CN101565413B - Isoflavone derivative modified by acetylaminoacid benzyl ester, preparation method and application thereof - Google Patents
Isoflavone derivative modified by acetylaminoacid benzyl ester, preparation method and application thereof Download PDFInfo
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- CN101565413B CN101565413B CN2009100843995A CN200910084399A CN101565413B CN 101565413 B CN101565413 B CN 101565413B CN 2009100843995 A CN2009100843995 A CN 2009100843995A CN 200910084399 A CN200910084399 A CN 200910084399A CN 101565413 B CN101565413 B CN 101565413B
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- benzyl ester
- obzl
- acetylaminoacid
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Abstract
The invention discloses an isoflavone derivative modified by acetylaminoacid benzyl ester of a general formula Ia-q, in which R1, R2 and R3 are all CH2CO-AA-OBzl or both R1 and R2 are all CH2CO-AA-OBzl, while R3 is H, wherein the AA in the CH2CO-AA-OBzl is selected from glycin, lactamine, phenyl alanine, tryptophan, isoleucine, leucine, valine, aspartic acid and glutamic acid. The invention also discloses a preparation method of the isoflavone derivative modified by the acetylaminoacid benzyl ester of the general formula Ia-q. The invention adopts an S180 mouse model to evaluate the antitumoreffects of the isoflavone derivative modified by the acetylaminoacid benzyl ester of the general formula Ia-q, thus indicating that the isoflavone derivative has excellent antitumor activity and can be used as an antitumor agent.
Description
Technical field
The present invention relates to isoflavone derivative of a series of modified by acetylaminoacid benzyl ester and preparation method thereof, further relate to their purposes in the preparation antitumor drug.The invention belongs to biomedicine field.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and the mortality ratio that the mankind cause because of malignant tumour is second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.The tumor treatment method has operative treatment, radiotherapy and pharmacological agent (chemotherapy).At present, chemotherapy remains the main means of clinical treatment tumour.Seeking antitumor drug is one of focus of new drug research.
5,7,4 '-trihydroxy-isoflavone is a kind of known natural product with anti-tumor activity, its antitumor action by to the cytotoxicity of tumour cell, to the restraining effect of epithelial cell growth factor receptor 2 body, to the restraining effect of tumor-blood-vessel growth, realize a plurality of approach such as specific inhibitory effect of wanting drug-resistant protein (MPR) more.But, 5,7,4 '-that the anti-tumor activity of trihydroxy-isoflavone can not satisfy antineoplaston is required.Drug invention the people recognize, 5,7,4 '-7,4 of trihydroxy-isoflavone ' position introduce simultaneously amino-acid benzyl ester or 5,7,4 ' position introduce amino-acid benzyl ester simultaneously and can strengthen 5,7,4 '-anti-tumor activity of trihydroxy-isoflavone.
Summary of the invention
One of purpose of the present invention is, 5,7,4 '-7,4 ' position of trihydroxy-isoflavone introduces amino-acid benzyl ester simultaneously or 5,7,4 ' position is introduced amino-acid benzyl ester simultaneously, obtained anti-tumor activity enhanced isoflavone derivative.
One of purpose of the present invention is achieved through the following technical solutions:
The isoflavone derivative of the modified by acetylaminoacid benzyl ester of general formula I a-q, R in the formula
1, R
2And R
3Be CH
2CO-AA-Obzl, perhaps R
1And R
2Be CH
2CO-AA-OBzl, R
3Be H; Wherein, described CH
2AA among the CO-AA-OBzl is selected from glycine, L-Ala, phenylalanine, tryptophane, Isoleucine, leucine, Xie Ansuan, aspartic acid, L-glutamic acid.
Two of purpose of the present invention is that a kind of method for preparing the isoflavone derivative of above-mentioned modified by acetylaminoacid benzyl ester is provided.
Two of purpose of the present invention is achieved through the following technical solutions:
(1) with monobromo-acetic acid and amino-acid benzyl ester coupling, obtain the acetobrom amino-acid benzyl ester, wherein, described amino acid is selected from glycine, L-Ala, phenylalanine, tryptophane, Isoleucine, leucine, Xie Ansuan, aspartic acid, L-glutamic acid;
(2) the acetobrom amino-acid benzyl ester is introduced 5,7,4 '-7 and 4 ' position of trihydroxy-isoflavone or the acetobrom amino-acid benzyl ester introduced 5,7,4 '-5,7 and 4 ' of trihydroxy-isoflavone.
This preparation method can summarize with the route of Fig. 1.
The present invention adopts mouse S
180The sarcoma model evaluation antitumor action of isoflavone derivative of modified by acetylaminoacid benzyl ester of general formula I a-q, show that they have outstanding anti-tumor activity, can be used as antineoplastic agent.
Description of drawings
Fig. 1 is the synthetic route of isoflavone derivative of the modified by acetylaminoacid benzyl ester of general formula I a-q.I) THF, DCC, NMM, ice bath; Ii) acetone, K
2CO
3, ice bath.R wherein
1, R
2And R
3Be CH
2CO-AA-OBzl, perhaps R
1And R
2Be CH
2CO-AA-OBzl, R
3Be H; CH
2AA among the CO-AA-OBzl is selected from glycine, L-Ala, phenylalanine, tryptophane, Isoleucine, leucine, Xie Ansuan, aspartic acid, L-glutamic acid.
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment
The logical method of embodiment 1 preparation acetobrom amino-acid benzyl ester
The 0.005mol monobromo-acetic acid is dissolved in the 100ml eggplant bottle with the anhydrous THF of 60ml, ice bath adds 0.005mol DCC down, question response is (about 30 minutes) fully, add 0.005mol AA-OBzl, add NMM and regulate PH-8～9, TLC monitoring reaction situation is treated AA-OBzl raw material disappearance back termination reaction, filter, filtrate decompression is concentrated into dried.The resistates that obtains with the 100mL acetic acid ethyl dissolution, place the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3).The ethyl acetate layer that merges is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression, the compound acetobrom amino-acid benzyl ester that obtains is a colorless solid.
Embodiment 2 preparation acetobrom glycine benzyl esters
According to the logical method of embodiment 1, make 585mg (yield 68.9%) acetobrom glycine benzyl ester with 1g TosGly-OBzl, be colorless solid.ESI
+-MS(m/z)310[M+H+Na]
+。
Embodiment 3 preparation acetobrom alanine benzyl esters
According to the logical method of embodiment 1, make 455mg (yield 53.2%) acetobrom alanine benzyl ester with 1g TosAla-OBzl, be colorless solid.ESI
+-MS(m/z)324[M+H+Na]
+。
Embodiment 4 preparation bromoacetyl benzene alanine benzyl esters
According to the logical method of embodiment 1, make 534mg (yield 60.6%) bromoacetyl benzene alanine benzyl ester with 1g TosPhe-OBzl, be colorless solid.ESI
+-MS(m/z)400[M+H+Na]
+。
Embodiment 5 preparation acetobrom tryptophan benzyl esters
According to the logical method of embodiment 1, use 1g H
3PO
4Trp-OBzl makes 643mg (yield 60.7%) acetobrom tryptophan benzyl ester, is colorless solid.ESI
+-MS(m/z)439[M+H+Na]
+。
Embodiment 6 preparation acetobrom Isoleucine benzyl esters
According to the logical method of embodiment 1, make 367mg (yield 42.1%) acetobrom Isoleucine benzyl ester with 1g TosIle-OBzl, be colorless solid.ESI
+-MS(m/z)366[M+H+Na]
+。
Embodiment 7 preparation acetobrom leucine benzyl esters
According to the logical method of embodiment 1, make 250mg (yield 28.7%) acetobrom leucine benzyl ester with 1g TosLeu-OBzl, be colorless solid.ESI
+-MS(m/z)366[M+H+Na]
+。
Embodiment 8 preparation acetobrom Xie Ansuan benzyl esters
According to the logical method of embodiment 1, make 441mg (yield 50.9%) acetobrom Xie Ansuan benzyl ester with 1g TosVal-OBzl, be colorless solid.ESI
+-MS(m/z)352[M+H+Na]
+。
Embodiment 9 preparation acetobrom aspartic acid benzyl esters
According to the logical method of embodiment 1, make 463mg (yield 51.7%) acetobrom aspartic acid benzyl ester with 1g TosAsp-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)458[M+H+Na]
+。
Embodiment 10 preparation acetobrom benzyl glutamates
According to the logical method of embodiment 1, make 511mg (yield 56.9%) acetobrom benzyl glutamate with 1g TosGlu-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)449[M+H]
+。
Embodiment 11 preparation 5-hydroxyls-7,4 '-the logical method of diacetyl amino-acid benzyl ester-isoflavones
0.001mol genistein in 100ml eggplant bottle, adds 0.0035mol 0.007molK altogether with the 60ml acetone solution at twice under the ice bath
2CO
3, after about 2 hours, adding 0.006mol acetobrom amino acid, TLC monitoring reaction situation is treated genistein raw material disappearance back termination reaction, filters, filtrate decompression is concentrated into dried.The resistates that obtains with the 100mL acetic acid ethyl dissolution, place the 250ml separating funnel, successively with saturated sodium bicarbonate aqueous solution wash (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3).The ethyl acetate layer that merges is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression.Obtain 5-hydroxyl-7,4 '-diacetyl amino-acid benzyl ester-isoflavones, be colorless solid.
Embodiment 12 preparation 5-hydroxyls-7,4 '-diacetyl glycine benzyl ester-isoflavones (Ia)
According to the logical method of embodiment 11, make 68mg (yield 17.2%) target compound with 1g BrAC-Gly-OBzl, be colorless solid.ESI
+-MS(m/z)681[M+H]
+。
Embodiment 13 preparation 5-hydroxyls-7,4 '-diacetyl alanine benzyl ester-isoflavones (Ib)
According to the logical method of embodiment 11, make 99mg (yield 25.4%) target compound with 1g BrAC-Ala-OBzl, be colorless solid.ESI
+-MS(m/z)709[M+H]
+。
Embodiment 14 preparation 5-hydroxyls-7,4 '-diacetyl benzene alanine benzyl ester-isoflavones (Ic)
According to the logical method of embodiment 11, make 100mg (yield 20.5%) target compound with 1g BrAC-Phe-OBzl, be colorless solid.ESI
+-MS(m/z)861[M+H]
+。
Embodiment 15 preparation 5-hydroxyls-7,4 '-diacetyl tryptophan benzyl ester-isoflavones (Id)
According to the logical method of embodiment 11, make 84mg (yield 22.3%) target compound with 1g BrAC-Trp-OBzl, be colorless solid.ESI
+-MS(m/z)939[M+H]
+。
Embodiment 16 preparation 5-hydroxyls-7,4 '-diacetyl Isoleucine benzyl ester-isoflavones (Ie)
According to the logical method of embodiment 11, make 166mg (yield 42.9%) target compound with 1g BrAC-Ile-OBzl, be colorless solid.ESI
+-MS(m/z)793[M+H]
+。
Embodiment 17 preparation 5-hydroxyls-7,4 '-diacetyl leucine benzyl ester-isoflavones (If)
According to the logical method of embodiment 11, make 75mg (yield 19.4%) target compound with 1g BrAC-Leu-OBzl, be colorless solid.ESI
+-MS(m/z)793[M+H]
+。
Embodiment 18 preparation 5-hydroxyls-7,4 '-data of diacetyl Xie Ansuan benzyl ester-isoflavones (Ig)
According to the logical method of embodiment 11, make 47mg (yield 12.1%) target compound with 1g BrAC-Val-OBzl, be colorless solid.ESI
+-MS(m/z)765[M+H]
+。
Embodiment 19 preparation 5-hydroxyls-7,4 '-diacetyl aspartic acid benzyl ester-isoflavones (Ih)
According to the logical method of embodiment 11, make 85mg (yield 22.7%) target compound with 1g BrAC-Asp-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)978[M+H+Na]
+。
Embodiment 20 preparation 5-hydroxyls-7,4 '-diacetyl benzyl glutamate-isoflavones (Ii)
According to the logical method of embodiment 11, make 127mg (yield 34.0%) target compound with 1g BrAC-Glu-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)1005[M+H]
+。
Embodiment 21 preparation 5,7,4 '-the logical method of triacetyl amino-acid benzyl ester-isoflavones
0.001mol genistein in 100ml eggplant bottle, adds 0.0035mol 0.007molK altogether with the 60ml acetone solution at twice under the ice bath
2CO
3, after about 2 hours, adding 0.006mol acetobrom amino acid, TLC monitoring reaction situation is treated genistein raw material disappearance back termination reaction, filters, filtrate decompression is concentrated into dried.The resistates that obtains with the 100mL acetic acid ethyl dissolution, place the 250ml separating funnel, successively with saturated sodium bicarbonate aqueous solution wash (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3).The ethyl acetate layer that merges is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression.Obtain 5,7,4 '-triacetyl amino-acid benzyl ester-isoflavones, be colorless solid.
Embodiment 22 preparations 5,7,4 '-triacetyl glycine benzyl ester-isoflavones (Ij)
According to the logical method of embodiment 21, make 80mg (yield 15.5%) target compound with 1g BrAC-Gly-OBzl, be colorless solid.ESI
+-MS(m/z)886[M+H]
+。
Embodiment 23 preparations 5,7,4 '-triacetyl alanine benzyl ester-isoflavones (Ik)
According to the logical method of embodiment 21, make 140mg (yield 27.2%) target compound with 1g BrAC-Ala-OBzl, be colorless solid.ESI
+-MS(m/z)938[M+H]
+。
Embodiment 24 preparations 5,7,4 '-triacetyl phenylalanine benzyl ester-isoflavones (Il)
According to the logical method of embodiment 21, make 250mg (yield 48.8%) target compound with 1g BrAC-Phe-OBzl, be colorless solid.ESI
+-MS(m/z)1156[M+H]
+。
Embodiment 25 preparations 5,7,4 '-triacetyl tryptophan benzyl ester-isoflavones (Im)
According to the logical method of embodiment 21, make 108mg (yield 21.1%) target compound with 1g BrAC-Trp-OBzl, be colorless solid.ESI
+-MS(m/z)1273[M+H]
+。
Embodiment 26 preparations 5,7,4 '-triacetyl leucine benzyl ester-isoflavones (In)
According to the logical method of embodiment 21, make 76mg (yield 14.8%) target compound with 1g BrAC-Leu-OBzl, be colorless solid.ESI
+-MS(m/z)1054[M+H]
+。
Embodiment 27 preparations 5,7,4 '-triacetyl Xie Ansuan benzyl ester-isoflavones (Io)
According to the logical method of embodiment 21, make 390mg (yield 75.9%) target compound with 1g BrAC-Val-OBzl, be colorless solid.ESI
+-MS(m/z)1012[M+H]
+。
Embodiment 28 preparations 5,7,4 '-triacetyl aspartic acid benzyl ester-isoflavones (Ip)
According to the logical method of embodiment 21, make 204mg (yield 40.0%) target compound with 1g BrAC-Asp-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)1331[M+H]
+。
Embodiment 29 preparations 5,7,4 '-triacetyl benzyl glutamate-isoflavones (Iq)
According to the logical method of embodiment 21, make 177mg (yield 34.7%) target compound with 1g BrAC-Glu-(OBzl)-OBzl, be colorless solid.ESI
+-MS(m/z)1372[M+H]
+。
The anti-tumor activity experiment of the compound of test example 1 general formula I a-q
1) positive reference substance is a Zorubicin.
2) laboratory animal: the ICR mouse, male, body weight 20 ± 2g (x ± s); One group of per 10 mouse, each one group of blank and positive control.
3) dosage setting
Compound of the present invention is made as 8.9 μ mol/kg, and positive control is made as 2.0 μ mol/kg, all adopts the abdominal cavity single-dose.
3) medicine preparation
General formula I a-q compound of the present invention indissoluble in water adds the wetting hydrotropy of a spot of tween 80 during experiment, add 0.5%CMC-Na solution gradually to desired concn.The positive reference substance Zorubicin is used with quadrat method and is dissolved.
4) dosage regimen
Compound intraperitoneal administration every day of the present invention once, the 0.2ml/ mouse, successive administration 7 days, altogether administration is 7 times.
Negative control once a day, 0.2ml 0.5%CMC-Na/ mouse, successive administration 7 days, altogether administration is 7 times.
The positive control intraperitoneal administration.Once a day intraperitoneal administration once, the 0.2ml/ mouse, successive administration 7 days, altogether administration is 7 times.
5) animal model
Adopt anti-tumor in vivo armpit subcutaneous vaccination model: under aseptic condition, extract inoculation 7d, after get the vigorous S of growth
180Ascitic tumor knurl liquid, be diluted to the liquid thorough mixing of (1: 2) with physiological saline, the tumour cell suspension is dyeed with freshly prepared 0.2% trypan blue, count by the white blood cell count(WBC) method behind the mixing, dye blue person and be dead cell, tinter is not a viable cell, is calculated as follows cell concn and cell survival rate.
Viable count/4 * 10 in the big grid in cell concn=4
4* extension rate=cell count/ml
Cell survival rate=viable count/(viable count+dead cell number) * 100%
Survival rate is prepared into 1 * 10 greater than 90% knurl liquid with the homogenate method
7The cell suspension of individual/ml in corresponding host's armpit subcutaneous vaccination 0.2ml/ mouse, is made the solid tumor animal model.
6) mensuration of solid tumor tumour inhibiting rate and body weight gain
Each organized successive administration after 7 days, took off cervical vertebra in the 8th day and put to death mouse, took by weighing body weight (execution body weight), with the fixing right armpit tumor location of mouse of tweezers, cut off skin then, the exposure tumour, and blunt separation is weighed, and is calculated as follows tumour inhibiting rate.
The average knurl of the average knurl weight-administration of tumour inhibiting rate %=[(negative control group group is heavily) the average knurl weight of ÷ CMC-Na control group] * 100%
7) statistical method
This experimental data statistics all adopts t check and variance analysis, with (x ± SD) expression.
8) experimental result
Compound of the present invention is to lotus S
180The anti-tumor in vivo activity experiment result of sarcoma is as shown in table 1.After abdominal cavity administration in continuous 7 days, the S180 mouse tumor there is significant inhibitory effect at compound of the present invention under the 8.9 μ mol/kg dosage.
The anti-tumor activity of table 1 general formula I a-q of the present invention compound
Annotate: compare * P＜0.05, * * P＜0.01 with control group; Ia-q dosage=8.9 μ mol/kg; Zorubicin dosage=2.0 μ mol/kg
Claims (5)
1. the isoflavone derivative of the modified by acetylaminoacid benzyl ester of general formula I a-q, R in the formula
1, R
2And R
3Be CH
2CO-AA-OBzl, perhaps R
1And R
2Be CH
2CO-AA-OBzl, R
3Be H; Wherein, described CH
2AA among the CO-AA-OBzl is selected from glycine, L-Ala, phenylalanine, tryptophane, Isoleucine, leucine, Xie Ansuan, aspartic acid, L-glutamic acid,
2. the method for isoflavone derivative of the modified by acetylaminoacid benzyl ester of preparation claim 1, this method comprises:
(1) with monobromo-acetic acid and amino-acid benzyl ester coupling, obtains the acetobrom amino-acid benzyl ester;
(2) the acetobrom amino-acid benzyl ester is introduced 5,7,4 '-7 and 4 ' position of trihydroxy-isoflavone or the acetobrom amino-acid benzyl ester introduced 5,7,4 '-5,7 and 4 ' of trihydroxy-isoflavone.
3. pharmaceutical composition for the treatment of tumour is made up of the isoflavone derivative and the pharmaceutically acceptable carrier of the modified by acetylaminoacid benzyl ester of the claim 1 of significant quantity.
4. pharmaceutical composition for the treatment of tumour is made up of the isoflavone derivative and the acceptable accessories of the modified by acetylaminoacid benzyl ester of the claim 1 of significant quantity.
5. the isoflavone derivative of the modified by acetylaminoacid benzyl ester of claim 1 is in the purposes of preparation in the antitumor drug.
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