CN112574272B - Preparation and application of ganoderic acid A derivative - Google Patents

Preparation and application of ganoderic acid A derivative Download PDF

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CN112574272B
CN112574272B CN202011572509.5A CN202011572509A CN112574272B CN 112574272 B CN112574272 B CN 112574272B CN 202011572509 A CN202011572509 A CN 202011572509A CN 112574272 B CN112574272 B CN 112574272B
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ganoderic acid
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田瑜
罗云
贾怡
魏菲
孙晓波
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Abstract

The invention discloses a ganoderic acid A derivative and preparation and application thereof, and relates to the technical field of biological medicines. The structure of the ganoderic acid A derivative is shown as a general formula (I), and the structure of the ganoderic acid A is modified by using an amide condensation reaction to obtain the ganoderic acid A derivative. The ganoderic acid A derivative prepared by the method improves the bioactivity of ganoderic acid A, solves the problem of low bioavailability, and has practical significance in improving biological effects such as antitumor activity.
Figure DDA0002861380440000011

Description

Preparation and application of ganoderic acid A derivative
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to preparation and application of a ganoderic acid A derivative.
Background
Ganoderma is the dry fruiting body of Ganoderma lucidum (Ganoderma lucidum Karst) and Ganoderma sinense (Ganoderma sinense) of Polyporaceae (Polyporaceae) of Basidiomycetes, has effects of invigorating qi, tranquilizing mind, relieving cough and asthma, can be used for treating giddiness, cardiopalmus, short breath, consumptive cough and asthma, is the traditional famous and precious nourishing medicinal material in China, and has been used for more than two thousand years. Modern pharmacological studies show that ganoderma has wide physiological activities, such as tumor resistance, immunoregulation, virus resistance, liver protection, central nerve protection and the like. The chemical components of ganoderma lucidum are complex, more than 400 compounds are identified at present, and mainly comprise compounds such as triterpenes, polysaccharides, nucleosides, sterols and the like, wherein more than 300 compounds are triterpenes. The relative molecular mass of the ganoderma lucidum triterpenoid is generally 4 multiplied by 105-6×105The lanostane derivative has complex structure, is mostly a highly oxidized lanostane compound, has the activities of resisting tumor, protecting liver, expelling toxin, reducing cholesterol, resisting HIV virus and the like, and can be divided into panacea according to the difference of connected functional groups and side chain structuresMany kinds of acids, alcohols, aldehydes and lactones.
Ganoderic acid A is used as the main component of ganoderma triterpene, has high content, has the functions of resisting tumor, pulmonary fibrosis and protecting cardiac muscle, and can be used as a potential drug for developing potential resources. And the structure modification of natural compounds is an effective means for obtaining ideal active compounds, the source mode of the medicine can be expanded, the ganoderic acid compounds have various substituents such as hydroxyl, carboxyl, acetyl and the like, the groups endow the triterpenoids with various biological activities, and simultaneously, sites are provided for the structure modification, and the triterpenoids can be modified to obtain more effective active compounds.
Chinese patent CN201510580594.2 discloses an anti-tumor whole ganoderma lucidum soft capsule and a preparation process thereof. The health food is prepared from Ganoderma spore oil, Ganoderma lucidum extract, Ganoderma sinensis extract, defatted spore powder extract, suspending agent and gelatin skin. The formula of the contents is as follows: 70-80% of ganoderma lucidum spore oil, 10-15% of ganoderma lucidum extract, 5-10% of ganoderma sinensis extract, 5-10% of defatted spore powder extract and 5% of suspending agent. Detection shows that the index component polysaccharide content is not less than 5.0%, and ganoderic acid A content is not less than 30mg/100 g. Animal experiments prove that the traditional Chinese medicine composition has the effects of resisting tumors and improving the immunity of organisms. However, the active ingredients of the ganoderma lucidum are the effective ingredients of the ganoderma lucidum, the ganoderma sinensis extract, the ganoderma lucidum spore oil and the defatted ganoderma lucidum spore powder, and the operation is complex.
At present, the research on ganoderic acid A focuses on content analysis, pharmacological action mechanism, biosynthesis method and mechanism, and ganoderic acid A is taken as a compound with stronger activity and highest content in ganoderma triterpene, and the skeleton of the ganoderic acid A possibly has the problems of strong fat solubility, low bioavailability and the like, so the invention carries out structural modification on the ganoderic acid A, improves the biological effects of the ganoderic acid A such as antitumor activity and the like, and is applied to the preparation of antitumor drugs.
Disclosure of Invention
The invention provides a preparation method and application of a ganoderic acid A derivative aiming at the problem of low bioavailability of ganoderic acid A in the prior art, and the preparation method and application of the ganoderic acid A derivative are used for modifying ganoderic acid A to improve the biological activity of the ganoderic acid A and have practical significance in the aspects of improving the biological effects such as antitumor activity.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a ganoderic acid A derivative, which is shown as the following general formula (I),
Figure BDA0002861380420000021
wherein R is selected from-NH-R' or
Figure BDA0002861380420000022
R' is selected from C1-C10 alkyl,
Figure BDA0002861380420000023
Wherein n is an integer of 0 to 4, R2Is a substituent on a benzene ring, represents 1 to 5 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus;
R1is selected from alkyl or phenyl of C1-C10.
Further, R' is selected from C1-C6 alkyl,
Figure BDA0002861380420000024
Wherein n is an integer of 0 to 4, R2Is a substituent on a benzene ring, represents 1 to 2 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus;
R1is selected from alkyl or phenyl of C1-C6.
Further, n is 1 or 2; the R is2Is a substituent on a benzene ring, represents 1 to 2 substituents, and each R2Each independently selected from methyl or halogen;
R1is selected from alkyl or phenyl of C1-C4.
Further, R' is selected from
Figure BDA0002861380420000031
Figure BDA0002861380420000032
Figure BDA0002861380420000033
R1Selected from methyl, ethyl or phenyl; denotes the site of attachment to the mother nucleus.
Most preferably, the ganoderic acid A derivative provided by the invention has the following structure:
Figure BDA0002861380420000034
Figure BDA0002861380420000041
the invention also provides a preparation method of the ganoderic acid A derivative, and the chemical reaction formula is as follows:
Figure BDA0002861380420000042
further, the preparation method specifically comprises the following steps:
weighing ganoderic acid A, sequentially adding a solvent, an amine compound, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and N, N-Diisopropylethylamine (DIPEA), and reacting at room temperature to obtain the ganoderic acid A derivative.
The structure of the ganoderic acid A is as follows
Figure BDA0002861380420000043
Further, the solvent is dichloromethane; the reaction time is 20-60min, preferably 30 min.
Further, the molar ratio of the ganoderic acid A, the amine compound, the O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the N, N-Diisopropylethylamine (DIPEA) is 1:1.0-3.0:1-1.5: 1.5-3.0; preferably 1:2:1.2: 2.
Further, the ganoderic acid A derivative is applied to preparation of antitumor drugs.
Further, the tumors include liver cancer, lung cancer and leukemia.
The technical effects obtained by the invention are as follows:
1. ganoderic acid A is used as a compound with stronger activity and highest content in ganoderma triterpene, and the biological effects such as antitumor activity and the like are improved after the structure of the compound is modified.
2. The ganoderic acid A is modified, so that natural plant resources are saved, and sustainable development is facilitated.
3. The prepared ganoderic acid A derivative can be applied to the preparation of medicines for resisting liver cancer, lung cancer and leukemia.
Drawings
FIGS. 1-13 show the in vitro cytotoxic effects of ganoderic acid A derivatives A1-A13 on hepatoma tumor cell line HepaG 2;
wherein represents P <0.1, P <0.01, P <0.001, P <0.0001 compared to Con group.
Detailed Description
The present invention will be further explained with reference to specific embodiments in order to make the technical means, the original characteristics, the achieved objects and the effects of the present invention easy to understand, but the following embodiments are only preferred embodiments of the present invention, and not all embodiments are possible. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.
It is to be noted that materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Ganoderic acid A was purchased from Doctoreis Biotech, Inc. under the product number L-061;
O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) is available from Beijing YinuoKai Tech Co., Ltd., a good number A67999;
n, N-Diisopropylethylamine (DIPEA) was purchased from Beijing YinoKai science and technology, Inc., under the product number A53847.
Example 1 Synthesis of Ganoderic acid A1
Accurately weighing 20mg (0.0388mmol) of ganoderic acid A, adding the ganoderic acid A into a 50mL round-bottom flask, sequentially adding 2mL of dichloromethane, 7.68uL (0.0776mmol) of n-butylamine, 14.97mg (0.0466mmol) of TBTU and 12.73uL (0.0776mmol) of DIPEA at room temperature, stirring for 30min at room temperature, detecting the reaction by TLC, using dichloromethane-methanol (10:1) as a developing agent, adding a saturated NaCl solution after the reaction is finished, shaking, standing, separating liquid, taking the lower layer of solution, adding anhydrous sodium sulfate, drying, and filtering. Performing column chromatography with dichloroethane-methanol (20:1), collecting target product, and spin-drying solvent to obtain white solid ganoderic acid A116.2mg with yield of 80.6%. Method for preparing ganoderic acid A11H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:5.81(t,J＝5.6Hz,1H,CONH),4.80-4.77(m,1H,H-7),4.63-4.60(m,1H,H-15),4.16-4.15(m,1H,OH-7),3.55-3.52(m,1H,OH-15),3.22-3.19(m,2H,CONHCH2),1.48-1.44(m,3H,CONHCH2CH2,H-17),1.35-1.31(m,2H,CH2CH3),1.27(s,3H,CH3),1.25(s,3H,CH3),1.14(d,J＝7.0Hz,3H,CH3),1.12(s,3H,CH3),1.10(s,3H,CH3),0.99(s,3H,CH3),0.91(t,J＝7.3Hz,3H,CH2CH3),0.87(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.3,209.7,199.6,175.5,159.3,140.1,72.3,68.8,53.9,51.7,49.8,48.7,48.1,47.2,46.7,46.6,39.3,37.9,36.3,36.0,35.5,34.3,32.7,31.6,28.9,27.3,20.7,20.0,19.6,19.5,19.4,18.0,17.3,13.8。
Example 2 Synthesis of Ganoderic acid A2
The only difference from example 1 was that addition of 10.24uL (0.0776mmol) of n-hexylamine gave 65.6% yield of Ganoderic acid A213.12mg as a white solid. Method for preparing ganoderic acid A21H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:5.82(t,J＝5.6Hz,1H,CONH),4.79-4.77(m,1H,H-7),4.64-4.60(m,1H,H-15),4.22-4.16(m,1H,OH),3.60-3.54(m,1H,OH),3.21-3.17(m,2H,CONHCH2),1.49-1.45(m,3H,CONHCH2CH2,H-17),1.32-1.27(m,9H,(CH2)3CH3,CH3),1.25(s,3H,CH3),1.14(d,J＝7.1Hz,3H,CH3),1.12(s,3H,CH3),1.10(s,3H,CH3),0.99(s,3H,CH3),0.89-0.86(m,6H,2×CH3)。
13C-NMR(150MHz,CDCl3)δ:217.2,209.7,199.6,175.5,159.3,140.2,72.3,68.8,54.0,51.7,49.9,48.7,48.1,47.2,46.8,46.6,39.6,38.0,36.4,36.0,35.5,34.3,32.8,31.5,29.5,29.0,27.4,26.5,22.6,20.7,19.6,19.5,19.4,18.0,17.3,14.1。
Example 3 Synthesis of Ganoderic acid A3
The only difference from example 1 was that 9.9uL (0.0776mmol) of 4-methylbenzylamine was added to give ganoderic acid A318.36mg as a white solid in 91.8% yield. Method for preparing ganoderic acid A31H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.15-7.12(m,4H,Ph-H),6.16(t,J＝5.6Hz,1H,CONH),4.77-4.76(m,1H,H-7),4.60-4.58(m,1H,H-15),4.39-4.32(m,2H,CONHCH2),4.23-4.22(m,1H,OH-7),3.63-3.60(m,1H,OH-15),2.33(s,3H,CH3),1.26(s,3H,CH3),1.24(s,3H,CH3),1.17(d,J＝7.1Hz,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3),0.98(s,3H,CH3),0.86(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.3,209.6,199.7,175.5,159.4,140.1,137.2,135.1,129.4,127.6,72.3,68.8,54.0,51.7,49.8,48.7,48.1,47.2,46.8,46.6,43.3,38.0,36.3,36.0,35.5,34.3,32.8,28.9,27.4,21.1,20.7,19.6,19.5,19.4,18.0,17.3。
Example 4 Synthesis of Ganoderic acid A4
The only difference from example 1 was that addition of 8.9uL (0.0776mmol) of 4-fluorobenzylamine gave 90.2% yield of ganoderic acid A418.04mg as a white solid. Method for preparing ganoderic acid A41H NMR and13c NMR numberAs shown below.
1H-NMR(600MHz,CDCl3)δ:7.24-7.23(m,2H,Ph-H),7.02-6.99(m,2H,Ph-H),6.17(t,J＝5.8Hz,1H,CONH),4.78-4.77(m,1H,H-7),4.62-4.59(m,1H,H-15),4.41-4.34(m,2H,CONHCH2),3.87-3.86(m,1H,OH-7),3.34-3.30(m,1H,OH-15),1.27(s,3H,CH3),1.24(s,3H,CH3),1.17(d,J＝7.0Hz,3H,CH3),1.11(s,3H,CH3),1.09(s,3H,CH3),0.98(s,3H,CH3),0.85(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:216.1,208.6,198.5,174.5,161.9,160.3,158.0,139.2,133.0,133.0,128.2,128.2,114.6,114.4,71.4,67.8,52.9,50.7,48.7,47.6,47.0,46.2,45.7,45.6,41.8,36.9,35.3,34.9,34.5,33.2,31.7,28.0,26.3,19.6,18.6,18.5,18.4,16.9,16.2。
Example 5 Synthesis of Ganoderic acid A5
The only difference from example 1 was that 9.4uL (0.0776mmol) of 4-chlorobenzylamine was added to give Ganoderma acid A518.82mg as a white solid in 94.1% yield. Method for preparing ganoderic acid A51H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.29-7.27(m,2H,Ph-H),7.20-7.18(m,2H,Ph-H),6.33(t,J＝5.9Hz,1H,CONH),4.77-4.74(m,1H,H-7),4.62-4.57(m,1H,H-15),4.41-4.32(m,2H,CONHCH2),4.17-4.09(m,1H,OH-7),3.59-3.49(m,1H,OH-15),1.26(s,3H,CH3),1.24(s,3H,CH3),1.17(d,J＝7.1Hz,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3),0.97(s,3H,CH3),0.84(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.4,209.7,199.7,175.8,159.5,140.1,136.9,133.1,128.9,128.8,72.2,68.8,55.3,54.0,51.7,49.7,48.7,48.1,47.2,46.7,46.6,37.9,36.3,35.9,35.5,34.3,32.7,28.9,27.4,20.7,19.6,19.5,19.4,18.0,17.3。
Example 6 Synthesis of Ganoderic acid A6
The only difference from example 1 was that 10.3uL (0.0776mmol) of 3, 5-dichlorobenzylamine was added to give a white solidGanoderic acid A619.3mg, yield 96.5%. Method for preparing ganoderic acid A61H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.25-7.23(m,1H,Ph-H),7.15-7.14(m,2H,Ph-H),6.59-6.55(m,1H,CONH),4.75-4.74(m,1H,H-7),4.61-4.58(m,1H,H-15),4.47-4.26(m,2H,CONHCH2),1.26(s,3H,CH3),1.23(s,3H,CH3),1.18(d,J＝7.0Hz,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3),0.97(s,3H,CH3),0.84(d,J＝6.3Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.3,209.8,199.7,176.1,159.4,142.0,140.1,135.1,127.5,125.8,72.3,68.8,53.9,51.7,49.6,48.7,48.1,47.4,46.8,46.6,42.4,38.0,36.3,35.9,35.5,34.3,32.8,29.7,28.9,27.4,20.7,19.7,19.5,19.4,18.0,17.3。
Example 7 Synthesis of Ganoderic acid A7
The only difference from example 1 was that the addition of 11.3uL (0.0776mmol) of 4-methylphenethylamine gave 85.6% yield of ganoderic acid A717.12mg as a white solid. Method for preparing ganoderic acid A71H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.12(d,J＝8.0Hz,2H,Ph-H),7.09(d,J＝8.0Hz,2H,Ph-H),5.82-5.77(m,1H,CONH),4.80-4.76(m,1H,H-7),4.63-4.59(m,1H,H-15),4.18-4.12(m,1H,OH-7),3.55-3.39(m,3H,CONHCH2,OH-15),2.76-2.73(m,3H,CONHCH2CH2,H-25),1.49-1.45(m,3H,CONHCH2CH2,H-17),1.32-1.27(m,9H,(CH2)3CH3,CH3),1.25(s,3H,CH3),1.14(d,J＝7.1Hz,3H,CH3),1.12(s,3H,CH3),1.10(s,3H,CH3),0.99(s,3H,CH3),0.89-0.86(m,6H,2×CH3)。
13C-NMR(150MHz,CDCl3)δ:217.2,209.5,199.6,175.6,159.3,140.2,136.1,135.6,129.3,128.7,72.4,68.8,54.0,51.7,49.9,48.7,48.1,47.0,46.8,46.6,40.8,38.0,36.4,36.0,35.5,35.2,34.3,32.8,29.0,27.4,21.1,20.7,19.6,19.5,19.4,18.0,17.3。
Example 8 Synthesis of Ganoderic acid A8
The only difference from example 1 was that 10.2uL (0.0776mmol) of 4-fluorophenylethylamine was added to give white solid ganoderic acid A819.44mg, 97.2% yield. Method for preparing ganoderic acid A81H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.17-7.15(m,2H,Ph-H),7.01-6.98(m,2H,Ph-H),5.80(t,J＝5.8Hz,1H,CONH),4.79-4.77(m,1H,H-7),4.62-4.60(m,1H,H-15),3.97-3.89(m,1H,OH-7),3.50-3.40(m,2H,CONHCH2),3.39-3.31(m,1H,OH-15),2.87-2.82(m,2H,CONHCH2CH2),1.27(s,3H,CH3),1.25(s,3H,CH3),1.12(s,3H,CH3),1.10(d,J＝7.0Hz,3H,CH3),1.10(s,3H,CH3),0.99(s,3H,CH3),0.86(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.2,209.6,199.6,175.6,162.5,160.8,159.3,140.2,134.5,134.4,130.2,130.2,115.5,115.4,72.4,68.8,54.0,51.7,49.8,48.7,48.1,47.1,46.8,46.6,40.7,38.0,36.3,36.0,35.5,34.9,34.3,32.8,29.0,27.4,20.7,19.6,19.5,19.4,18.0,17.3。
Example 9 Synthesis of Ganoderic acid A9
The only difference from example 1 was that the addition of 10.2uL (0.0776mmol) of 4-chlorophenylethylamine gave 95.5% yield of ganoderic acid A919.1mg as a white solid. Method for preparing ganoderic acid A91H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.29-7.27(m,2H,Ph-H),7.20-7.18(m,2H,Ph-H),6.33(t,J＝5.9Hz,1H,CONH),4.77-4.74(m,1H,H-7),4.62-4.57(m,1H,H-15),4.41-4.32(m,2H,CONHCH2),4.17-4.09(m,1H,OH-7),3.59-3.49(m,1H,OH-15),1.26(s,3H,CH3),1.24(s,3H,CH3),1.17(d,J＝7.1Hz,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3),0.97(s,3H,CH3),0.84(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.4,209.7,199.7,175.8,159.5,140.1,136.9,133.1,128.9,128.8,72.2,68.8,55.3,54.0,51.7,49.7,48.7,48.1,47.2,46.7,46.6,37.9,36.3,35.9,35.5,34.3,32.7,28.9,27.4,20.7,19.6,19.5,19.4,18.0,17.3。
Example 10 Synthesis of Ganoderic acid A10
The only difference from example 1 was that 8.6uL (0.0776mmol) of N-methylpiperazine was added to give a white solid, ganoderic acid, A1018.54mg, in 92.7% yield. Method for preparing ganoderic acid A101H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:4.79-4.76(m,1H,H-7),4.62-4.60(m,1H,H-15),3.71-3.64(m,2H,CONCH2),3.60-3.53(m,2H,CONCH2),2.43-2.37(m,4H,2×CH2NCH3),2.34(s,3H,NCH3),1.27(s,3H,CH3),1.25(s,3H,CH3),1.12(s,3H,CH3),1.09(s,3H,CH3),1.09(d,J＝7.0Hz,3H,CH3),0.99(s,3H,CH3),0.87(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.3,209.7,199.6,174.0,159.3,140.1,72.3,68.8,55.2,54.7,54.0,51.7,50.0,48.7,48.2,47.2,46.8,46.6,46.0,45.4,41.7,38.0,36.4,35.5,34.3,32.8,30.9,29.7,29.0,27.4,20.7,19.7,19.5,19.4,17.6,17.3.
Example 11 Synthesis of Ganoderic acid A11
The only difference from example 1 was that addition of 9.8uL (0.0776mmol) of N-ethylpiperazine gave 98.1% yield of 98.1% of ganoderic acid A1119.62mg as a white solid. Method for preparing ganoderic acid A111H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:4.73-4.70(m,1H,H-7),4.56-4.54(m,1H,H-15),3.70-3.64(m,2H,CONCH2),3.58-3.50(m,2H,CONCH2),2.56-2.45(m,4H,2×CH2NCH3),2.36-2.31(s,2H,NCH2CH3),1.20(s,3H,CH3),1.18(s,3H,CH3),1.09(t,J＝7.0Hz,3H,NCH2CH3),1.05(s,3H,CH3),1.03(s,3H,CH3),1.02(d,J＝7.0Hz,3H,CH3),0.92(s,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:216.1,208.7,198.6,173.0,158.2,139.1,71.3,67.8,52.9,51.8,51.3,51.2,50.7,48.9,47.7,47.1,46.2,45.7,45.6,36.9,35.4,34.5,33.3,31.7,29.8,27.9,26.3,19.7,18.6,18.5,18.4,16.6,16.3。
Example 12 Synthesis of Ganoderic acid A12
The only difference from example 1 was that addition of 11.8uL (0.0776mmol) of N-phenylpiperazine gave 89.9% yield of Ganoderic acid A1217.98mg as a white solid. Method for preparing ganoderic acid A121H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.23-7.20(m,2H,Ph-H),6.88-6.83(m,2H,Ph-H),4.75-4.68(m,1H,H-7),4.58-4.51(m,1H,H-15),3.75-3.72(m,2H,CONCH2),3.66-3.61(m,3H,CONCH2,OH-7),1.20(s,3H,CH3),1.18(s,3H,CH3),1.06(d,J＝7.1Hz,3H,CH3),1.05(s,3H,CH3),1.03(s,3H,CH3),0.92(s,3H,CH3),0.80(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:216.1,208.6,198.5,173.1,158.0,149.9,139.2,128.2,119.5,115.6,71.4,67.8,52.9,50.7,48.9,48.7,48.4,47.7,47.1,46.2,45.7,45.6,44.6,40.8,36.9,35.4,34.5,33.3,31.7,29.9,28.0,26.3,19.7,18.6,18.5,18.4,16.6,16.3.
Example 13 Synthesis of Ganoderic acid A13
The only difference from example 1 is that the addition of 13.13mg (0.0776mmol) of 2-aminoindan hydrochloride gives ganoderic acid A1318.88mg as a white solid in 94.4% yield. Method for preparing ganoderic acid A131H NMR and13the C NMR data are shown below.
1H-NMR(600MHz,CDCl3)δ:7.23-7.21(m,2H,Ph-H),7.19-7.17(m,2H,Ph-H),6.10(d,J＝7.8Hz,1H,CONH),4.79-4.76(m,1H,H-7),4.69-4.63(m,1H,CONHCH),4.61-4.60(m,1H,H-15),4.18-4.15(m,1H,OH-7),4.59-4.55(m,1H,OH-15),1.27(s,3H,CH3),1.26(s,3H,CH3),1.12(s,3H,CH3),1.11(d,J＝7.1Hz,3H,CH3),1.09(s,3H,CH3),0.99(s,3H,CH3),0.85(d,J＝6.4Hz,3H,CH3)。
13C-NMR(150MHz,CDCl3)δ:217.1,209.5,199.5,175.3,159.0,140.8,140.7,140.2,126.8,126.7,124.8,124.7,72.4,68.8,53.9,51.7,50.5,49.8,48.7,48.1,47.2,46.8,46.6,43.4,40.1,40.0,37.9,36.4,35.9,35.5,34.3,32.7,29.0,27.3,20.7,19.6,19.5,19.4,17.9,17.3。
Pharmacological experiments
Testing in vitro antitumor activity of ganoderic acid A1-A13 on hepatoma cell HepaG2 by MTT method, using Ganoderic Acid A (GAA) as positive control drug at 1.5 μmol/L-1、3μmol·L-1、6μmol·L-1、12μmol·L-1、25μmol·L-1And the in vitro cytology experiments of the ganoderic acid A derivative A1-A13 at the concentration of 50 mu mol. L < -1 > were used for examining the in vitro cytotoxic effect of the ganoderic acid A derivative on liver cancer tumor cell lines. The results of the experiment are shown in FIGS. 1 to 13.
The concentrations of the sample solutions were 50. mu. mol L-1、25μmol L-1、12μmol L-1、6μmol L-1、3μmol L-1And 1.5. mu. mol L-1Six concentration gradients, the experimental results are shown in 50. mu. mol L-1、25μmol L-1Under the drug concentration of (3), the ganoderic acid A2, ganoderic acid A5, ganoderic acid A6, ganoderic acid A7 and ganoderic acid A9 compounds show better inhibition effects, especially, ganoderic acid A9 shows better activity of inhibiting liver cancer cells under the two concentrations, and the method is worthy of deep research.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

1. A ganoderic acid A derivative is characterized in that the structure of the ganoderic acid A derivative is shown as the following general formula (I),
Figure FDA0003174580370000011
wherein R is selected from-NH-R' or
Figure FDA0003174580370000012
R' is selected from C1-C10 alkyl,
Figure FDA0003174580370000013
Wherein n is 1 or 2, R2Is a substituent on a benzene ring, represents 1 to 5 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus;
R1is selected from alkyl or phenyl of C1-C10.
2. The ganoderic acid A derivatives of claim 1, wherein R' is selected from C1-C6 alkyl,
Figure FDA0003174580370000014
Wherein n is 1 or 2, R2Is a substituent on a benzene ring, represents 1 to 2 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus;
R1is selected from alkyl or phenyl of C1-C6.
3. The ganoderic acid a derivative of claim 2 where n is 1 or 2, R2Is a substituent on a benzene ring, represents 1 to 2 substituents, and each R2Each independently selected from methyl or halogen;
R1is selected from alkyl or phenyl of C1-C4.
4. The ganoderic acid a derivatives of claim 1, wherein R' is selected from the group consisting of
Figure FDA0003174580370000015
Figure FDA0003174580370000016
Figure FDA0003174580370000021
R1Selected from methyl, ethyl or phenyl; denotes the site of attachment to the mother nucleus.
5. The method for preparing ganoderic acid A derivatives according to claims 1-4, wherein the chemical reaction formula is as follows:
Figure FDA0003174580370000022
Figure FDA0003174580370000028
r is selected from-NH-R' or
Figure FDA0003174580370000023
R' is selected from C1-C10 alkyl,
Figure FDA0003174580370000024
Figure FDA0003174580370000025
Wherein n is 1 or 2, R2Is a substituent on a benzene ring, represents 1 to 5 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus; r1Is selected from alkyl or phenyl of C1-C10.
6. The preparation method according to claim 5, characterized by comprising the following steps:
weighing ganoderic acid A, sequentially adding a solvent, an amine compound, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and N, N-Diisopropylethylamine (DIPEA), and reacting at room temperature to obtain a ganoderic acid A derivative; the amine compound has the structure ofH2N-R' or
Figure FDA0003174580370000026
R' is selected from C1-C10 alkyl,
Figure FDA0003174580370000027
Wherein n is 1 or 2, R2Is a substituent on a benzene ring, represents 1 to 5 substituents, and each R2Each independently selected from C1-C4 alkyl or halogen; indicates the site of attachment to the mother nucleus; r1Is selected from alkyl or phenyl of C1-C10.
7. The method of claim 6, wherein: the solvent is dichloromethane, and the reaction time is 20-60 min.
8. The production method according to claims 5 to 7, characterized in that: the molar ratio of the ganoderic acid A, the amine compound, the O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and the N, N-Diisopropylethylamine (DIPEA) is 1:1.0-3.0:1-1.5: 1.5-3.0.
9. Use of the ganoderic acid A derivatives of any one of claims 1-4 in the preparation of an antitumor drug.
10. The use of claim 9, wherein the tumor comprises liver cancer, lung cancer and leukemia.
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