CN113563401A - Novel cordycepin alkanamide derivative and preparation method and application thereof - Google Patents

Novel cordycepin alkanamide derivative and preparation method and application thereof Download PDF

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CN113563401A
CN113563401A CN202110794754.9A CN202110794754A CN113563401A CN 113563401 A CN113563401 A CN 113563401A CN 202110794754 A CN202110794754 A CN 202110794754A CN 113563401 A CN113563401 A CN 113563401A
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cordycepin
novel
compound
alkanamide
iii
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曲书昊
朱丽飞
王小莉
李利红
樊克锋
李艳玲
匡秀华
郭永刚
李宇伟
赵玉丛
李慧娟
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Henan University of Animal Husbandry and Economy
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Henan University of Animal Husbandry and Economy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Abstract

The invention discloses a novel cordycepin alkanamide derivative, which has a structural formula shown as (I):

Description

Novel cordycepin alkanamide derivative and preparation method and application thereof
Technical Field
The invention relates to the field of cordycepin alkane derivatives, in particular to a novel cordycepin alkane amide derivative, a preparation method thereof and application thereof in inhibiting tumor cell proliferation.
Background
Cordycepin (cordycepin), also known as cordycepin, and 3' -deoxyadenosine, is the first nucleoside antibiotic isolated from fungi. Since Cunningham and the like separated cordycepin from the culture solution of cordyceps militaris in 1951, various biological activities of cordycepin are gradually known and become one of research hotspots in recent years.
The molecular formula of cordycepin is C10H13N5O3The cordycepin derivative is an analog of adenosine, shows alkalinity, is a needle-shaped or sheet-shaped crystal, and modern pharmacology shows that cordycepin and the derivative have the effects of resisting tumors, bacteria and viruses, regulating immunity, eliminating free radicals and the like, so that research work for searching the cordycepin derivative with stronger activity by modifying the structure of the cordycepin compound has great significance.
Disclosure of Invention
The invention aims to provide a novel cordycepin alkanamide derivative and a preparation method and application thereof.
In order to achieve the purpose, the invention is implemented according to the following technical scheme:
a novel cordycepin alkanamide derivative has a structural formula shown as (I):
Figure BDA0003162242500000011
wherein R is:
Figure BDA0003162242500000021
one of (1) and (b).
Further, the specific compound of the novel cordycepin alkanamide derivative has a structural formula as follows:
Figure BDA0003162242500000022
Figure BDA0003162242500000031
the preparation method of the novel cordycepin alkanamide derivative comprises the following steps:
s1, dissolving cordycepin, tert-butyldimethylsilyl chloride and 4-dimethylaminopyridine in N, N-dimethylformamide, and reacting under an alkaline condition to obtain a compound (II):
Figure BDA0003162242500000032
s2, dissolving the compound (II), R, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and N, N-diisopropylethylamine in N, N-dimethylformamide and dichloromethane to obtain the compound of the general formula (III):
Figure BDA0003162242500000033
wherein R is:
Figure BDA0003162242500000034
Figure BDA0003162242500000035
Figure BDA0003162242500000041
Figure BDA0003162242500000042
one of (1);
s3, concentrating the obtained reaction system, extracting saturated sodium bicarbonate water solution, ethyl acetate and saturated saline water, drying an organic phase, filtering and concentrating to obtain a reaction crude product;
s4, separating the obtained reaction crude product by column chromatography, and performing gradient elution to obtain a compound III1-III6：
Figure BDA0003162242500000043
Figure BDA0003162242500000051
S5, mixing the compound III1-III6With 1.0M tetrabutylammonium fluoride in tetrahydrofuran in a tetrahydrofuran reagent to give a compound of formula (I):
Figure BDA0003162242500000052
s6, concentrating the obtained reaction system, extracting with ethyl acetate and saturated brine, drying the organic phase, filtering, and concentrating to obtain a reaction crude product;
s7, separating the obtained reaction crude product by column chromatography, and performing gradient elution to obtain a compound I1-I6：
Figure BDA0003162242500000053
Preferably, the cordycepin is derived from chemical synthesis or is extracted and separated from cordyceps militaris and cordyceps sinensis.
Preferably, the R is derived from chemical synthesis or natural plant extraction and separation.
The novel cordycepin alkanamide derivative is applied to the aspect of inhibiting the proliferation of tumor cells.
Compared with the prior art, the method has the advantages that different alkyl chains and aromatic groups are connected at the primary amino group of the cordycepin through amido bonds, a series of novel cordycepin alkanamide derivatives are synthesized for the first time, the synthesis steps are simple, and the total yield is high. The novel cordycepin alkanamide derivative prepared by the invention shows better activity on the proliferation inhibition of HelA cells.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. The specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Figure BDA0003162242500000061
EXAMPLE 1 preparation of purine-6-Arachidamide-9-N- (3' -deoxy) ribofuranoside (I)1)
Cordycepin (590mg, 2348mmol), imidazole (15.50mmol) and 4-dimethylaminopyridine DMAP (0.235mmol) were dissolved in DMF (5mL), tert-butyldimethylsilyl chloride TBSCl (7.748mmol) was added to the above solution at 0 ℃ and the reaction was stirred at room temperature for 16 h. With saturated NH4The reaction was quenched with aqueous Cl and the crude mixture was extracted with EtOAc. Combined organic layers with H2O wash, saturated aqueous NaCl then concentrate in vacuo. Purification by flash chromatography (EtOAc: hexane ═ 1: 2) afforded compound II as a white solid in 85% yield.1H NMR(400MHz,CDCl3)δ8.33(d,J＝2.0,4.0Hz,2H),6.01(s,1H),5.72(s,2H),4.62-4.63(m,1H),4.54-4.58(m,1H),4.12(dd,J＝4.0,12.0Hz,1H),3.78(dd,J＝4.0,8.0Hz,1H),2.22-2.29(m,1H),1.83-1.88(m,1H),0.95(s,9H),0.90(s,9H),0.14(d,J＝4.0Hz,9H),0.08(s,3H).
Arachidonic acid (381mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol), and diisopropylethylamine (3.98mmol) were added. The reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexane to give III as a yellow oil1Yield 76%, starting material II (80mg) was recovered and used for the next reaction.
III1(357mg, 0.465mmol) was dissolved in dry THF (4mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 2.5% methanol in dichloromethane to give pure I1White powder, yield 75%.1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.51(s,1H),8.16(s,1H),5.81(d,J＝4.0Hz,1H),5.29-5.42(m,8H),5.04(s,1H),4.94-4.99(m,1H),4.57(s,1H),4.12(s,1H),4.01(d,J＝12.0Hz,1H),3.63(d,J＝12.0Hz,1H),2.78-2.86(m,6H),2.52-2.58(m,2H),2.24-2.31(m,1H),2.18-2.24(m,3H),2.01-2.07(m,2H),1.81-1.87(m,2H),1.25-1.37(m,6H),0.86-0.89(m,3H)；13CNMR(100MHz,CDCl3)δ151.8,149.6,142.3,130.5,129.0,128.9,128.2,128.2,127.8,127.5,93.3,80.7,74.3,64.5,37.3,33.8,31.9,31.5,31.4,30.2,29.7,29.4,27.2,26.6,25.7,24.6,22.7,22.6,14.1；(ESI+)(M+H+)m/z 538.2151；Anal.Calcd for C30H43N5O4.
EXAMPLE 2 preparation ofPreparation of purine-6-alpha-flanylamido-9-N- (3' -deoxy) ribofuranoside (I)2)
Alpha-linolenic acid (348mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol) and diisopropylethylamine (3.98mmol) were added. The reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexane to give III as a yellow oil2Yield 75%, starting material II (100mg) was recovered.
III2(344mg, 0.465mmol) was dissolved in dry THF (4mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 2.5% methanol in dichloromethane to give pure I2White powder, yield 74%.1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.48(s,1H),8.15(s,1H),5.80(d,J＝4.0Hz,1H),5.26-5.40(m,6H),5.11(s,1H),4.95(q,J＝8.0,12.0Hz,1H),4.56(s,1H),4.35(s,1H),3.96(d,J＝16.0Hz,1H),3.62(d,J＝12.0Hz,1H),2.74-2.80(m,2H),2.49-2.55(m,1H),2.22-2.29(m,1H),2.00-2.06(m,6H),1.68-1.73(m,2H),1.23-1.35(m,10H),0.80-0.86(m,3H)；13C NMR(100MHz,CDCl3)δ173.0,151.7,150.0,149.5,142.5,130.2,130.0,128.0,127.9,122.7,93.3,80.7,74.2,64.4,37.9,33.7,31.9,31.5,29.7,29.6,29.3,29.2,29.2,27.2,25.6,24.8,22.6,14.1；(ESI+)(M+H+)m/z 512.3751；Anal.Calcd for C28H41N5O4.
EXAMPLE 3 preparation of purine-6-linoleamido-9-N- (3' -deoxy) ribofuranoside (I)3)
Mixing linoleic acid (23)3mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol) and diisopropylethylamine (3.98mmol) were added. The reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexane to give III as a yellow oil3Yield 75%, starting material II (100mg) was recovered.
III3(345mg, 0.465mmol) was dissolved in dry THF (4mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 2.5% methanol in dichloromethane to give pure I3White powder, yield 75%.1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.49(s,1H),8.17(s,1H),5.81(d,J＝4.0Hz,1H),5.29-5.41(m,4H),5.12(s,1H),4.96(q,J＝8.0,12.0Hz,1H),4.57(s,1H),4.36(s,1H),4.00(d,J＝16.0Hz,1H),3.63(d,J＝12.0Hz,1H),2.75-2.81(m,2H),2.50-2.56(m,1H),2.23-2.30(m,1H),2.01-2.07(m,6H),1.70-1.75(m,2H),1.25-1.37(m,14H),0.82-0.89(m,3H)；13C NMR(100MHz,CDCl3)δ173.0,151.7,150.0,149.5,142.5,130.2,130.0,128.0,127.9,122.7,93.3,80.7,74.2,64.4,37.9,33.7,31.9,31.5,29.7,29.6,29.3,29.2,29.2,27.2,25.6,24.8,22.6,14.1；(ESI+)(M+H+)m/z 514.7621；Anal.Calcd for C28H43N5O4.
EXAMPLE 4 preparation of purine-6-Royal jelly amido-9-N- (3' -deoxy) ribofuranoside (I)4)
Royal jelly acid (253mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol) and diisopropylethylamine (3.98 mmol). The reaction mixture was stirred at room temperature for 120 hours, concentrated in vacuo, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexane to give white solid III4Yield 40%, starting material II (50mg) was recovered.
III4(301mg, 0.465mmol) was dissolved in dry THF (5mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give pure I4White powder, yield 60%.1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.49(s,1H),8.17(s,1H),6.27-6.30(m,1H),5.90-5.91(m,1H),5.81(d,J＝4.0Hz,1H),5.23(s,1H),4.94(s,1H),4.57(s,1H),4.00(d,J＝16.0Hz,1H),3.63(d,J＝12.0Hz,1H),3.37-3.43(m,4H),2.10-2.16(m,3H),1.66-1.80(m,1H),1.48-1.54(m,2H),1.25-1.37(m,8H)；13C NMR(100MHz,CDCl3)δ167.0,151.7,150.4,149.5,142.6,142.2,130.3,129.6,94.3,80.7,74.2,64.4,62.8,37.9,32.7,32.5,29.7,29.7,29.4,26.0；(ESI+)(M+H+)m/z 420.3311；Anal.Calcd for C20H29N5O5.
EXAMPLE 5 preparation of purine-6-Ferulamido-9-N- (3' -deoxy) ribofuranoside (I)5)
Ferulic acid (243mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol) and diisopropylethylamine (3.98mmol) were added. The reaction mixture was stirred at room temperature for 120 hours, concentrated in vacuo and taken up in sodium bicarbonateThe mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexane to give white solid III5Yield 30%, starting material II (60mg) was recovered.
III5(305mg, 0.465mmol) was dissolved in dry THF (4mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give pure I5White powder, yield 60%.1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.70(s,1H),8.48(s,1H),8.15(s,1H),7.08-7.11(m,1H),7.00(s,1H),6.96-6.97(m,1H),6.77-6.79(m,2H),5.81(d,J＝4.0Hz,1H),5.13(s,1H),4.94(s,1H),4.00(d,J＝16.0Hz,1H),3.83(s,3H),3.63(d,J＝12.0Hz,1H),2.76-2.82(m,2H),2.10-2.16(m,1H),1.66-1.80(m,1H)；13C NMR(100MHz,CDCl3)167.0,151.7,150.4,149.5,149.0,147.7,142.6,142.2,141.0,131.1,121.7,116.8,110.7,94.3,80.7,74.2,64.4,62.8,56.0,37.9；(ESI+)(M+H+)m/z 428.0331；Anal.Calcd for C20H21N5O6.
EXAMPLE 6 preparation of purine-6-Cinnamido-9-N- (3' -deoxy) ribofuranoside (I)6)
Cinnamic acid (185mg, 1.251mmol) was dissolved in a mixed solution of anhydrous dichloromethane (4mL) and DMF (0.02mL), and 1-hydroxybenzotriazole hydrate (1.50mmol), 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylhexafluorophosphate urea (1.50mmol), II (1.251mmol) and diisopropylethylamine (3.98mmol) were added. The reaction mixture was stirred at room temperature for 96 hours, concentrated in vacuo, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, MgSO4Drying and suction filtration the filtrate was concentrated by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate in cyclohexaneTo obtain a white solid III6Yield 50%, starting material II (60mg) was recovered.
III6(284mg, 0.465mmol) was dissolved in dry THF (3mL) and n-Bu was added at 0 deg.C4NF (1.0M in THF, 1.18mL, 1.18mmol) and the reaction stirred at room temperature for 90 min. The mixture was rotary evaporated and the mixture was extracted with brine and ethyl acetate. The combined organics were dried over magnesium sulfate, filtered off with suction and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 2.5% methanol in dichloromethane to give pure I6White powder, yield 70%.1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.47(s,1H),8.13(s,1H),7.26-7.32(m,3H),7.05-7.09(m,2H),7.01-7.04(m,1H),6.94-6.97(m,1H),5.80(d,J＝4.0Hz,1H),5.12(s,1H),4.93(s,1H),3.98(d,J＝16.0Hz,1H),3.62(d,J＝12.0Hz,1H),2.74-2.80(m,2H),2.08-2.14(m,1H),1.64-1.78(m,1H)；13C NMR(100MHz,CDCl3)167.0,151.7,150.4,149.5,142.2,131.1,130.2,128.6,128.6,128.4,128.4,127.8,118.7,94.2,80.7,74.0,64.3,62.7,37.8；(ESI+)(M+H+)m/z 382.1415；Anal.Calcd for C19H19N5O4.
Example 7
In order to verify the effect of the novel cordycepin alkanamide derivative on inhibiting tumor cell proliferation, the following experiments are carried out:
cells used for the experiments: cervical cancer Hela and human liver cancer HepG2 cells.
Main reagents and instruments:
CCK8 cell activity detection reagent, trypsin; DMEM medium was purchased from Gibco; newborn bovine serum, product of Hangzhou Sijiqing biology Co. CO 22Incubator (type 371), manufactured by Thermo corporation; cell culture flasks and 96-well cell culture plates, manufactured by Nunclon, germany; inverted microscope, manufactured by Chongqing optical instrument factory.
Cordycepin alkylamide analogue I synthesized by the above example1-I6For example, inhibition of 2 cancer cells:
taking cervical carcinoma growing in logarithmic phaseHela and human liver cancer HepG2 cells, trypsinizing, centrifuging, discarding the supernatant, re-suspending into cell suspension by using a fresh complete culture medium, adjusting the cell number to be inoculated into a 96-well plate at 1000-2000 cells/well, setting 100 mu L of each well, and setting a non-drug addition group, a 70% DMSO group, an cytarabine group and a cordycepin alkylamide analogue group. After the cells proliferate to 70-80% of the pore volume within 24h, cordycepin alkanamide analogue group and cytarabine group with different concentrations are respectively added, so that the drug concentration is 0.75, 1.5, 3, 12.5 and 50 mu mol/L, and each concentration is provided with 3 compound pores and 70% DMSO group. Adding 10 mu LCCK8 detection solution into each hole after adding 44h of medicine, adding CCK8 detection solution for 4h, and detecting the absorbance value of each hole by a microplate reader at the wavelength of 450 nm. Cell inhibition ═ 100% (1-absorbance value of experimental group/absorbance value of control group). Calculating median inhibitory concentration IC using dose-effect relationship50。
Analysis of Experimental data
The experimental data are analyzed by using Graphpad Prism 5 software, and the experimental results uniformly adopt the mean value plus or minus standard deviation
Figure BDA0003162242500000131
The comparison between groups was performed by one-way anova with a test level α of 0.05 and p<0.05 is statistically significant.
Results of the experiment
Cordycepin alkylamide analogue I1Inhibitory Effect on 2 cancer cells
CCK8 cell viability measurement results show that cordycepin alkanamide analogue I1Has obvious inhibition effect on the growth of Hela cells of cervical cancer, is dose-dependent and has IC of 48h50The value was (4.82. + -. 1.99). mu. mol/L, and the difference in cell viability among the treated groups was statistically significant (P)<0.05), and the cell proliferation inhibition rate is obviously increased along with the increase of the drug dosage; cordycepin alkylamide analogue I1Slightly inhibiting human liver cancer HepG2 cell growth, and 48h IC50The value was (47.02. + -. 1.71). mu. mol/L, and the difference in cell viability among the treated groups was statistically significant (P)<0.05) cordycepin alkanamide analogue I shown in Table 11For cervical cancer Hela andinhibition of human liver cancer HepG2 cells.
TABLE 1
Figure BDA0003162242500000132
Figure BDA0003162242500000141
Cordycepin alkylamide analogue I1-I6Inhibitory Effect on Hela cells of cervical cancer
CCK8 cell viability measurement results show that cordycepin alkanamide analogue I1IC for 48h of growth of Hela cells of cervical cancer50The value is (4.82 +/-1.99) mu mol/L, and the IC of the positive control cytarabine hydrochloride group is 48h50The value is (86.27 +/-11.85) mu mol/L, the compound has obvious effect of inhibiting the growth of Hela cells of cervical carcinoma, has obvious effect of inhibiting the growth of Hela cells of cervical carcinoma compared with cordycepin and other analogues, and has statistical significance (P) for the difference of cell viability of each treatment group<0.05) cordycepin alkanamide analogs I as shown in Table 21-I6Inhibiting cervical cancer Hela.
TABLE 2
Figure BDA0003162242500000142
In overview, cervical cancer ranks second among the most common cancers in women, and it is also one of the leading causes of cancer death in women in underdeveloped areas, and Xinjiang is a high-incidence area of cervical cancer. Cervical cancer is a highly malignant cancer, prone to metastasis and invasion, and has a poor prognosis. Early stages usually have no obvious symptoms and signs and are easy to ignore and neglect diagnosis. Even though the diagnostic techniques and therapeutic strategies for cervical cancer have been improved, the mortality rate of cervical cancer is still high, and tumor invasion and metastasis are the main causes of death of cervical cancer patients. Cordycepin has good antitumor, antiviral and antibacterial activities, and different alkyl groups are connected at the primary amino group of cordycepin through amido bondCordycepin alkanamide analogue I synthesized from chain and aromatic group1Has obvious effect of inhibiting the proliferation of cervical cancer Hela cells; the same synthetic cordycepin alkanamide analog I2-I6Also has potential proliferation inhibiting effect on HELA cells.
The technical solution of the present invention is not limited to the limitations of the above specific embodiments, and all technical modifications made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims (6)

1. A novel cordycepin alkanamide derivative is characterized in that: the novel cordycepin alkanamide derivative has a structural formula shown as (I):
Figure FDA0003162242490000011
wherein R is:
Figure FDA0003162242490000012
one of (1) and (b).
2. A novel cordycepin alkanamide derivative according to claim 1, wherein: the structural formula of the specific compound of the novel cordycepin alkanamide derivative is as follows:
Figure FDA0003162242490000013
Figure FDA0003162242490000021
3. a method for preparing a novel cordycepin alkanamide derivative as defined in claim 1, comprising the steps of:
s1, dissolving cordycepin, tert-butyldimethylsilyl chloride and 4-dimethylaminopyridine in N, N-dimethylformamide, and reacting under an alkaline condition to obtain a compound (II):
Figure FDA0003162242490000022
s2, dissolving the compound (II), R, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and N, N-diisopropylethylamine in N, N-dimethylformamide and dichloromethane to obtain the compound of the general formula (III):
Figure FDA0003162242490000031
wherein R is:
Figure FDA0003162242490000032
Figure FDA0003162242490000033
Figure FDA0003162242490000034
one of (1);
s3, concentrating the obtained reaction system, extracting saturated sodium bicarbonate water solution, ethyl acetate and saturated saline water, drying an organic phase, filtering and concentrating to obtain a reaction crude product;
s4, separating the obtained reaction crude product by column chromatography, and performing gradient elution to obtain a compound III1-III6：
Figure FDA0003162242490000035
Figure FDA0003162242490000041
S5, mixing the compound III1-III6With 1.0M tetrabutylammonium fluoride in tetrahydrofuran in a tetrahydrofuran reagent to give a compound of formula (I):
Figure FDA0003162242490000042
s6, concentrating the obtained reaction system, extracting with ethyl acetate and saturated brine, drying the organic phase, filtering, and concentrating to obtain a reaction crude product;
s7, separating the obtained reaction crude product by column chromatography, and performing gradient elution to obtain a compound I1-I6：
Figure FDA0003162242490000051
4. The process for producing a novel cordycepin alkanamide derivative according to claim 3, wherein: the cordycepin is obtained by chemical synthesis or extraction and separation from Cordyceps militaris and Cordyceps sinensis.
5. The process for producing a novel cordycepin alkanamide derivative according to claim 3, wherein: the R is derived from chemical synthesis or natural plant extraction and separation.
6. Use of a novel cordycepin alkanamide derivative according to claim 1 or 2 for inhibiting tumor cell proliferation.
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