CN116444508A - Brefeldin A derivative and preparation method and application thereof - Google Patents

Brefeldin A derivative and preparation method and application thereof Download PDF

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CN116444508A
CN116444508A CN202310249708.XA CN202310249708A CN116444508A CN 116444508 A CN116444508 A CN 116444508A CN 202310249708 A CN202310249708 A CN 202310249708A CN 116444508 A CN116444508 A CN 116444508A
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brefeldin
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李达翃
华会明
潘华奇
王茗莹
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Shenyang Pharmaceutical University
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses a brefeldin A derivative, a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. According to the invention, the brefeldin A is used as a lead compound, a series of brefeldin A derivatives are designed and synthesized, the biological activity of the synthetic brefeldin A derivatives in the aspect of resisting tumors is tested, and pharmacological tests prove that the target derivatives prepared by the method have the effect of resisting tumor cell proliferation and good selectivity on normal cells, and can be used for further preparing antitumor drugs.

Description

Brefeldin A derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, relates to 5- (4-hydroxyphenyl) -3H-1, 2-dithiole-3-thione derivatives of brefeldin A, a preparation method and application thereof, and in particular relates to a series of brefeldin A derivatives with anti-tumor activity, a preparation method and application thereof in anti-tumor aspect.
Background
Brefeldin A is a macrolide compound and has various biological activities such as antibiosis, antivirus, antimitotic, antitumor and the like. Among them, the anticancer activity of brefeldin a has attracted extensive attention from researchers. Brefeldin a can inhibit the growth of various tumor cell lines by inducing apoptosis, which makes it one of the hotspot lead compounds for drug development. The related research of the application of the brefeldin A derivative to the antitumor drugs is less, and the research of the structural modification and the derivative synthesis of the brefeldin A is more and more emphasized, so that more derivatives with the activity of resisting the proliferation of various tumor cells are expected to be applied to clinical drugs.
Disclosure of Invention
In order to solve the technical problems in the background technology, the invention aims to provide a series of brefeldin A derivatives with anti-tumor activity, a preparation method and application thereof in anti-tumor aspect.
In order to solve the technical problems, the invention provides the following technical scheme:
the structural general formula of the brefeldin A derivatives is shown in formula 4, formula 5, formula 9, formula 10 and formula 11:
wherein R is a benzene ring or an alkyl group having 1 to 6 carbon atoms; n is an integer of 1 to 8.
Based on the technical scheme, further, R is benzene ring or alkyl containing 2-6 carbon atoms; n is an integer of 2 to 8.
Based on the technical scheme, further, the structural formula of the brefeldin A derivative is shown as follows:
in another aspect, the present invention provides a preparation method of the above brefeldin a derivative, wherein the preparation route of the preparation method is as follows:
a: anhydride reagents, TEA, DMAP;
b：DMAP,EDCI；
c: bromohydrin reagent, K 2 CO 3 。
Based on the technical scheme, the preparation method is further as follows:
the preparation method of the derivatives 4 and 5 comprises the following steps:
the preparation method comprises the steps of dissolving brefeldin A (56.1 mg,0.2 mmol) and anhydride reagents (0.25-0.5 mmol) in an organic solvent, adding triethylamine (83-139 mu L, 0.6-1 mmol) and catalytic amount of DMAP (2.4 mg,0.02 mmol), reacting at room temperature for 10-24 h, dissolving the obtained compound 2 or compound 3 and compound 6 (22.6-90.4 mg,0.1-0.4 mmol) in the organic solvent, adding EDCI (95.9-191.7 mg, 0.5-1.0 mmol) and catalytic amount of DMAP (2.4 mg,0.02 mmol), reacting at room temperature for 4-10 h, loading the obtained product onto a silica gel column, and gradient eluting with DCM/MeOH mixed solution to obtain brefeldin A derivatives 4 or 5;
the preparation method of the derivatives 9, 10 and 11 comprises the following steps:
(1) Compound 6 (226 mg,1 mmol) and bromohydrin reagent (2 mmol) were dissolved in an organic solvent and K was added 2 CO 3 Reacting for 4-8 h at 80 ℃, and loading the obtained productEluting with PE/EA mixed solution to obtain compound 7;
(2) The compound 7 and anhydride reagent are respectively dissolved in an organic solvent, triethylamine (83-139 mu L, 0.6-1 mmol) and catalytic amount of DMAP (2.4 mg,0.02 mmol) are added, the reaction is carried out for 10-24 hours at room temperature, the obtained compound 8 and the brefeldin A are dissolved in the organic solvent, EDCI (95.9-191.7 mg, 0.5-1.0 mmol) and catalytic amount of DMAP (2.4 mg,0.02 mmol) are added, the reaction is carried out for 4-10 hours at room temperature, the obtained product is loaded on a silica gel column chromatography column, and gradient elution is carried out by using DCM/MeOH mixed solution, thus obtaining the brefeldin A derivative 9, 10 or 11.
Based on the technical scheme, further, the anhydride reagent comprises succinic anhydride, glutaric anhydride or phthalic anhydride.
Based on the technical scheme, the bromohydrin reagent further comprises 2-bromoethanol, 4-bromobutanol or 6-bromohexanol.
Based on the above technical scheme, further, the organic solvent comprises chloromethane, dichloromethane, trichloromethane or acetone.
In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the above-described brefeldin a derivatives.
Based on the technical scheme, the medicine composition further comprises a therapeutically effective amount of the brefeldin A derivative and a pharmaceutically acceptable carrier.
The invention also provides application of the brefeldin A derivative and the pharmaceutical composition in preparing medicines for treating tumor diseases.
Further, the tumor includes breast cancer tumor, lung cancer tumor, prostate cancer tumor, malignant melanoma tumor, cervical cancer tumor or liver cancer tumor.
Compared with the prior art, the invention has the following beneficial effects:
the invention takes the brefeldin A as a lead compound, designs and synthesizes a series of brefeldin A derivatives, tests the biological activity of the synthesized derivatives in the aspect of resisting tumors, and pharmacological tests prove that part of target derivatives prepared by the invention have excellent proliferation activity of resisting human breast cancer cells, human lung cancer cells, human prostate cancer cells, human malignant melanoma cells, human cervical cancer cells and human liver cancer cells and good selectivity to normal cells, and can be used for further preparing antitumor drugs.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way.
The synthetic route of the derivative of the embodiment of the invention is as follows:
reaction reagents and conditions: (a) the corresponding anhydride reagent, TEA, DMAP, rt, 10-24 h; (b) DMAP, EDCI, rt, 4-10 h; (c) Corresponding bromohydrin reagent, K 2 CO 3 ,80℃,6h。
Example 1
The preparation method of the brefeldin A derivatives 4a and 5a mainly comprises the following steps:
(1) Brefeldin A (56.1 mg,0.2 mmol) and succinic anhydride (25.0 mg,0.25 mmol) were dissolved in 10mL of dichloromethane, triethylamine (83. Mu.L, 0.6 mmol) and catalytic amounts of DMAP (2.4 mg,0.02 mmol) were added, reacted at room temperature for 12h, extracted with dichloromethane (3X 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
(2) The resultant product and compound 6 (67.8 mg,0.3 mmol) were dissolved in 10mL of dichloromethane, EDCI (191.7 mg,1.0 mmol) and a catalytic amount of DMAP (2.4 mg,0.02 mmol) were added, reacted at room temperature for 8 hours, extracted with dichloromethane (3X 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and eluted with a silica gel column chromatography gradient (dichloromethane: anhydrous methanol=400:1-100:1) to give compounds 4a and 5a as orange oil, respectively, in yields of 25% and 12%, respectively.
Compound 4a was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.67(4H,m,Ar-H),7.39(2H,m,2×-C＝CH),7.23(5H,m,H-3,Ar-H),5.72(2H,m,H-2,H-11),5.32(1H,ddd,J＝10.1,3.3,1.8Hz,H-10),5.19(2H,m,H-4,H-7),4.86(1H,m,H-15),2.92(4H,m,2×-COCH 2 -),2.80(2H,m,-COCH 2 -),2.71(2H,m,-COCH 2 -),0.90～2.52(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.5(×2),171.6,171.5,171.4,170.9,170.4,170.2,165.5,153.4(×2),146.5,136.0(×2),135.4,131.4,129.3,129.2,128.2(×4),122.8(×4),118.7,75.8,71.9,49.8,44.0,40.0,38.3,34.1,31.7,29.3,29.2(×2),28.8,26.5,20.7。
compound 5a was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.68(2H,d,J＝8.6Hz,Ar-H),7.40(1H,s,-C＝CH),7.24(3H,m,H-3,Ar-H),5.71(2H,m,H-2,H-11),5.29(2H,m,H-7,H-10),4.86(1H,m,H-15),4.31(1H,m,H-4),2.94(2H,m,-COCH 2 -),2.82(2H,m,-COCH 2 -),0.91～2.46(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.5,171.7,171.0,170.2,165.6,153.5,146.8,136.3,136.1,130.8,129.3,128.2(×2),122.9(×2),118.4,72.4,71.9,49.5,44.3,43.2,41.0,34.1,31.8,29.2,28.9,26.6,20.8。
example 2
The preparation method of the brefeldin A derivatives 4b and 5b, the experimental procedure refers to the synthesis method of example 1, except that succinic anhydride in step (1) is replaced by glutaric anhydride, and silica gel column chromatography gradient elution is carried out to obtain orange oily compounds 4b and 5b respectively, with yields of 22% and 14%, respectively.
Compound 4b was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.68(4H,m,Ar-H),7.39(2H,s,2×-C＝CH),7.24(5H,m,H-3,Ar-H),5.72(2H,m,H-2,H-11),5.30(1H,ddd,J＝10.1,3.2,1.6Hz,H-4),5.22(1H,dd,J＝15.1,9.6Hz,H-10),5.16(1H,m,H-7),4.87(1H,m,H-15),2.68(4H,m,2×-COCH 2 -),2.54(2H,m,-COCH 2 -),0.90～2.51(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,-COCH 2 -,2×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.5(×2),172.2,171.6,171.5(×2),170.8,170.7,165.5,153.4(×2),146.9,136.0(×2),135.5,131.4,129.3,129.2,128.2(×4),122.9(×2),122.8(×2),118.5,76.4,75.3,71.9,49.8,44.1,40.1,38.3,34.1,33.3(×2),33.2,32.9,31.8,26.5,20.7,19.9,19.8。
compound 5b was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.69(2H,d,J＝8.6Hz,Ar-H),7.41(1H,s,-C＝CH),7.24(3H,m,H-3,Ar-H),5.70(2H,m,H-2,H-11),5.29(2H,m,H-7,H-10),4.86(1H,m,H-15),4.32(1H,m,H-4),2.69(2H,m,-COCH 2 -),2.55(2H,m,-COCH 2 -),0.90～2.47(17H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.5,171.8(×2),170.7,165.6,153.5,147.1,136.2,136.0,130.7,129.2,128.2(×2),122.9(×2),118.3,76.5,72.3,71.9,49.5,44.3,43.3,40.9,34.1,33.3,33.0,31.8,26.6,20.8,19.9。
example 3
The preparation method of the brefeldin A derivatives 4c and 5c, the experimental procedure refers to the synthesis method of example 1, except that succinic anhydride in step (1) is replaced by phthalic anhydride, and silica gel column chromatography gradient elution is carried out to obtain orange oily compounds 4c and 5c respectively, with yields of 27% and 10%, respectively.
Compound 4c was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.90(2H,m,Ar-H),7.80(2H,m,Ar-H),7.64(8H,m,Ar-H),7.38(4H,m,Ar-H),7.34(2H,m,2×-C＝CH),7.24(1H,dd,J＝15.7,3.4Hz,H-3),5.75(2H,m,H-2,H-11),5.51(1H,ddd,J＝10.4,3.0,1.7Hz,H-10),5.36(1H,m,H-7),5.22(1H,dd,J＝15.1,9.6Hz,H-4),4.85(1H,m,H-15),0.87～2.59(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.4(×2),171.7,171.4,166.4,165.7,165.5,165.4,165.3,153.7(×2),146.3,136.0,135.9,135.4,132.3,131.9(×3),131.5(×2),131.4,131.3,131.1,128.2(×4),122.9(×2),122.7(×2),118.8,77.7,71.9,50.0,44.2,39.8,38.4,34.0,31.7,26.5,20.7。
compound 5c was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.90(2H,m,Ar-H),7.69(4H,m,Ar-H),7.42(3H,m,-C＝CH,Ar-H),7.29(1H,dd,J＝15.7,3.4Hz,H-3),5.81(1H,dd,J＝15.7,1.7Hz,H-2),5.72(1H,m,H-11),5.51(1H,ddd,J＝10.6,3.2,1.8Hz,H-10),5.30(1H,dd,J＝15.4,9.7Hz,H-7),4.84(1H,m,H-15),4.30(1H,m,H-4),0.90～2.51(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.5,171.8,165.8,165.6,165.5,153.8,146.6,136.3,136.0,132.0,131.8(×2),131.1,130.8,129.4,129.3(×2),128.3(×2),122.9(×2),118.6,77.8,72.4,71.9,49.7,44.4,43.2,41.0,34.0,31.8,26.6,20.8。
example 4
The preparation method of the brefeldin A derivatives 9a and 10a mainly comprises the following steps:
(1) Compound 6 (226 mg,1 mmol) was dissolved in 10mL of acetone and K was added 2 CO 3 (414.6 mg,3 mmol) and 2-bromoethanol (213 μl,3 mmol) were reacted under stirring at 80deg.C for 6h, suction filtered, concentrated under reduced pressure, and chromatographed on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 7a as an orange powder;
(2) Compound 7a and succinic anhydride (100 mg,1 mmol) were dissolved in 10mL of dichloromethane, triethylamine (417. Mu.L, 3 mmol) and catalytic amount of DMAP (12.0 mg,0.1 mmol) were added, reacted at room temperature for 12h, extracted with dichloromethane (3X 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
(3) Brefeldin a (56.1 mg,0.2 mmol) and the resulting product were dissolved in 10mL of dichloromethane, EDCI (191.7 mg,1.0 mmol) and a catalytic amount of DMAP (2.4 mg,0.02 mmol) were added, reacted at room temperature for 8h, dichloromethane extraction (3×30 mL), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and gradient elution by silica gel column chromatography (dichloromethane: anhydrous methanol=400:1 to 100:1) to give orange oily compounds 9a and 10a, respectively, in 30% and 32% yields.
Compound 9a was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.61(4H,m,Ar-H),7.38(2H,m,2×-C＝CH),7.23(1H,dd,J＝15.7,3.4Hz,H-3),7.00(4H,m,Ar-H),5.71(2H,m,H-2,H-11),5.23(2H,m,H-4,H-10),5.11(1H,m,H-7),4.86(1H,m,H-15),4.48(4H,m,2×-OCH 2 -),4.23(4H,m,2×-OCH 2 -),2.66(8H,m,4×-COCH 2 -),0.89～2.49(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.2(×2),172.8,172.7,172.2,171.9,171.6,171.0,165.5,161.7(×2),146.7,135.5,134.8(×2),131.3,128.6(×4),124.7,124.6,118.5,115.6(×2),115.5(×2),76.6,75.6,71.9,66.1(×2),62.7,62.6,49.7,44.0,40.0,38.2,34.1,31.8,29.2,28.9(×3),26.5,20.7。
compound 10a was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.62(2H,d,J＝8.7Hz,Ar-H),7.40(1H,s,-C＝CH),7.22(1H,dd,J＝15.7,3.3Hz,H-3),7.00(2H,d,J＝8.7Hz,Ar-H),5.70(2H,m,H-2,H-11),5.27(2H,m,H-4,H-10),4.85(1H,m,H-15),4.49(2H,m,-COOCH 2 -),4.30(1H,m,H-7),4.25(2H,m,-COOCH 2 -),2.71(4H,m,2×-COCH 2 -),0.89～2.44(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.1,172.8,171.9,171.1,165.6,161.7,146.9,136.3,134.8,130.7,128.6(×2),124.6,118.3,115.6(×2),72.3,71.9,66.1,62.7,49.5,44.3,43.2,41.0,34.0,31.8,29.0,28.9,26.6,20.8。
example 5
The preparation method of the brefeldin A derivatives 9b and 10b, the experimental procedure refers to the synthesis method of example 4, except that 2-bromoethanol in step (1) is replaced by 4-bromobutanol, and silica gel column chromatography gradient elution respectively obtains orange oily compounds 9b and 10b with yields of 27% and 32%, respectively.
Compound 9b was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(4H,m,Ar-H),7.39(2H,m,2×-C＝CH),7.21(1H,dd,J＝15.7,3.3Hz,H-3),6.96(4H,m,Ar-H),5.71(2H,m,H-2,H-11),5.23(2H,m,H-4,H-10),5.14(1H,m,H-7),4.85(1H,m,H-15),4.18(4H,m,2×-OCH 2 -),4.05(4H,m,2×-OCH 2 -),2.66(8H,m,4×-COCH 2 -),0.91～2.48(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,4×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1(×2),173.0(×2),172.3,172.0,171.7,171.2,165.5,162.3,162.2,146.7,135.6,134.6(×2),131.3,128.6(×4),124.1(×2),118.5,115.4(×4),76.6,75.5,71.9,67.7(×2),64.3,64.2,49.7,44.0,40.0,38.2,34.1,31.8,29.3,29.0(×3),26.5,25.6(×2),25.3(×2),20.7。
compound 10b was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.61(2H,d,J＝8.7Hz,Ar-H),7.40(1H,s,-C＝CH),7.23(1H,dd,J＝15.7,3.3Hz,H-3),6.96(2H,d,J＝8.8Hz,Ar-H),5.69(2H,m,H-2,H-11),5.28(2H,m,H-4,H-10),4.85(1H,m,H-15),4.31(1H,m,H-7),4.19(2H,t,J＝6.2Hz,-COOCH 2 -),4.06(2H,t,J＝5.9Hz,-COOCH 2 -),2.67(4H,m,2×-COCH 2 -),0.89～2.45(19H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,2×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1,173.1,172.0,171.2,165.6,162.3,147.0,136.3,134.6,130.7,128.6(×2),124.1,118.3,115.4(×2),76.7,72.3,71.9,67.7,64.3,49.5,44.3,43.2,40.9,34.0,31.8,29.1,29.0,26.6,25.6,25.3,20.8。
example 6
The preparation method of the brefeldin A derivatives 9c and 10c, the experimental procedure referred to the synthesis method of example 4, was only different in that 2-bromoethanol in step (1) was replaced with 6-bromohexanol, and the silica gel column chromatography gradient elution gave orange oily compounds 9c and 10c, respectively, in 34% and 31% yields, respectively.
Compound 9c was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(4H,m,Ar-H),7.39(2H,m,2×-C＝CH),7.21(1H,dd,J＝15.7,3.4Hz,H-3),6.95(4H,m,Ar-H),5.71(2H,m,H-2,H-11),5.23(2H,m,H-4,H-10),5.13(1H,m,H-7),4.85(1H,m,H-15),4.10(4H,m,2×-OCH 2 -),4.02(4H,m,2×-OCH 2 -),2.64(8H,m,4×-COCH 2 -),0.91～2.47(31H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,8×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1(×2),173.1(×2),172.3,172.0,171.7,171.2,165.5,162.5(×2),146.8,135.6,134.5(×2),131.2,128.6(×4),124.0,123.9,118.5,115.4(×4),76.6,75.5,71.8,68.2(×2),64.7,64.6,49.7,44.0,40.0,38.2,34.1,31.7,29.3,29.1,29.0(×2),28.9(×2),28.5(×2),26.5,25.6(×4),20.7。
compound 10c was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.61(2H,d,J＝8.7Hz,Ar-H),7.40(1H,s,-C＝CH),7.22(1H,dd,J＝15.7,3.3Hz,H-3),6.96(2H,d,J＝8.7Hz,Ar-H),5.69(2H,m,H-2,H-11),5.28(2H,m,H-4,H-10),4.85(1H,m,H-15),4.31(1H,m,H-7),4.12(2H,t,J＝6.7Hz,-COOCH 2 -),4.02(2H,t,J＝6.4Hz,-COOCH 2 -),2.66(4H,m,2×-COCH 2 -),0.89～2.45(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,4×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1,173.2,172.1,171.3,165.6,162.5,147.0,136.3,134.5,130.7,128.6(×2),124.0,118.3,115.4(×2),76.7,72.4,71.8,68.2,64.7,49.5,44.3,43.2,40.9,34.0,31.8,29.1,29.0,28.9,28.5,26.6,26.0(×2),20.8。
example 7
The preparation method of the brefeldin A derivatives 9d and 10d, the experimental procedure refers to the synthesis method of example 4, except that succinic anhydride in the step (2) is replaced by glutaric anhydride, and silica gel column chromatography gradient elution is carried out to obtain orange oily compounds 9d and 10d respectively, with yields of 25% and 31%, respectively.
Compound 9d was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.61(4H,m,Ar-H),7.38(2H,m,2×-C＝CH),7.23(1H,dd,J＝15.7,3.5Hz,H-3),6.98(4H,m,Ar-H),5.71(1H,m,H-11),5.65(1H,dd,J＝15.7,1.7Hz,H-2),5.25(1H,ddd,J＝10.1,3.2,1.7Hz,H-4),5.17(1H,dd,J＝15.2,9.6Hz,H-10),5.11(1H,m,H-7),4.85(1H,m,H-15),4.46(4H,m,2×-OCH 2 -),4.24(4H,m,2×-OCH 2 -),0.88～2.48(27H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,6×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1(×2),172.8,172.7(×2),172.6,172.3,171.6,165.5,161.7(×2),147.0,135.5,134.8,134.7,131.3,128.6(×4),124.6(×2),118.4,115.5(×4),76.3,75.2,71.9,66.1(×2),62.4,62.3,49.6,44.0,40.0,38.2,34.0,33.4,33.0(×2),32.9,31.7,26.5,20.7,20.0(×2)。
compound 10d was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.63(2H,d,J＝8.7Hz,Ar-H),7.41(1H,s,-C＝CH),7.21(1H,dd,J＝15.7,3.3Hz,H-3),7.00(2H,d,J＝8.8Hz,Ar-H),5.67(2H,m,H-2,H-11),5.24(2H,m,H-7,H-10),4.84(1H,m,H-15),4.49(2H,m,-COOCH 2 -),4.28(3H,m,H-4,-COOCH 2 -),0.87～2.48(21H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,3×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.2,172.8,172.6,171.8,165.6,161.7,147.2,136.3,134.8,130.7,128.6(×2),124.6,118.2,115.6(×2),76.4,72.3,71.9,66.1,62.4,49.5,44.3,43.3,40.9,34.0,33.1,33.0,31.8,26.6,20.8,20.1。
example 8
The preparation method of the brefeldin A derivatives 9e and 10e, the experimental procedure refers to the synthesis method of example 7, except that 2-bromoethanol in the step is replaced by 4-bromobutanol, and silica gel column chromatography gradient elution is performed to obtain orange oily compounds 9e and 10e respectively with yields of 29% and 35%, respectively.
Compound 9e was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(4H,m,Ar-H),7.39(2H,m,2×-C＝CH),7.22(1H,dd,J＝15.7,3.4Hz,H-3),6.96(4H,m,Ar-H),5.69(2H,m,H-2,H-11),5.25(1H,ddd,J＝10.3,3.1,1.7Hz,H-4),5.19(1H,dd,J＝15.2,9.6Hz,H-10),5.12(1H,m,H-7),4.85(1H,m,H-15),4.16(4H,m,2×-OCH 2 -),4.05(4H,m,2×-OCH 2 -),0.89～2.49(35H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,10×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0(×2),173.1,173.0,172.9,172.4,171.7,165.5,162.3,162.2,147.0,135.5,134.6(×2),131.3,128.6(×4),124.1(×2),118.4,115.4(×4),76.3,75.2,71.9,67.7(×2),64.0,63.9,49.7,44.0,40.1,38.2,34.0,33.5,33.2(×2),33.1,31.7,26.5,25.7(×2),25.3(×2),20.7,20.1,20.0。
compound 10e was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(2H,d,J＝8.8Hz,Ar-H),7.40(1H,s,-C＝CH),7.23(1H,dd,J＝15.7,3.4Hz,H-3),6.96(2H,d,J＝8.7Hz,Ar-H),5.69(2H,m,H-2,H-11),5.27(2H,m,H-7,H-10),4.84(1H,m,H-15),4.31(1H,m,H-4),4.17(2H,t,J＝6.2Hz,-COOCH 2 -),4.06(2H,t,J＝5.9Hz,-COOCH 2 -),0.89～2.48(25H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,5×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1,173.1,172.7,171.8,165.6,162.3,147.2,136.3,134.6,130.7,128.6(×2),124.1,118.2,115.4(×2),76.4,72.3,71.9,67.7,64.0,49.5,44.3,43.2,40.9,34.0,33.2(×2),31.8,26.6,25.7,25.3,20.8,20.1。
example 9
The preparation method of the brefeldin A derivatives 9f and 10f, the experimental procedure refers to the synthesis method of example 7, except that 2-bromoethanol in the step is replaced by 6-bromohexanol, and the silica gel column chromatography gradient elution respectively obtains orange oily compounds 9f and 10f with the yields of 23% and 36%, respectively.
Compound 9f was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(4H,m,Ar-H),7.39(2H,m,2×-C＝CH),7.22(1H,dd,J＝15.7,3.4Hz,H-3),6.96(4H,m,Ar-H),5.69(2H,m,H-2,H-11),5.25(1H,ddd,J＝10.3,3.1,1.7Hz,H-4),5.19(1H,dd,J＝15.2,9.6Hz,H-10),5.12(1H,m,H-7),4.85(1H,m,H-15),4.16(4H,m,2×-OCH 2 -),4.05(4H,m,2×-OCH 2 -),0.89～2.49(43H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,14×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1(×2),173.1(×2),172.9,172.4,171.7,165.5,162.5,162.4,147.0,135.6,134.5(×2),131.2,128.6(×4),124.0,123.9,118.4,115.4(×4),76.2,75.1,71.9,68.2(×2),64.4(×2),49.7,44.1,40.1,38.3,34.1,33.5,33.3,33.2,33.1,31.7,28.9(×2),28.5(×2),26.5,25.6(×4),20.7,20.1(×2)。
compound 10f was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.60(2H,d,J＝8.6Hz,Ar-H),7.40(1H,s,-C＝CH),7.23(1H,dd,J＝15.7,3.4Hz,H-3),6.96(2H,d,J＝8.8Hz,Ar-H),5.68(2H,m,H-2,H-11),5.28(2H,m,H-7,H-10),4.85(1H,m,H-15),4.31(1H,m,H-4),4.10(2H,t,J＝6.6Hz,-COOCH 2 -),4.02(2H,t,J＝6.4Hz,-COOCH 2 -),0.88～2.47(29H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,7×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0,173.2,172.8,171.9,165.6,162.5,147.2,136.3,134.5,130.7,128.6(×2),123.9,118.2,115.4(×2),76.3,72.3,71.9,68.2,64.4,49.5,44.3,43.2,40.9,34.0,33.3,33.2,31.8,28.9,28.5,26.6,25.6(×2),20.8,20.1。
example 10
Preparation methods of brefeldin A derivatives 9g, 10g and 11a, experimental procedures refer to the synthesis method of example 4, except that succinic anhydride in step (2) is replaced with phthalic anhydride, and silica gel column chromatography gradient elution respectively obtain orange oily compounds 9g, 10g and 11a with yields of 23%, 12% and 10%, respectively.
Compound 9g characterization data are as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.75(2H,m,Ar-H),7.69(2H,m,Ar-H),7.56(8H,m,Ar-H),7.38(1H,s,-C＝CH),7.35(1H,s,-C＝CH),7.24(1H,dd,J＝15.7,3.5Hz,H-3),6.96(4H,m,Ar-H),5.82(1H,dd,J＝15.7,1.6Hz,H-2),5.74(1H,m,H-11),5.51(1H,ddd,J＝10.3,3.2,1.7Hz,H-10),5.29(1H,m,H-7),5.22(1H,dd,J＝15.2,9.5Hz,H-4),4.88(1H,m,H-15),4.64(4H,m,2×-OCH 2 -),4.28(4H,m,2×-OCH 2 -),0.90～2.53(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.1(×2),172.7,172.6,167.3,167.0,166.6,166.1,165.5,161.8,161.7,153.7(×2),146.5,135.4,134.8,134.7,132.0,131.7,131.6(×2),131.5(×2),131.4,131.3,131.2,129.1,128.9(×3),128.6(×2),128.5(×2),124.6,124.5,118.8,115.6(×2),115.5(×2),77.5,76.7,72.0,66.0(×2),63.5,63.4,50.0,44.2,39.9,38.3,34.1,31.8,26.5,20.8。
compound 10g characterization data are as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.81(1H,m,Ar-H),7.71(1H,m,Ar-H),7.61(2H,d,J＝8.7Hz,Ar-H),7.58(2H,m,Ar-H),7.39(1H,s,-C＝CH),7.27(1H,m,H-3),7.02(2H,d,J＝8.8Hz,Ar-H),5.82(1H,dd,J＝15.7,1.6Hz,H-2),5.71(1H,m,H-11),5.43(1H,ddd,J＝10.5,3.1,1.9Hz,H-4),5.30(1H,dd,J＝15.3,9.6Hz,H-10),4.87(1H,m,H-15),4.69(2H,t,J＝4.8Hz,-COOCH 2 -),4.34(3H,m,H-7,-COOCH 2 -),0.91～2.48(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.2,172.8,167.4,165.9,165.6,161.8,146.7,136.3,134.7,132.1,131.6,131.3,131.0,130.8,129.1,128.9,128.6(×2),124.5,118.6,115.7(×2),77.6,72.4,71.9,66.0,63.5,49.7,44.4,43.2,41.1,34.1,31.8,26.6,20.8。
compound 11a was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.71(2H,m,Ar-H),7.62(2H,d,J＝8.7Hz,Ar-H),7.55(2H,m,Ar-H),7.40(1H,s,-C＝CH),7.34(1H,dd,J＝15.7,3.1Hz,H-3),7.02(2H,d,J＝8.7Hz,Ar-H),5.91(1H,dd,J＝15.7,1.8Hz,H-2),5.71(1H,m,H-11),5.32(1H,m,H-7),5.20(1H,dd,J＝15.2,9.3Hz,H-10),4.86(1H,m,H-15),4.70(2H,m,-COOCH 2 -),4.36(2H,t,J＝4.6Hz,-COOCH 2 -),4.15(1H,m,H-4),0.90～2.44(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 )；
13 C NMR(150MHz,CDCl 3 ):δ215.1,172.8,167.5,166.8,166.1,161.8,151.3,135.9,134.8,132.1,131.7,131.3,131.2,131.0,129.0,128.9,128.6(×2),124.6,117.8,115.6(×2),76.7,75.7,71.7,66.1,63.5,52.3,43.9,39.9,38.6,34.1,31.7,26.6,20.8。
example 11
Preparation methods of brefeldin A derivatives 9h, 10h and 11b, experimental procedures refer to the synthetic method of example 10, except that 2-bromoethanol in the procedure is replaced by 4-bromobutanol, and silica gel column chromatography gradient elution respectively obtain orange oily compounds 9h, 10h and 11b with yields of 25%, 12% and 13%, respectively.
Compound 9h characterization data are as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.76(1H,m,Ar-H),7.70(3H,m,Ar-H),7.55(8H,m,Ar-H),7.39(2H,m,-C＝CH),7.24(1H,dd,J＝15.7,3.5Hz,H-3),6.93(4H,m,Ar-H),5.83(1H,dd,J＝15.7,1.7Hz,H-2),5.74(1H,m,H-11),5.52(1H,ddd,J＝10.3,3.2,1.7Hz,H-10),5.39(1H,m,H-7),5.24(1H,dd,J＝15.1,9.6Hz,H-4),4.86(1H,m,H-15),4.36(4H,m,2×-OCH 2 -),4.02(4H,m,2×-OCH 2 -),0.90～2.59(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,4×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0(×2),173.1,173.0,167.3,167.2,166.9,166.2,165.5,162.3,162.2,146.6,135.6,134.6,134.5,132.3,132.2,132.0,131.5,131.3(×2),131.2,131.1,131.0,129.0,128.8(×3),128.6(×4),124.1,124.0,118.8,115.4(×4),77.5,76.7,71.9,67.7,67.6,65.3,65.1,50.1,44.3,39.9,38.4,34.1,31.7,26.5,25.7,25.6,25.2(×2),20.8。
compound 10h characterization data are as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.79(1H,m,Ar-H),7.70(1H,m,Ar-H),7.58(4H,m,Ar-H),7.39(1H,s,-C＝CH),7.30(1H,dd,J＝15.7,3.4Hz,H-3),6.96(2H,d,J＝8.8Hz,Ar-H),5.83(1H,dd,J＝15.7,1.6Hz,H-2),5.72(1H,m,H-11),5.49(1H,d,J＝10.5Hz,H-4),5.31(1H,dd,J＝15.3,9.7Hz,H-10),4.86(1H,m,H-15),4.37(3H,m,H-7,-COOCH 2 -),4.07(2H,m,-COOCH 2 -),0.90～2.51(19H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,2×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1,173.1,167.5,166.1,165.6,162.3,146.8,136.3,134.6,132.5,131.5,131.1(×2),130.8,129.0,128.8,128.6(×2),124.1,118.6,115.5(×2),77.6,72.4,71.9,67.7,65.2,49.7,44.4,43.2,41.1,34.1,31.8,26.6,25.7,25.2,20.8。
compound 11b was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.69(2H,m,Ar-H),7.56(4H,m,Ar-H),7.40(1H,s,-C＝CH),7.34(1H,dd,J＝15.7,3.2Hz,H-3),6.96(2H,d,J＝8.7Hz,Ar-H),5.91(1H,dd,J＝15.7,1.8Hz,H-2),5.71(1H,m,H-11),5.38(1H,m,H-7),5.21(1H,dd,J＝15.2,9.1Hz,H-10),4.85(1H,m,H-15),4.40(2H,m,-COOCH 2 -),4.15(1H,dt,J＝9.2,2.5Hz,H-4),4.08(2H,m,-COOCH 2 -),0.89～2.47(15H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,2×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0,173.1,167.5,167.1,166.1,162.3,151.4,135.9,134.6,132.3,132.0,131.1,131.0(×2),128.9,128.8,128.6(×2),124.1,117.7,115.4(×2),76.7,75.7,71.7,67.7,65.2,52.3,44.0,39.9,38.6,34.1,31.7,26.6,25.7,25.2,20.8。
example 12
The preparation method of the brefeldin A derivatives 9i, 10i and 11c, the experimental procedure was referred to the synthesis method of example 10, except that 2-bromoethanol in the procedure was replaced with 6-bromohexanol, and the silica gel column chromatography gradient elution gave orange oily compounds 9i, 10i and 11c, respectively, in 22%, 10% and 12% yields, respectively.
Compound 9i was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.74(2H,m,Ar-H),7.68(2H,m,Ar-H),7.58(4H,m,Ar-H),7.53(4H,m,Ar-H),7.38(2H,m,2×-C＝CH),7.31(1H,dd,J＝15.7,3.4Hz,H-3),6.94(4H,m,Ar-H),5.82(1H,dd,J＝15.7,1.8Hz,H-2),5.74(1H,m,H-11),5.52(1H,ddd,J＝10.4,3.3,1.8Hz,H-10),5.40(1H,m,H-7),5.25(1H,dd,J＝15.1,9.6Hz,H-4),4.86(1H,m,H-15),4.29(4H,m,2×-OCH 2 -),3.99(4H,m,2×-OCH 2 -),0.90～2.53(31H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,8×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0(×2),173.1(×2),167.4,167.2,167.0,166.3,165.5,162.5,162.4,146.7,135.7,134.5(×2),132.4,132.2,132.1,131.6,131.3,131.2,131.1,131.0(×2),129.0,128.8(×3),128.5(×4),124.0,123.9,118.7,115.4(×4),77.5,76.7,71.8,68.2(×2),65.7,65.5,50.1,44.3,39.9,38.4,34.1,31.7,28.9(×2),28.4(×2),26.5,25.6(×4),20.8。
compound 10i was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.77(1H,m,Ar-H),7.71(1H,m,Ar-H),7.58(4H,m,Ar-H),7.39(1H,s,-C＝CH),7.31(1H,dd,J＝15.6,3.3Hz,H-3),6.95(2H,d,J＝8.8Hz,Ar-H),5.82(1H,dd,J＝15.6,1.7Hz,H-2),5.72(1H,m,H-11),5.50(1H,ddd,J＝10.5,3.2,1.9Hz,H-4),5.31(1H,dd,J＝15.2,9.6Hz,H-10),4.86(1H,m,H-15),4.33(3H,m,H-7,-COOCH 2 -),4.02(2H,m,-COOCH 2 -),0.90～2.50(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,4×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.1,173.1,167.5,166.2,165.6,162.5,146.8,136.3,134.5,132.6,131.4,131.3,131.0,130.7,129.0,128.8,128.6(×2),124.0,118.6,115.4(×2),77.5,72.5,71.8,68.2,65.7,49.7,44.4,43.2,41.1,34.1,31.8,28.9,28.4,26.6,25.6(×2),20.8。
compound 11c was characterized as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.69(2H,m,Ar-H),7.56(4H,m,Ar-H),7.40(1H,s,-C＝CH),7.34(1H,dd,J＝15.7,3.1Hz,H-3),6.95(2H,d,J＝8.9Hz,Ar-H),5.91(1H,dd,J＝15.7,1.9Hz,H-2),5.71(1H,m,H-11),5.37(1H,m,H-7),5.21(1H,dd,J＝15.2,9.1Hz,H-10),4.85(1H,m,H-15),4.32(2H,t,J＝6.7Hz,-COOCH 2 -),4.15(1H,m,H-4),4.03(2H,t,J＝6.4Hz,-COOCH 2 -),0.90～2.47(23H,m,H-5,H-6a,H-6b,H-8a,H-8b,H-9,H-12a,H-12b,H-13a,H-13b,H-14a,H-14b,-CH 3 ,4×-CH 2 -)；
13 C NMR(150MHz,CDCl 3 ):δ215.0,173.2,167.5,167.2,166.1,162.5,151.4,135.9,134.5,132.5,132.0,131.1,130.9(×2),128.9,128.8,128.6(×2),124.0,117.7,115.4(×2),76.6,75.8,71.7,68.2,65.6,52.2,44.0,39.9,38.6,34.1,31.7,28.9,28.4,26.6,25.7,25.6,20.8。
example 13
This example is an evaluation of the pharmacological activity of the compounds prepared in examples 1 to 12.
Experimental device and reagent
TABLE 1 instruments, reagents and cell lines used in the experimental procedure of this example
Experimental method
Cell growth inhibition activity experimental method
The antiproliferative activity of the target compounds in six cancer cells (human breast cancer cell line MDA-MB-231, human lung cancer cell line A549, human prostate cancer cell line DU-145, human malignant melanoma cell line A375, human cervical cancer cell line Hela and human liver cancer cell line HepG-2, bel-7402) and one normal cell (human normal liver cell line L-02) was examined by CCK-8 method. All cell lines were from Nanjing Keygen Biotech, china, MDA-MB-231, A549, A375 and Hela cell cultures were grown on standard DMEM medium, DU-145, hepG-2, bel-7402 and L-02 on standard RPMI-1640 medium, then on 5% CO 2 After 24h incubation at 37℃in a humid environment, the logarithmically grown cells were seeded in 96-well plates at 37℃and 5% CO 2 Incubating for 24 hours, then adding target compound or positive control (taxol) to different cell lines at predetermined concentration, culturing for 48 hours, carefully sucking the culture solution, adding 90 μl of the corresponding culture medium and 10 μl of mixed solution of CCK-8 to each well, incubating for 1 hour, and measuring OD value of each well on an enzyme-labeling instrument at a wavelength of 450nm, calculating IC of the target compound 50 Values.
Experimental results
TABLE 2 antiproliferative effect of target compounds on different cell lines
a IC 50 : half inhibition concentrations were measured by CCK-8 assay, and the above values are the mean.+ -. Standard deviation of three independent experiments.
Pharmacological tests prove that the target derivative prepared by the invention has proliferation activity in resisting human breast cancer cells, human lung cancer cells, human prostate cancer cells, human malignant melanoma cells, human cervical cancer cells and human liver cancer cells, and part of the target derivative has excellent proliferation activity in resisting human breast cancer cells, human lung cancer cells, human prostate cancer cells, human malignant melanoma cells, human cervical cancer cells and human liver cancer cells and has good selectivity to normal cells, so that the target derivative can be used for further preparing antitumor drugs.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (10)

1. The brefeldin A derivatives are characterized by having structural general formulas shown in formula 4, formula 5, formula 9, formula 10 and formula 11:
wherein R is a benzene ring or an alkyl group having 1 to 6 carbon atoms; n is an integer of 1 to 8.
2. The brefeldin a derivative according to claim 1, wherein R is a benzene ring or an alkyl group having 2 to 6 carbon atoms; n is an integer of 2 to 8.
3. The brefeldin a derivative according to claim 1, wherein the structural formula of the brefeldin a derivative is as follows:
4. a process for the preparation of a brefeldin a derivative according to any one of claims 1 to 3, wherein the preparation route of the process is as follows:
a: anhydride reagents, TEA, DMAP;
b：DMAP,EDCI；
c: bromohydrin reagent, K 2 CO 3 。
5. The preparation method according to claim 4, wherein the preparation method mainly comprises one of the following methods:
the preparation method of the derivatives 4 and 5 comprises the following steps:
dissolving brefeldin A and anhydride reagents in an organic solvent, adding triethylamine and DMAP, reacting for 10-24 hours at room temperature, dissolving the obtained compound 2 or compound 3 and compound 6 in the organic solvent, adding EDCI and catalytic amount of DMAP, reacting for 4-10 hours at room temperature, loading the obtained product on a silica gel column chromatography column, eluting with a DCM/MeOH mixed solution, and obtaining a brefeldin A derivative 4 or 5;
the preparation method of the derivatives 9, 10 and 11 comprises the following steps:
(1) Dissolving compound 6 and bromohydrin reagent in organic solvent, adding K 2 CO 3 Reacting for 4-8 h at 80 ℃, loading the obtained product to a silica gel column chromatography, eluting with a PE/EA mixed solution, and obtaining a compound 7;
(2) Respectively dissolving the compound 7 and an anhydride reagent in an organic solvent, adding triethylamine and DMAP, reacting for 10-24 hours at room temperature, dissolving the obtained compound 8 and the brefeldin A in the organic solvent, adding EDCI and DMAP, reacting for 4-10 hours at room temperature, loading the obtained product on a silica gel column chromatography column, eluting with a DCM/MeOH mixed solution, and obtaining the brefeldin A derivative 9, 10 or 11.
6. The method according to claim 5, wherein the acid anhydride reagent comprises succinic anhydride, glutaric anhydride or phthalic anhydride; the bromohydrin reagent comprises 2-bromoethanol, 4-bromobutanol or 6-bromohexanol; the organic solvent comprises chloromethane, dichloromethane, trichloromethane or acetone.
7. A pharmaceutical composition comprising one or two or more of the brefeldin a derivatives according to any one of claims 1 to 3.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises a therapeutically effective amount of the brefeldin a derivative and a pharmaceutically acceptable carrier.
9. Use of a brefeldin a derivative according to any one of claims 1-3, a pharmaceutical composition according to any one of claims 7-8 for the manufacture of a medicament for the treatment of a neoplastic disease.
10. The use according to claim 9, wherein the tumor comprises a breast cancer tumor, a lung cancer tumor, a prostate cancer tumor, a malignant melanoma tumor, a cervical cancer tumor or a liver cancer tumor.
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