CN106565739B - A kind of novel gambogic acid-type derivative and its preparation method and application - Google Patents

A kind of novel gambogic acid-type derivative and its preparation method and application Download PDF

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CN106565739B
CN106565739B CN201610931207.XA CN201610931207A CN106565739B CN 106565739 B CN106565739 B CN 106565739B CN 201610931207 A CN201610931207 A CN 201610931207A CN 106565739 B CN106565739 B CN 106565739B
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gambogicacid
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gambogic acid
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CN106565739A (en
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陶移文
黄雁
陈美君
张志佳
黎金海
凌惠平
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Guangzhou Medical University
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Guangzhou Medical University
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
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Abstract

The invention belongs to anti-tumor drug preparation technical field, a kind of novel gambogic acid-type derivative and its preparation method and application is disclosed；The derivative of the structure with to gambogicacid C-30 be transformed based on, obtain multiple novel Cs -30 substitution benzonitrile class, miazines, imidazoles ester derivant and amide derivatives.These compounds prove there is anti-tumor activity through Bioexperiment, can be used for preparing anti-tumor drug.Part Gamboges acid derivative is quite or more preferable to the inhibitory effect of lung cancer, liver cancer and breast carcinoma cell strain and natural gambogicacid, and part of compounds water solubility is better than gambogicacid, embodies the application value better than gambogicacid.

Description

A kind of novel gambogic acid-type derivative and its preparation method and application
Technical field
The present invention relates to anti-tumor drug preparation technical fields, more particularly, to a kind of novel gambogic acid-type derivative And its preparation method and application.
Background technique
Gambogicacid (Gambogic acid, GA) is in dry resin secreted by Garcinia maingayii gamboge (Gamboge) Main component, content are about 23%~37%, with wide spectrum anti-tumor activity, to liver cancer, human colon carcinoma, lung cancer, human breast carcinoma, The cell strains such as gastric cancer, chronic granulocyte, mouse melanoma are active,
And the kill cancer cell for the property of can choose, and toxicity on normal hematopoietic cell and function of immune system influence compared with It is small.But it exists simultaneously the disadvantages of stability is poor, water-soluble small, bioavilability is low, local irritation is larger, so uncommon Prestige obtain the Gamboges acid derivative that good water solubility, stability are good, anti-tumor activity is high on the basis of, domestic and foreign scholars to its into It has gone a large amount of structural modification, has obtained the compound that multiple and different sites are carried out with base group modification.Wherein, to gambogicacid C-30 The structure of modification of position carboxyl will not cause the decline of chemical combination microbic activity, while water solubility can be improved and improve biological utilisation Degree.
Summary of the invention
That technical problem to be solved by the invention is to provide a kind of bioavilabilities is high, stability is high, good water solubility rattan Yellow acid analog derivative.
A second object of the present invention is to provide the preparation methods of the gambogic acid-type derivative.
Third object of the present invention is to provide the applications of the gambogic acid-type derivative.
The purpose of the present invention is what is be achieved by the following technical programs:
A kind of gambogic acid-type derivative, the structural formula of the Gamboges acid derivative are as follows:
Wherein, R1 O, NH or NCH3, the integer that n is 0~3, as n ≠ 0, R2 is cyano-benzene oxygen, 2-pyrimidinyl oxy, miaow Oxazolyl, methylamino, pyrrolidinyl；As n=0, R2 is cyano-phenyl, pyrimidine radicals.
For the present invention on the basis of Structure-activity analysis, design has synthesized that multiple C-30 are bit esterified and amidated products, introduces Different carbon atom number linking arm long-chains and aromatic heterocycle or nonaromatic heterocycles, it is contemplated that obtain the good Gamboges acid derivative of activity.
Gambogic acid-type derivative provided by the invention is prepared by reactions such as esterification, amidations.
Specifically, when R1 is O or NH, when n ≠ 0, R2 is cyano-benzene oxygen, 2-pyrimidinyl oxy, imidazole radicals；Or when R1 be O or NH, n=0, (such as compound 1 arrives compound 13), the preparation method of gambogic acid-type derivative when R2 is cyano-phenyl, pyrimidine radicals It is gambogicacid and oxyl alcohol intermediate, alcohol or amine in organic solvent 1, reaction is changed accordingly under the action of catalyst Close object, i.e. gambogic acid-type derivative；The catalyst is EDCI and DMAP；The organic solvent 1 is methylene chloride, synthesis esterification The reaction time for closing object is for 24 hours.
Wherein, oxyl alcohol intermediate the preparation method comprises the following steps: cyano fortified phenol and bromine substituted alcohols in 60~100 DEG C of conditions Under, in organic solvent, under Anhydrous potassium carbonate protection, reacts, obtained among corresponding oxyl alcohol in the case where being heated to reflux effect Body；Preferably, the organic solvent is DMF, and the time being heated to reflux is 16~20h.
It is as shown in Equation 1 that it reacts synthetic route:
Formula 1
Preferably, when R1 is NH or NCH3；When R2 is methylamino, pyrrolidinyl (such as compound 14 and compound 15), The preparation method of gambogic acid-type derivative the following steps are included:
S1. gambogicacid and n-hydroxysuccinimide are in organic solvent 3, under the action of catalyst, in -10~30 DEG C Reaction generates GA-OSU activated ester intermediate；
S2. GA-OSU activated ester intermediate with corresponding alcohol or amine under the conditions of -10~30 DEG C, in organic solvent 4, Generate gamboge acid esters or gambogicacid amide.
Preferably, organic solvent 3 described in S1 is methylene chloride, and catalyst is dicyclohexylcarbodiimide, organic described in S2 Solvent 4 is tetrahydrofuran.
It is as shown in Equation 2 that it reacts synthetic route:
Formula 2
The present invention also provides the gambogic acid-type derivative application in preparations of anti-tumor drugs；Preferably, described anti- Tumour medicine is anti-lung-cancer medicament or/and medicines resistant to liver cancer or/and anti-breast cancer medicines.
Compared with prior art, the invention has the following advantages:
For the present invention on the basis of Structure-activity analysis, design has synthesized that multiple C-30 are bit esterified and amidated products, introduces Different carbon atom number linking arm long-chains and aromatic heterocycle or nonaromatic heterocycles, obtain a kind of gambogic acid-type derivative；Part gamboge Acid derivative is quite or more preferable to the inhibitory effect of lung cancer, liver cancer and breast carcinoma cell strain and natural gambogicacid, part chemical combination Object high water solubility embodies the application value better than gambogicacid in gambogicacid.
Specific embodiment
The contents of the present invention are further illustrated combined with specific embodiments below, but should not be construed as limiting the invention. Without departing from the spirit and substance of the case in the present invention, to simple modifications or substitutions made by the method for the present invention, step or condition, It all belongs to the scope of the present invention；Unless otherwise specified, technological means used in embodiment is well known to those skilled in the art Conventional means.
In the specific embodiment of the invention, the preparation reaction equation of each compound is as follows:
Compound 1 prepares equation to compound 13 are as follows:
Formula 1
Compound 14 to 15 prepares equation are as follows:
Formula 2
Embodiment 1
One, the synthesis of compound 1a 3- (4- cyano-benzene oxygen) propyl alcohol.
4- cyanophenol (0.5 g, 4.20 mmol) is dissolved in the anhydrous DMF of 10 mL, the bromo- 1- third of 3- is then added Alcohol (1.16 g, 8.40 mmol) and Anhydrous potassium carbonate (1.16 g, 8.40 mmol), it is heated to reflux 16 at 60~100 DEG C~ 20 hours, until reaction terminates.Mixed liquor is diluted with ethyl acetate, filtering is washed after filtering with saturated common salt, anhydrous sodium sulfate It is dry, solvent is steamed, column chromatographs [V (petroleum ether): V (ethyl acetate)=3:1] elution, obtains white solid powder 1a, 390 mg, Yield 53%.
Compound 1a,1H NMR (600 MHz, CDCl3) δ: 7.61 (s, 1H, 3-H), 7.59 (s, 1H, 5-H), 6.99 (s, 1H, 2-H), 6.97 (s, 1H, 6-H), 4.19 (t, J = 6.1 Hz, 2H, OCH 2CH2CH2), 3.89 (d, J = 4.9 Hz, 2H, OCH2CH2CH 2), 2.09 (m, 2H, OCH2CH 2CH2), 1.63 (s, 1H, OH)；ESI-MS m/z:176.95 [M+H]+。
Two, the synthesis of 1 gambogicacid -3- of compound (4- cyano-benzene oxygen) propyl diester.
Gambogicacid (0.20 g, 0.32 mmol) is dissolved in the anhydrous CH of 10 mL2Cl2In, be added product 1a(62 mg, 0.38 Mmol), EDCI(0.10g, 0.53mmol) and DMAP(22mg, 0.18 mmol), reaction is stirred at room temperature 16~24 hours, until Reaction terminates, concentration, and column chromatography [V (petroleum ether): V(ethyl acetate)=2:1] elution, obtain 1,200 mg of orange/yellow solid, yield 65%。
Compound 1,1H NMR (CDCl3, 600 MHz) δ: 12.80(s, 1H, 6-OH), 7.60(m, 2H, 3’-CH, 5’-CH), 7.47(d, J = 6.9 Hz, 1H, 10-H), 6.99(d, J = 8.9 Hz, 2H, 2’-CH, 6’-CH), 6.66(d, J = 10.1 Hz, 1H, 4-H), 6.28(t, J = 8.4 Hz, 1H, 27-H), 5.47(d,J = 10.1 Hz, 1H, 3-H), 5.15(m, 2H, 32-H, 37-H), 4.26(m, 2H, COOCH 2CH2CH2), 4.09(m, 2H, COOCH2CH2CH 2), 3.50(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.71(m, 2H, 26-H), 2.55(d, J = 9.4 Hz, 1H, 22-H), 2.16(m, 2H, 21-H), 2.07(m, 2H, 36-H), 1.81(m, 2H, COOCH2CH 2CH2), 1.77(s, 3H, 25-H), 1.73(s, 3H, 29-H), 1.68(s, 5H, 20-H, 34-H), 1.60(s, 3H, 39-H), 1.58(s, 3H, 35-H), 1.44(s, 3H, 40-H), 1.39(s, 3H, 24-H), 1.32(s, 3H, 19-H)；ESI-MS m/z:810.95 [M+Na]+。
Embodiment 2
One, the preparation of compound 2a 2- (4- cyano-benzene oxygen) ethyl alcohol
Experimental method with the step of embodiment 1 one, it is unique unlike: the bromo- 1- propyl alcohol of 3- is replaced with into ethylene bromohyrin, instead White solid powder 2a, 420 mg, yield 62% should be completed to obtain obtaining.
Compound 2a,1H NMR (600 MHz, CDCl3) δ: 7.63 (s, 1H, 3-H), 7.61 (s, 1H, 5-H), 7.01 (s, 1H, 2-H), 7.00 (s, 1H, 6-H), 4.16 (m, 2H, OCH 2CH2), 4.03 (m, 2H, OCH2CH 2), 3.51 (s, 1H, OH)；ESI-MS m/z:185.9 [M+Na]+。
Two, the preparation of 2 gambogicacid -2- of compound (4- cyano-benzene oxygen) ethyl ester
Experimental method with the step of embodiment 1 two, it is unique unlike: compound 1a is replaced with into compound 2a, is obtained orange 2,180 mg of yellow solid, yield 62%.
Compound 2,1H NMR (CDCl3, 600 MHz) δ: 12.79(s, 1H, 6-OH), 7.62(m, 2H, 3’-CH, 5’-CH), 7.38(d, J = 9.1 Hz, 1H, 10-H), 7.01(m, 1H, 2’-CH), 6.93(m, 1H, 6’-CH), 6.64(d, J = 12.1 Hz, 1H, 4-H), 6.19(m, 1H, 27-H), 5.43(m, 1H, 3-H), 5.11(m, 2H, 32-H, 37-H), 4.24(m, 2H, COOCH 2CH2), 4.11(m, 2H, COOCH2CH 2), 3.44 (m, 1H, 11-H), 3.26(m, 2H, 31-H), 2.96(m, 2H, 26-H), 2.54(d, J = 12.2 Hz, 1H, 22-H), 2.20(s, 2H, 21-H), 2.09(m, 2H, 36-H), 1.73(m, 3H, 25-H), 1.68(s, 3H, 29-H), 1.59(s, 14H, 20-H, 34-H, 39-H, 35-H, 40-H), 1.41(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/z:796.20 [M+Na]+。
The preparation of 3 compound of embodiment, 3 gambogicacid -4- benzonitrile ester
4- cyanophenol uniquely the difference is that, is replaced 1a, obtained orange-yellow solid by experimental method with the step of embodiment 1 two 3,300 mg of body, yield 86%.
Compound 3,1H NMR (CDCl3, 600 MHz) δ: 12.82(s, 1H, 6-OH), 7.55(m, 3H, 10-H, 3’-CH, 5’-CH), 6.94(m, 4H, 4-H, 27-H, 2’-CH, 6’-CH), 5.43(m, 1H, 3-H), 4.15(m, 2H, 32-H, 37-H), 3.45(m, 3H, 11-H, 31-H), 3.08(m, 2H, 26-H), 2.57(d,J = 8.7 Hz, 1H, 22-H), 2.08(m, 4H, 21-H, 36-H), 1.75(s, 3H, 25-H), 1.73(s, 3H, 29-H), 1.62(m, 2H, 20-H), 1.38(m, 3H, 34-H), 1.32(s, 3H, 39-H), 1.30(s, 3H, 35-H), 1.29(s, 3H, 40-H), 1.28(s, 3H, 24-H), 1.27(s, 3H, 19-H) ；ESI-MS m/ z:752.2 [M+Na]+。
Embodiment 4
One, the preparation of compound 4a 3- (3- cyano-benzene oxygen) propyl alcohol
Experimental method is unique the difference is that 3- cyanophenol replacement 4- cyanophenol is obtained white solid powder with embodiment 1 Last 4a, 400 mg, yield 54%.
Compound 4a,1H NMR (600 MHz, CDCl3) δ: 7.34 (m, 1H, 2-H), 7.22 (m, 1H, 4-H), 7.16 (m, 1H, 5-H), 7.12 (m, 1H, 6-H), 4.16 (m, 2H, OCH 2CH2CH2), 3.94 (m, 2H, OCH2CH2CH 2), 2.24 (m, 2H, OCH2CH 2CH2), 2.11 (m, 1H, OH)；ESI-MS m/z:200.0 [M +Na]+。
Two, the preparation of 4 gambogicacid -3- of compound (3- cyano-benzene oxygen) propyl diester
Experimental method with embodiment 2, the difference is that, 4a is replaced into 1a, obtains 4,210 mg of orange/yellow solid, yield 84%。
Compound 4,1H NMR (CDCl3, 600 MHz) δ: 12.80(s, 1H, 6-OH), 7.61(s, 1H, 5’- CH), 7.60(s, 1H, 4’-CH), 7.47(d, J = 6.9 Hz, 1H, 10-H), 6.99(d, J = 8.9 Hz, 2H, 2’-CH, 6’-CH), 6.66(d, J = 10.1 Hz, 1H, 4-H), 6.27(t, J = 7.7 Hz, 1H, 27- H), 5.47(d, J = 10.1 Hz, 1H, 3-H), 5.12(m, 2H, 32-H, 37-H), 4.25(m, 2H, COOCH 2CH2CH2), 4.09(m, 2H, COOCH2CH2CH 2), 3.50(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.70(m, 2H, 26-H), 2.55(d, J = 9.4 Hz, 1H, 22-H), 2.35(m, 2H, 21-H), 2.16(m, 2H, 36-H), 2.08(m, 2H, COOCH2CH 2CH2), 1.77(s, 3H, 25-H), 1.73(s, 3H, 29-H), 1.68(s, 2H, 20-H), 1.61(s, 9H, 34-H, 39-H, 35-H), 1.44(s, 3H, 40-H), 1.39(s, 3H, 24-H), 1.32(s, 3H, 19-H)；ESI-MS m/z:810.95[M+Na]+。
Embodiment 5
One, the preparation of compound 5a 2- (3- cyano-benzene oxygen) ethyl alcohol
3- cyanophenol uniquely the difference is that, is replaced 4- cyanophenol, by ethylene bromohyrin with embodiment 1 by experimental method The bromo- 1- propyl alcohol of 3- is replaced, white solid powder 5a, 530 mg, yield 82% are obtained.
Compound 5a,1H NMR (600 MHz, CDCl3) δ: 7.41 (m, 1H, 2-H), 7.38 (t, J = 5.8 Hz, 1H, 4-H), 7.27 (m, 1H, 5-H), 7.18 (m, 1H, 6-H), 4.54 (m, 2H, OCH 2CH2), 4.04 (m, 2H, OCH2CH 2), 2.17 (s, 1H, OH)；ESI-MS m/z:185.9 [M+Na]+。
Two, the preparation of 5 gambogicacid 2- of compound (3- cyano-benzene oxygen) ethyl ester
With the step of embodiment 1 two, difference is 5a replacing 1a experimental method, obtains 5,220 mg of orange/yellow solid, produces Rate 92%.
Compound 5,1H NMR (CDCl3, 600 MHz) δ: 12.79(s, 1H, 6-OH), 7.44(d, J = 6.9 Hz, 1H, 10-H), 7.40(d, J = 8.0 Hz, 1H, 5’-CH), 7.21(m, 1H, 4’-CH), 7.19 (m, 1H, 6’-CH), 7.12(m, 1H, 2’-CH), 6.64(d, J = 10.1 Hz, 1H, 4-H), 6.34(m, 1H, 27-H), 5.45(t, J = 13.3 Hz, 1H, 3-H), 5.15(m, 2H, 32-H, 37-H), 4.41(m, 2H, COOCH 2CH2), 4.17(m, 2H, COOCH2CH 2), 3.50(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.71(m, 2H, 26-H), 2.54(d, J = 9.4 Hz, 1H, 22-H), 2.36(m, 2H, 21-H), 2.19(s, 2H, 36-H), 1.77(s, 3H, 25-H), 1.72(s, 3H, 29-H), 1.68(s, 2H, 20-H), 1.59(s, 6H, 34-H, 39-H), 1.42(s, 3H, 35-H), 1.40(s, 3H, 40-H), 1.31(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/z:796.25 [M+Na]+。
Embodiment 6
One, the preparation of compound 6a 3- (2- cyano-benzene oxygen) propyl alcohol
Experimental method with embodiment 1, it is unique it is different be, 2- cyanophenol is replaced into 4- cyanophenol, is obtained white solid Body powder 6a, 428 mg, yield 58%.
Compound 6a,1H NMR (600 MHz, CDCl3) δ: 7.56 (m, 1H, 5-H), 7.53 (m, 1H, 3-H), 7.02 (m, 1H, 4-H), 7.01 (m, 1H, 6-H), 4.25 (m, 2H, OCH 2CH2CH2), 3.93 (s, 2H, OCH2CH2CH 2), 2.18 (d, J = 2.1 Hz, 2H, OCH2CH 2CH2), 2.12 (m, 1H, OH)；ESI-MS m/z:199.85 [M+Na]+。
Two, the preparation of 6 gambogicacid -3- of compound (2- cyano-benzene oxygen) propyl diester
Experimental method with the step of embodiment 1 two, the difference is that, 6a is replaced into 1a, obtains orange/yellow solid 6,190 Mg, yield 76%.
Compound 6,1H NMR (CDCl3, 500 MHz) δ: 12.81(s, 1H, 6-OH), 7.58(dd, J = 7.6, 1.5 Hz, 1H, 5’-CH), 7.55(m, 1H, 3’-CH), 7.50(d, J = 6.9 Hz, 1H, 10-H), 7.04(m, 1H, 4’-CH), 7.02(m, 1H, 6’-CH), 6.67(d, J = 10.1 Hz, 1H, 4-H), 6.29 (m, 1H, 27-H), 5.47(m, 1H, 3-H), 5.13(m, 2H, 32-H, 37-H), 4.31(m, 2H, COOCH 2CH2CH2), 4.15(m, 2H, COOCH2CH2CH 2), 3.52(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.68(m, 2H, 26-H), 2.54(d, J = 9.4 Hz, 1H, 22-H), 2.36(m, 2H, 21-H), 2.22(m, 2H, 36-H), 2.07(s, 2H, COOCH2CH 2CH2), 1.77(s, 3H, 25-H), 1.73(s, 3H, 29-H), 1.68(s, 5H, 20-H, 34-H), 1.58(s, 3H, 39-H), 1.44(s, 3H, 35-H), 1.38(s, 3H, 40-H), 1.32(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/z:810.20 [M+Na]+。
Embodiment 7
One, the preparation of compound 7a 2- (2- cyano-benzene oxygen) ethyl alcohol
With embodiment 1, difference is experimental method, and 2- cyanophenol is replaced 4- cyanophenol, ethylene bromohyrin is replaced The bromo- 1- propyl alcohol of 3-, obtains white solid powder 7a, 410 mg, yield 63%.
Compound 7a,1H NMR (600 MHz, CDCl3) δ: 7.59 (d, J = 7.6 Hz, 1H, 5-H), 7.56 (m, 1H, 3-H), 7.06 (t, J = 7.5 Hz, 1H, 4-H), 7.01 (d, J = 8.5 Hz, 1H, 6- H), 4.22 (s, 2H, OCH 2CH2), 4.05 (d, J = 4.0 Hz, 2H, OCH2CH 2), 2.19 (s, 1H, OH)；ESI-MS m/z:185.85 [M+Na]+。
Three, the preparation of 7 gambogicacid -2- of compound (2- cyano-benzene oxygen) ethyl ester
With the step of embodiment 1 two, difference is experimental method, and 7a is replaced 1a, obtains 7,223 mg of orange/yellow solid, produces Rate 92%.
Compound 7,1H NMR (CDCl3, 500 MHz) δ: 12.77(s, 1H, 6-OH), 7.59(m, 1H, 5’- CH), 7.57(m, 1H, 3’-CH), 7.54(d, J = 7.0 Hz, 1H, 10-H), 7.06(m, 1H, 4’-CH), 7.03(m, 1H, 6’-CH), 6.61(d, J = 10.1 Hz, 1H, 4-H), 6.27(m, 1H, 27-H), 5.42(m, 1H, 3-H), 5.13(m, 2H, 32-H, 37-H), 4.47(m, 2H, COOCH 2CH2), 4.20(m, 2H, COOCH2CH 2), 3.55(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.73(m, 2H, 26-H), 2.53(d, J = 9.4 Hz, 1H, 22-H), 2.30(m, 2H, 21-H), 1.78(m, 2H, 36-H), 1.73(s, 3H, 25-H), 1.67(m, 5H, 29-H, 20-H), 1.61(s, 3H, 34-H), 1.58(s, 3H, 39-H), 1.42(s, 3H, 35-H), 1.37(s, 3H, 40-H), 1.31(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/z: 796.20 [M+Na]+。
Embodiment 8
One, the preparation of 8 gambogicacid -2- benzonitrile ester of compound
With the step of embodiment 1 two, difference is experimental method, and 2- cyanophenol is replaced 1a, obtains orange/yellow solid 8, 190 mg, yield 83%.
Compound 8,1H NMR (CDCl3, 600 MHz) δ: 12.78 (s, 1H, 6-OH), 7.67(m, 1H, 5’-CH), 7.65(d, J = 9.1 Hz, 1H, 10-H), 7.62(d, J = 6.9 Hz, 1H, 3’-CH), 7.41 (d, J = 8.1 Hz, 1H, 4’-CH), 7.33(t, J = 7.2 Hz, 1H, 6’-CH), 6.68(m, 1H, 4-H), 6.66(d, J = 10.1 Hz, 1H, 27-H), 5.46(d, J = 10.1 Hz, 1H, 3-H), 5.13(m, 2H, 32-H, 37-H), 3.56(m, 1H, 11-H), 3.34(m, 2H, 31-H), 2.79(m, 2H, 26-H), 2.58(d,J = 9.3 Hz, 1H, 22-H), 2.38(m, 2H, 21-H), 2.07(m, 2H, 36-H), 1.76(s, 3H, 25- H), 1.69(s, 3H, 29-H), 1.68(s, 2H, 20-H), 1.58(s, 3H, 34-H), 1.53(s, 3H, 39- H), 1.44(s, 3H, 35-H), 1.34(s, 3H, 40-H), 1.29(d, J = 7.2 Hz, 3H, 24-H), 1.27 (d, J= 3.9 Hz, 3H, 19-H)；ESI-MS m/z:752.2 [M+Na]+。
Embodiment 9
One, the preparation of compound 9a 3- (4- 2-pyrimidinyl oxy) propyl alcohol
With embodiment 1, difference is experimental method, and 4- hydroxy pyrimidine is replaced 4- cyanophenol, obtains white solid powder 9a, 310 mg, yield 65%.
Compound 9a,1H NMR (600 MHz, CDCl3) δ: 9.02 (m, 1H, 2-H), 9.01 (m, 1H, 6- H), 6.95 (m, 1H, 5-H), 4.05 (m, 2H, OCH 2CH2CH2), 3.53 (m, 2H, OCH2CH2CH 2), 2.11 (m, 2H, OCH2CH 2CH2), 2.02 (s, 1H, OH).；ESI-MS m/z:178.90 [M+Na]+。
Two, the preparation of 9 gambogicacid -3- of compound (4- 2-pyrimidinyl oxy) propyl diester
With the step of embodiment 1 two, difference is experimental method, and 9a is replaced 1a, obtains 9,186 mg of orange/yellow solid, produces Rate 76%.
Compound 9,1H NMR (CDCl3, 500 MHz) δ: 12.77(s, 1H, 6-OH), 8.78(d, J = 4.8 Hz, 1H, 2’-CH), 8.25(d, J = 6.3 Hz, 1H, 6’-CH), 7.56(dd, J = 10.4, 7.0 Hz, 1H, 10-H), 6.75(d, J = 4.7 Hz, 1H, 5’-CH), 6.68(d, J = 10.2 Hz, 1H, 4-H), 6.53(d, J = 6.6 Hz, 1H, 27-H), 5.47(m, 1H, 3-H), 5.14(d, J = 9.3 Hz, 2H, 32- H, 37-H), 4.49(m, 2H, COOCH 2CH2CH2), 4.25(m, 2H, COOCH2CH2CH 2), 3.53(m, 1H, 11- H), 3.30(m, 2H, 31-H), 2.68(m, 2H, 26-H), 2.54(d, J = 9.4 Hz, 1H, 22-H), 2.37 (m, 2H, 21-H), 2.06(m, 2H, 36-H), 1.87(s, 2H, COOCH2CH 2CH2), 1.77(s, 3H, 25- H), 1.74(s, 3H, 29-H), 1.68(s, 5H, 20-H, 34-H), 1.58(s, 3H, 39-H), 1.44(m, 3H, 35-H), 1.38(m, 3H, 40-H), 1.32(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/ z:765.30 [M+H]+。
Embodiment 10
One, the preparation of compound 10a 2- (4- 2-pyrimidinyl oxy) ethyl alcohol
With embodiment 1, difference is experimental method, and 4- hydroxy pyrimidine is replaced 4- cyanophenol, ethylene bromohyrin is replaced The bromo- 1- propyl alcohol of 3-, obtains white solid powder 10a, 355 mg, yield 81%.
Compound 10a,1H NMR (600 MHz, CDCl3) δ: 8.99 (m, 1H, 2-H), 8.95 (s, 1H, 6-H), 6.92 (m, 1H, 5-H), 4.33 (m, 2H, OCH 2CH2), 3.68 (m, 2H, OCH2CH 2), 2.13 (s, 1H, OH)；ESI-MS m/z:140.90 [M+H]+。
Two, the preparation of 10 gambogicacid -2- of compound (4- 2-pyrimidinyl oxy) ethyl ester
With the step of embodiment 1 two, difference is experimental method, and 10a is replaced 1a, obtains 11,137 mg of orange/yellow solid, Yield 57%.
Compound 10,1H NMR (CDCl3, 500 MHz) δ: 12.76(s, 1H, 6-OH), 8.87(s, 1H, 2’-CH), 8.50(s, 1H, 6’-CH), 7.50(m, 1H, 10-H), 6.91(s, 1H, 5’-CH), 6.65(d, J = 10.1 Hz, 1H, 4-H), 6.34(m, 1H, 27-H), 5.47(m, 1H, 3-H), 5.17(m, 2H, 32-H, 37-H), 4.67(d, J = 3.9 Hz, 2H, COOCH 2CH2), 4.43(m, 2H, COOCH2CH 2), 3.54(d, J = 11.1 Hz, 1H, 11-H), 3.29(d, J = 7.4 Hz, 2H, 31-H), 2.68(m, 2H, 26-H), 2.55(d,J = 8.9 Hz, 1H, 22-H), 2.37(m, 2H, 21-H), 2.09(m, 2H, 36-H), 1.77(s, 3H, 25- H), 1.73(s, 3H, 29-H), 1.68(s, 5H, 20-H, 34-H), 1.58(s, 3H, 39-H), 1.41(m, 3H, 35-H), 1.28(s, 9H, 40-H, 24-H, 19-H)；ESI-MS m/z:751.3 [M+H]+。
Embodiment 11
One, the preparation of 11 gambogicacid -4- pyrimidine ester of compound
With the step of embodiment 1 two, difference is experimental method, and 4- hydroxy pyrimidine is replaced 1a, obtains orange/yellow solid Huang 11,100 mg of color solid, yield 90%.
Compound 11,1H NMR (CDCl3, 500 MHz) δ: 12.80(s, 1H, 6-OH), 8.15(s, 1H, 6’-CH), 8.03(d, J = 6.7 Hz, 1H, 2’-CH), 7.56(d, J = 6.9 Hz, 1H, 10-H), 6.69 (d, J = 10.1 Hz, 1H, 5’-CH), 6.56 (t, J = 7.5 Hz, 1H, 4-H), 6.52(d, J = 6.0 Hz, 1H, 27-H), 5.48(t, J = 8.7 Hz, 1H, 3-H), 5.12(m, 2H, 32-H, 37-H), 3.54(m, 1H, 11-H), 3.28(m, 2H, 31-H), 2.66(m, 2H, 26-H), 2.56(d, J = 9.4 Hz, 1H, 22- H), 2.37(dd, J = 13.6,4.7 Hz, 2H, 21-H), 2.08(m, 2H, 36-H), 1.76(s, 3H, 25- H), 1.74(s, 3H, 29-H), 1.68(s, 5H, 20-H, 34-H), 1.58(s, 3H, 39-H), 1.44(s, 3H, 35-H), 1.40(s, 3H, 40-H), 1.32(s, 3H, 24-H), 1.28(s, 3H, 19-H)；ESI-MS m/ z:736.20 [M+Na]+。
The preparation of 12 N-3- of embodiment (1- imidazole radicals) gamboge propionamide
With the step of embodiment 1 two, difference is experimental method, and 1- (3- aminopropyl) imidazoles is replaced 1a(66 mg, 0.53 mmol), obtain 12,306 mg of yellow solid, yield 87%.
Compound 12,1H NMR (CDCl3, 500 MHz) δ: 12.87(s, 1H, 6-OH), 8.22(d, J = 6.6 Hz, 1H, CONH), 7.58(d, J = 6.8 Hz, 1H, 10-H), 7.56(s, 1H, 2’-CH), 7.07(s, 1H, 4’-CH), 7.00(s, 1H, 5’-CH), 6.69(t, J = 10.5 Hz, 1H, 4-H), 6.52(d, J = 5.1 Hz, 1H, 27-H), 5.49(d, J = 10.2 Hz, 1H, 3-H), 4.14(m, 2H, 32-H, 37-H), 4.11(m, 2H, CONHCH2CH2CH 2), 3.52(m, 1H, 11-H), 3.36(m, 2H, 31-H), 3.21(m, 2H, CONHCH 2CH2CH2), 2.72(m, 2H, 26-H), 2.58(d, J = 9.4 Hz, 1H, 22-H), 2.19(s, 2H, 21-H), 1.97(s, 2H, CONHCH2CH 2CH2), 1.80(m, 2H, 36-H), 1.75(s, 3H, 25-H), 1.69 (m, 3H, 29-H), 1.59(s, 2H, 20-H), 1.58(s, 3H, 34-H), 1.46(s, 3H, 39-H), 1.39 (s, 3H, 35-H), 1.35(s, 3H, 40-H), 1.28(m, 6H, 24-H, 19-H)；ESI-MS m/z:736.20 [M+Na]+。
The preparation of 13 compound of embodiment 13 gambogicacid -2- (1- imidazole radicals) ethyl ester
With the step of embodiment 1 two, difference is experimental method, and 1- (2- hydroxyethyl) imidazoles is replaced replacement 1a, is obtained 13,410 mg of yellow solid, yield 71%.
Compound 13,1H NMR (CDCl3, 500 MHz) δ: 12.83(s, 1H, 6-OH), 7.53(s, 1H, 2’-CH), 7.47(d, J = 6.9 Hz, 1H, 10-H), 7.09(s, 1H, 4’-CH), 6.95(s, 1H, 5’- CH), 6.69(d, J = 10.1 Hz, 1H, 4-H), 6.26(m, 1H, 27-H), 5.49(d, J = 10.1 Hz, 1H, 3-H), 5.14(m, 2H, 32-H, 37-H), 4.32(t, J = 5.5 Hz, 2H, COOCH2), 4.21(m, 2H, COOCH2CH2), 3.56(m, 1H, 11-H), 3.27(m, 2H, 31-H), 2.71(m, 2H, 26-H), 2.55 (d, J = 9.3 Hz, 1H, 22-H), 2.37(m, 2H, 21-H), 2.19(s, 5H, 36-H, 25-H), 2.07 (s, 3H, 29-H), 1.77(s, 2H, 20-H), 1.74(s, 3H, 34-H), 1.68(s, 3H, 39-H), 1.58 (s, 3H, 35-H), 1.45(s, 3H, 40-H), 1.36(s, 3H, 24-H), 1.33(s, 3H, 19-H)；ESI-MS m/z:723.20 [M+H]+。
The preparation of embodiment 14 N- methyl-N- (3- methylamine) gamboge propionamide
Gambogicacid (0.20 g, 0.32 mmol) and n-hydroxysuccinimide (HOSU) (73 mg, 0.64 mmol) is molten In the drying CH of 10 ml2Cl2, it is placed in -10~10 DEG C of ice bath and mixing 30 min of reaction is sufficiently stirred, DCC(bis- is then added Cyclohexyl diimine) (0.13 g, 0.64 mmol) stirring, it is warmed to room temperature, reaction 1 hour is stirred at room temperature, filter, be concentrated, do It is dry, N is added, N- dimethyl -1,3- propane diamine (79 mg, 0.64 mmol) is dissolved in the THF solution of 15 ml, is placed in -10~10 DEG C ice bath in be sufficiently stirred, reaction 15 hours after, ethyl acetate extraction, saturated salt solution washing, separate ethyl acetate layer, nothing Aqueous sodium persulfate is dry, is spin-dried for being concentrated, column chromatography, and Shi You Mi ∕ ethyl acetate (2:1) purifying obtains yellow jelly 14,163 Mg, yield 74%.
Compound 14,1H NMR (CDCl3, 500 MHz) δ: 11.95(s, 1H, 6-OH), 7.51(d, J = 6.9 Hz, 1H, 10-H), 6.69(d, J = 10.0 Hz, 1H, 4-H), 5.92(s, 1H, 27-H), 5.48(m, 1H, 3-H), 5.23(m, 2H, 32-H, 37-H), 3.33(d, J =7.5 Hz, 1H, 11-H), 3.10(s, 2H, 31-H), 2.83(d, J = 8.3 Hz, 2H, 26-H), 2.54(d, J = 10.0 Hz, 1H, 22-H), 2.35(s, 3H, NCH3), 2.30(m, 2H, 21-H), 2.27(s, 2H, NCH2CH2CH 2), 2.08(s, 3H, NHCH 3), 2.06 (s, 2H, 36-H), 1.99(s, 1H, NH), 1.76(s, 5H, 25-H, NCH2CH 2CH2), 1.71(s, 3H, 29- H), 1.67(s, 5H, 20-H, 34-H), 1.58(s, 3H, 39-H), 1.46(s, 3H, 35-H), 1.41(s, 3H, 40-H), 1.30(s, 3H, 24-H), 1.28(s, 3H, 19-H), 1.16(s, 2H, NCH 2CH2CH2)； ESI- MS m/z:713.25 [M+H]+。
The preparation of 15 N-3- of embodiment (1- pyrrolidines) gamboge propionamide
Experimental method replaces N with embodiment 14, by 1- (3- aminopropyl) pyrrolidines, and N- dimethyl -1,3- propane diamine obtains 15,180 mg of yellow jelly, yield 76%.
Compound 15,1H NMR (CDCl3, 500 MHz) δ: 11.97(s, 1H, 6-OH), 8.01(d, J = 8.6 Hz, 1H, CONH), 7.58(m, 1H, 10-H), 6.70(m, 1H, 4-H), 5.88(d, J = 12.3 Hz, 1H, 27-H), 5.34(t, J = 8.3 Hz, 1H, 3-H), 5.10(m, 2H, 32-H, 37-H), 3.50(m, 1H, 11-H), 3.30(m, 2H, 31-H), 2.82(m, 2H, 26-H), 2.55(d, J = 9.3 Hz, 1H, 22-H), 2.34(d, J = 9.0 Hz, 2H, 21-H), 2.04(s, 2H, CONHCH2CH2CH 2), 1.98(m, 2H, 36-H), 1.90(s, 2H, 2’-CH2), 1.82(s, 2H, 5’-CH2), 1.76(m, 3H, 25-H), 1.70(s, 3H, 29- H), 1.67(s, 5H, 20-H, 34-H), 1.61(s, 2H, CONHCH2CH 2CH2), 1.59(s, 2H, 3’-CH2), 1.58(s, 2H, 4’-CH2), 1.46(s, 3H, 39-H), 1.41(s, 3H, 35-H), 1.38(s, 3H, 40-H), 1.31(s, 3H, 24-H), 1.29(s, 3H, 19-H), 1.17(d, J = 8.1 Hz, 2H, CONHCH 2CH2CH2)； ESI-MS m/z:739.60 [M+H]+。
The extracorporeal anti-tumor cell activity of 16 Gamboges acid derivative of embodiment is tested
Using tetrazolium method (3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium Bromide, MTT), with gambogicacid (GA) for positive control, determining synthesized Gamboges acid derivative, (embodiment 1~15 is made Standby obtained compound 1~15) to lung carcinoma cell (A549), liver cancer cells (HepG-2), breast cancer cell (MCF-7) half Inhibition concentration IC50Value, as a result such as table 1.
IC of the table 1 to tumour cell50Value
Cyano has stronger polarity, is a good hydrogen bond receptor, and therefore, introducing cyano in drug molecule can be with The solubility of drug is effectively improved, bioavilability is improved；Pyrimidine and imidazoles are nitrogenous aromatic heterocycle compounds, are had weak Alkalinity is good hydrogen bond receptor, can form hydrogen bond with water and increase water solubility；The nitrogenous non-aromatic heterocyclyl groups group such as pyrrolidines Also it can be used as hydrogen bond receptor, increase water-soluble.

Claims (4)

1. a kind of gambogic acid-type derivative, which is characterized in that the structural formula of the Gamboges acid derivative are as follows:
Or。
2. the preparation method of gambogic acid-type derivative described in claim 1, which is characterized in that the preparation of gambogic acid-type derivative Method is gambogicacid and alcohol, and in organic solvent dichloromethane, reaction obtains corresponding under the action of catalyst EDCI and DMAP Compound, i.e. gambogic acid-type derivative.
3. the preparation method of gambogic acid-type derivative according to claim 2, which is characterized in that the reaction time is 24h。
4. gambogic acid-type derivative described in claim 1 is preparing anti-lung-cancer medicament or/and medicines resistant to liver cancer or/and anti-breast cancer Application in drug.
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