
3. preparation method according to claim 2 is characterized in that: described trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and the amino acid whose mol ratio of Diisopropoxy phosphoryl are 1: 1-1: 1.1; Described trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and N, the mol ratio of N '-dicyclohexylcarbodiimide is 1: 1-1: 1.1; Described trans 3, the mol ratio of 5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and 1-hydroxy benzo triazole is 1: 1-1: 1.1.
4. preparation method according to claim 3 is characterized in that: trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and the amino acid whose mol ratio of Diisopropoxy phosphoryl are 1: 1.05; Described trans 3,5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene and N, the mol ratio of N '-dicyclohexylcarbodiimide is 1: 1.05; Described trans 3, the mol ratio of 5-dimethoxy 4 ' amino-stilbene or trans 4-amino-stilbene and 1-hydroxy benzo triazole is 1: 1.05.
5. according to claim 2 or 3 described preparation methods, it is characterized in that: temperature of reaction is a room temperature, and the reaction times is 12-14 hour.
6. according to claim 2 or 3 described preparation methods; it is characterized in that: described Diisopropoxy phosphoryl amino acid and trans 3; when 5-dimethoxy-4 ' ' amino-stilbene or trans 4-amino-stilbene reacted, solvent was tetrahydrofuran (THF) or methylene dichloride.
7. according to claim 2 or 3 described preparation methods, it is characterized in that: after described reaction finishes, product is carried out following purification procedures:
Reaction system is filtered, and resistates washs with tetrahydrofuran (THF), adds saturated NaHCO after revolving steaming
3Solution fully stirs the back and uses chloroform extraction, uses saturated NaHCO more successively
3The aqueous solution, massfraction are that 10% citric acid solution, the saturated NaCl aqueous solution wash, and use anhydrous Na afterwards
2SO
4Drying, remove chloroform after, use purification by silica gel column chromatography, used silica gel column chromatography elutriant is that volume ratio is 1: 120-1: 60 the methyl alcohol and the mixed solution of chloroform.
8. be the antitumor drug of activeconstituents with the described phosphoryl amino acid stilbene derivative of claim 1.
9. the application of the described phosphoryl amino acid stilbene derivative of claim 1 in the preparation antitumor drug.
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|---|---|---|---|---|
| US20040097593A1 (en) * | 1999-11-08 | 2004-05-20 | Partha Neogi | Compounds for treatment of inflammation, diabetes and related disorders |
| CN1515586A (en) * | 2003-01-08 | 2004-07-28 | 清华大学 | Diisopropoxyphosphorylated dipeptide methyl ester, its preparation and application |
| CN1789277A (en) * | 2005-11-18 | 2006-06-21 | 清华大学深圳研究生院 | Diisopropoxy phosphoryl dipeptide trimethoxy benzamide compound and its preparation process |
| CN101139305A (en) * | 2006-09-08 | 2008-03-12 | 江苏正大天晴药业股份有限公司 | 4'-amido diphenyl ethylene alkyl derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040097593A1 (en) * | 1999-11-08 | 2004-05-20 | Partha Neogi | Compounds for treatment of inflammation, diabetes and related disorders |
| CN1515586A (en) * | 2003-01-08 | 2004-07-28 | 清华大学 | Diisopropoxyphosphorylated dipeptide methyl ester, its preparation and application |
| CN1789277A (en) * | 2005-11-18 | 2006-06-21 | 清华大学深圳研究生院 | Diisopropoxy phosphoryl dipeptide trimethoxy benzamide compound and its preparation process |
| CN101139305A (en) * | 2006-09-08 | 2008-03-12 | 江苏正大天晴药业股份有限公司 | 4'-amido diphenyl ethylene alkyl derivative |
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| 周莲 等.DTPA-双(3,5-二甲氧基-4′-氨基二苯乙烯)的合成.《化学试剂》.2007,第29卷(第2期),88-90. * |
| 周莲等.DTPA-双(3 5-二甲氧基-4′-氨基二苯乙烯)的合成.《化学试剂》.2007 |
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